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Synthesis and Characterization of 5-MeO-DMT Succinate for Clinical Use

Alexander M. Sherwood*
Alexander M. Sherwood
Usona Institute, 2800 Woods Hollow Road, Madison, Wisconsin 53711, United States
*Email: [email protected]
More by Alexander M. Sherwood
http://orcid.org/0000-0003-0895-0791
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Romain Claveau
Romain Claveau
Almac Sciences, 20 Seagoe Industrial Estate, Craigavon BT63 5QD, United Kingdom
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Rafael Lancelotta
Rafael Lancelotta
Habituating to Wholeness, 6500 W 13th Avenue, Lakewood, Colorado 80214, United States
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Kristi W. Kaylo
Kristi W. Kaylo
Usona Institute, 2800 Woods Hollow Road, Madison, Wisconsin 53711, United States
More by Kristi W. Kaylo
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Kelsey Lenoch
Kelsey Lenoch
Usona Institute, 2800 Woods Hollow Road, Madison, Wisconsin 53711, United States
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Cite this: ACS Omega 2020, 5, 49, 32067–32075

Publication Date (Web):December 2, 2020

https://doi.org/10.1021/acsomega.0c05099

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Abstract

To support clinical use, a multigram-scale process has been developed to provide 5-MeO-DMT, a psychedelic natural product found in the parotid gland secretions of the toad, Incilius alvarius. Several synthetic routes were initially explored, and the selected process featured an optimized Fischer indole reaction to 5-MeO-DMT freebase in high-yield, from which the 1:1 succinate salt was produced to provide 136 g of crystalline active pharmaceutical ingredient (API) with 99.86% peak area by high-performance liquid chromatography (HPLC) and a net yield of 49%. The report provides in-process monitoring, validated analytical methods, impurity formation and removal, and solid-state characterization of the API essential for subsequent clinical development.

Introduction

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Recently, interest has increased in understanding the clinical applications of psychedelic, entactogenic, and dissociative psychoactive drugs, such as psilocybin (1), DMT (2), LSD (3), MDMA (4), or ketamine (5) in combination with psychotherapeutic support to promote improved mental health conditions (Figure 1). (1,2) In particular, research has indicated favorable results in treating post-traumatic stress disorder (PTSD), depression, end of life conditions, and anxiety-related disorders. (1,3−6) This research shows that while the therapeutic mechanisms are not fully understood, some factors have been correlated with improvement in mental health. These factors include the intensity of mystical experience occasioned by the psychedelic, the context in which the session was conducted (known as set and setting), the dose at which the drug is administered, psychological flexibility, connectedness, emotional breakthrough, and increased neural entropy. (1,7−10)

Figure 1. Structures of clinically explored psychedelic, entactogenic, and dissociative psychoactive drugs.

5-MeO-DMT (6) is a tryptamine natural product most commonly identified as the primary psychoactive component of the parotid gland secretions of Incilius alvarius, the Sonoran Desert toad (Figure 2). (11) The alkaloid is also known to be present in low concentrations in a variety of plants, shrubs, and seeds. Human consumption of this material for its psychoactive properties has been reported in the scientific literature for at least 100 years. (12−15) Although it has been historically suggested that 5-MeO-DMT may have been used by indigenous cultures, (11) there is no known documentation to support this assertion. Due to the recent discovery of high concentrations of 5-MeO-DMT in I. alvarius secretions, there has been a reported increase in its recreational and spiritual use. (11,16,17) Recent evidence has indicated the presence of 5-MeO-DMT existing in concentrations between 20 and 30% of total dry weight or approximately 200–300 mg of 5-MeO-DMT per dried gram of toad secretion, (17) concentrations much higher when compared to plant-derived sources of 5-MeO-DMT.

Figure 2. (Left) *I. alvarius* (image courtesy of Holger Krisp, Ulm, Germany, 2011 under CC BY 3.0) with the parotid gland highlighted. (Right) Structure of 5-MeO-DMT (6).

Anecdotally, and suggested by research over the last 5 years, 5-MeO-DMT has been reported to be helpful in treating clinical mental health conditions. (8,9,16−18) These data suggest that 5-MeO-DMT produces mystical experiences with comparative intensity as seen with psilocybin, (8) has a significantly shorter duration of effect—between 10 and 45 min depending on the route of administration used, (19) and produces increased desired effects when the context of the experience is carefully curated. (20,21)

An extensively supported hypothesis is that commonly encountered psychedelic effects in humans (e.g., visual hallucinations, altered sense of self, time, and space, and atypical thought patterns) are mediated primarily via activation of the serotonergic 5-HT_2A receptor in the central nervous system (CNS). (22,23) Notably, all currently known psychedelics are also nonselective, simultaneously interacting with numerous other monoaminergic receptors and transporters in the CNS, and hence exhibit variable degrees of synergistic polypharmacology in addition to agonist activity at the 5-HT_2A receptor. (24) 5-MeO-DMT has demonstrated sub-micromolar binding affinity across most serotonin receptor subtypes expressed in the CNS, with about 300-fold selectivity for the human 5-HT_1A (3 ± 0.2 nM) versus 5-HT_2A (907 ± 170 nM) receptor subtypes. (25) Data has suggested that activation of the 5-HT_1A receptor may also play a significant role in contributing to the subjective and behavioral effects elicited by psychedelics in a synergistic way with 5-HT_2A activation. (26−28) In contrast to 5-MeO-DMT, psilocin (the active metabolite of psilocybin) is about 5-fold more selective for human 5-HT_2A receptors (107 nM) versus 5-HT_1A (567 nM). (29) In a controlled study in healthy human volunteers, coadministration of psilocin with the antianxiety medication buspirone, a selective 5-HT_1A agonist, altered the subjective effects produced by psilocin, notably reducing the intensity of certain visual hallucinations. (30) Interestingly, anecdotal reports on 5-MeO-DMT consumption have described a general lack of colorful geometric visual hallucinations typically associated with other psychedelics. (31)

To date, a comprehensive understanding of the correlation between psychedelics’ polypharmacology and the corresponding influence on their subjective effects is not well established. While a number of potential mechanisms have been hypothesized to rationalize the therapeutic mode of action of psychedelics, such as increased structural plasticity in the prefrontal cortex, (32) still no direct connection has been made between specific psychedelic pharmacodynamics and positive therapeutic outcomes. (33) Nevertheless, randomized clinical trials with the psychedelic psilocybin (1) in the treatment of serious mental health conditions such as major depressive disorder (MDD) continue to show promise. (34) To this end, 5-MeO-DMT appears to be pharmacodynamically unique compared to previous clinically studied psychedelics and could provide a useful comparator in contemporary controlled clinical studies with psychedelics to better understand their mode of action.

Unlike psilocybin, psychedelic tryptamines such as DMT (2) and 5-MeO-DMT (6) are subject to rapid first-pass metabolism by monoamine oxidase and are therefore not orally active. When consumed parenterally, they produce a significantly shorter duration of action, typically less than 1 h, compared to the 5–8 h duration of effects produced by psilocybin. The shorter duration of action may help in reducing the amount of time a patient would spend in the clinic. Additionally, compared to DMT, 5-MeO-DMT is known to be approximately 10–20 times more potent in humans. (13) With a short duration of action and possibly significant 5-HT_1A receptor selectivity, 5-MeO-DMT possesses unique pharmacodynamic and pharmacokinetic properties compared to other clinically studied psychedelics. These features may correlate with more positive therapeutic outcomes in controlled human clinical trials. To test this hypothesis and to better understand the psychotherapeutic utility of 5-MeO-DMT and enable such clinical trials, the preparation of active pharmaceutical ingredient (API) is required with adequate controls to ensure its identity, potency, purity, and strength. The development of this process is the topic of this report.

Results and Discussion

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5-MeO-DMT Dosage and Salt Form Selection

The most commonly reported route of administration is by vaporization of the freebase drug, which is generally not a pharmaceutically acceptable approach compared to other dosage forms. While other intraperitoneal routes of administration with 5-MeO-DMT such as dry powder inhalation, transdermal, or intravenous administration are possible, an intramuscular injection has been identified as a preferable compromise for administering this material. In addition to allowing precise metering of dose, the intramuscular injection of 5-MeO-DMT in a naturalistic setting has been previously reported and was claimed to possess an advantageous duration of action compared to the intense rapid-onset produced by other intraperitoneal routes. (19) The injectable drug formulated as a 20 mg/mL solution of API in sterile water with excipients is capable of delivering a precise dose of API in the range of 2–15 mg, consistent with the dose range described in previous anecdotal reports with this material. 5-MeO-DMT freebase has low water solubility (<10 mg/mL) and the unionized amine may degrade on exposure to atmospheric oxygen to give the corresponding N-oxide degradant (vide infra). A water-soluble, pharmaceutically acceptable salt form of 5-MeO-DMT was therefore required.

In parallel to the exploration of viable synthetic routes to 5-MeO-DMT freebase, a range of pharmaceutically acceptable salt forms were considered from acids with sufficient pK_a difference to fully protonate 6, including the counterions chloride, sulfate, fumarate, succinate, maleate, lysate, oxalate, benzoate, tartrate, mesylate, or acetate. (35) Using analytically pure 5-MeO-DMT freebase, the hydrochloride, sulfate, fumarate, and succinate salts were initially evaluated. Attempts at formation of the sulfate salt yielded an intractable gum and the approach was abandoned. The hydrochloride salt was readily prepared as an apparent crystalline solid, but the material was found to be hygroscopic and was deliquescent under high-humidity conditions. Both the fumarate and succinate salts were readily prepared and provided stable, free-flowing, crystalline materials. The fumarate salts of structurally analogous tryptamines are commonly reported, possibly due to their ease of synthesis. (36) DMT (2) fumarate, for example, has been previously used in clinical studies as an intravenous injection. (37) Fumaric acid is, however, a known Michael acceptor and has been shown to form covalent products with amine-containing APIs under mild conditions. (38,39) Given that terminal sterilization by an autoclave may be required in the future preparation of sterile solutions of the 5-MeO-DMT drug product, the potential for this known reactivity with fumaric acid eliminated it as an acceptable salt form. Succinic acid is a structurally similar dicarboxylic acid but lacks the conjugated double bond present in fumaric acid and would not exhibit similar chemical reactivity.

The succinate salt was therefore explored further as a potential pharmaceutically acceptable salt form. The material was prepared and subjected to thorough solid-state characterization, including equilibrium water solubility, X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), hyper-DSC, dynamic vapor sorption (DVS), ¹H nuclear magnetic resonance (NMR), and optical microscopy (see the Supporting Information). Briefly, 5-MeO-DMT succinate (1:1) was not hygroscopic and XRPD indicated that multiple crystallization conditions resulted in a common stable crystalline anhydrate (form A) with only a few conditions that formed unique solvated forms (see the Supporting Information). The data supported the use of 5-MeO-DMT succinate (1:1) as a stable and pharmaceutically acceptable salt form. Given its ease of synthesis and favorable solid-state properties, this salt form was selected for further development.

5-MeO-DMT Route Scouting

For clinical development, the ideal synthetic route to 5-MeO-DMT would utilize commercially available starting materials, would be scalable to readily provide the product in the range of 0.1–1 kg, would not rely on flash silica gel chromatography or fractionation, and would provide a high-purity final product with no unidentified individual impurity >0.15% peak area by a validated high-performance liquid chromatography (HPLC) method. The literature survey revealed three potentially viable synthetic routes, and each was explored and evaluated for the ability to meet the above criteria.

Route 1

A seemingly attractive single-step process employed a modified Eschweiler–Clarke reaction via reductive amination between formaldehyde and commercially available 5-methoxy tryptamine (7) with sodium cyanoborohydride as the reducing agent (Scheme 1). (40) Several small-scale attempts were initially evaluated with reaction monitoring by liquid chromatography-mass spectrometry (LCMS). Though product formation was evident, the reaction was plagued by challenges that would likely multiply at larger scales. The Pictet–Spengler reaction to the corresponding tryptoline (8) was difficult to suppress and removal of this structurally similar and possibly biologically active byproduct was challenging. Further optimization to Route 1 may be possible, but ultimately, the reaction was not recommended for further development. A related reaction involving N-methylation of tryptamine 7 by methyl iodide has also been suggested; however, this approach would inevitably lead to difficult-to-control quaternization at the amine and was therefore also not considered for large-scale synthesis.

Scheme 1. Eschweiler–Clarke Reaction to 6 and Mechanism of Pictet–Spengler Byproduct Formation

Route 2

The Speeter–Anthony tryptamine synthesis (Scheme 2) is the most cited general method for preparing substituted psychedelic tryptamines and has also been used to prepare 5-MeO-DMT previously. (31,41) Given recent learnings and optimizations from the large-scale synthesis of psilocin and psilocybin produced by an analogous process, the route was considered for the large-scale synthesis of 6 from 5-methoxyindole 9. (42−44) A key consideration in this approach is performing the final reduction on the ketoamide 10 with pyrophoric lithium aluminum hydride (LAH) with the subsequent quench and tedious extraction from solid aluminum waste salts; the difficulty of this process tends to increase with scale. Our data has indicated that in most cases when synthesizing tryptamines, the reduction step will stall at approximately 90% conversion with 5–10% of an expected β-hydroxy intermediate, such as 11, remaining (Scheme 2). On workup, further manipulations of the crude freebase, especially acidic conditions, can initiate conversion of the β-hydroxy impurity to a reactive electrophile, such as 12 (Scheme 2), and give mixtures of isomeric dimerized impurities. Crookes et al. provided a thorough investigation into the formation of analogous dimeric byproducts in the LAH reduction to produce DMT (2) by the mechanism analogous to the depiction in Scheme 2. (45) Though Route 2 was a viable process, given the known challenges with scale-up, this route would require additional process development to ensure that the final product could reliably meet high-purity specifications without relying on column chromatography. Therefore, a single-step procedure based on the Fischer indole reaction was next explored.

Scheme 2. Speeter–Anthony Tryptamine Synthesis and Byproduct Formation via Reactive Impurity 11

Route 3

Several attributes inherent to the Fischer indole reaction approach to 6 from 4-methoxyphenylhydrazine (13) and 4,4-diethoxy-N,N-dimethylbutan-1-amine (14), a masked aldehyde protected as the diethyl acetal derivative (Scheme 3A), were attractive for the development of a scalable process: the transformation occurs in a single step, it does not rely on high temperatures, occurs in aqueous solvent, and does not rely on air-sensitive or pyrophoric reactants such as lithium aluminum hydride. Additionally, literature precedent exists for its use specifically in the synthesis of 5-MeO-DMT in addition to related substituted N,N-dimethyltryptamines, (46) with reported examples for the use of an analogous process in the commercial manufacture of structurally similar 5-substituted dimethyltryptamine antimigraine medicines, such as sumatriptan (15), zolmitriptan (16), and rizatriptan (17) (Scheme 3B). (47) Importantly, the pharmaceutical relevance of tryptamines 15–17 provided some assurance that the key butanamine starting material 14 common to all three processes was well-characterized and would remain commercially available and inexpensive.

Scheme 3. (A) Fischer Indole Reaction in the preparation of 6 and (B) Approved Antimigraine Medications Prepared by the Analogous Process

As per the previously published protocol, the reaction was first conducted in refluxing dilute aqueous sulfuric acid solution (Table 1, entry 1). (46) Reaction monitoring by LCMS indicated that the phenylhydrazine limiting reagent 13 was consumed within 2 h with a crude reaction purity of about 63% peak area, including several high-molecular-weight impurities representing the remaining 37% peak area. With the significant impurity profile, the reaction would have likely required chromatography to isolate the product of sufficient purity. Serendipitously, we observed that an aliquoted LCMS sample removed prior to reflux prepared in acetonitrile instead of water proceeded to near completion at or below room temperature and contained almost exclusively 6 with few byproducts. Following this observation, an experiment was repeated using 1:1 water/acetonitrile as the solvent system at room temperature overnight to confirm 88% conversion to the product by LCMS (Table 1, entry 2). Based on the encouraging results, the process was repeated, and additional conditions were explored.

Table 1. Reaction Optimization Conditions

entry	equiv 14 (x)	cosolvent, (vol)	time (h)	temp. (°C)	conversion (area %)^a
1	1.2	(0)	2	100	63
2	1.2	MeCN, (10)	19	22	88
3	1.2	MeCN, (10)	3	40	90
4	1.2	MeOH, (10)	3	40	84
5	1.2	DMSO, (10)	3	40	87
6	1.2	MeTHF, (10)	3	40	79
7	1.2	DCM, (10)	3	40	77
8	1.2	H₂O, (10)^b	3	40	66
9	1.05	MeCN, (5)	3	35	90
9b	1.05	MeCN, (5)	28	35	89
10	1.05	MeCN, (5)	3	35	90 (80)^c

^{^a}

UPLC-UV percent area at 269 nm.

^{^b}

Total water was 20 vol.

^{^c}

Isolated yield.

Raising the temperature to 40 °C, the reaction was found to reach completion within 3 h with acetonitrile cosolvent (Table 1, entry 3). To better understand the role of the cosolvent, several additional reactions were trialed with different cosolvents, including methanol, dimethyl sulfoxide (DMSO), 2-methyltetrahydrofuran (2-MeTHF), and dichloromethane (DCM) (Table 1, entries 4–7) compared to the same volume of only water under otherwise identical conditions (Table 1, entry 8). The results indicated that all cosolvents tested were advantageous in increasing reaction conversion, with water-miscible polar aprotic DMSO providing results comparable to that of acetonitrile. Methanol also exhibited a significant enhancing effect on the reaction. The water-immiscible solvents 2-MeTHF and DCM also moderately improved reaction conversion. These data indicated that most cosolvents improved the conversion and purity profile of the reaction, and the water-miscible polar aprotic cosolvents demonstrated a significant rate-enhancing effect and minimized side reactions in the formation of 6. Though both reactants 13 and 14 appeared to be water soluble in the absence of cosolvent, we hypothesized that the addition of cosolvent possibly assisted in solubilizing either reactant or prevented the formation of hydrophobic clusters. The hypothesis is supported by the observation that in the absence of cosolvent, the major side reaction impurities formed were indicative of high-molecular-weight oligomers, which could potentially form from localized high-concentration clusters of starting reactants. Though DMSO and acetonitrile performed comparably, acetonitrile was selected for further development as the high-boiling point and low volatility of DMSO may have introduced additional complexity by its eventual removal in the workup.

Further optimization revealed that diethyl acetal 14 could be reduced to 1.05 equiv relative to limiting reagent 13. Acetonitrile cosolvent was reduced from 10 to 5 vol, and the temperature was reduced to 35 °C without measurable impact on the crude reaction profile or reaction rate (Table 1, entry 9). Further, stressing the same reaction with an extended 28-h hold time had only a slight impact on the reaction profile with an overall 1% reduction in a HPLC purity of the crude reaction mixture (Table 1, entry 9b). The reaction’s indifference to extended hold times was advantageous and suggested that reaction time was not a critical process parameter and could allow for some flexibility with timing when running the process at scale. Based on the optimizations described, the process was scaled to 100 mmol (∼35 g) and isolation conditions were explored to ultimately provide high-purity 6 as the succinate salt in 80% isolated yield (Table 1, entry 9).

Optimization of Workup, Isolation, and Salt Formation

Workup

Crude freebase product was initially isolated by a routine acid/base workup procedure employing dichloromethane as both a washing solvent for the acidic crude reaction mixture and, upon basification, an extraction solvent for the freebase as well. On larger-scale reactions where extended hold times of the freebase product in methylene chloride were required, formation of a heavy insoluble oil impurity was encountered. Consistent with several literature reports on the chemical reactivity of DMT and other tertiary amines with methylene chloride, (48−52) 5-MeO-DMT was suspected to have undergone a similar reaction to form the quaternary ammonium byproduct 18 (Scheme 4). The crude heavy oil was analyzed by ¹H NMR, which provided a singlet at 5.69 ppm that integrated to 2H; these data were consistent with the identity of structure 18 (Scheme 4 and Supporting Information S14). The apparent reactivity between product 6 and dichloromethane indicated that an alternative solvent should be used in the workup process, especially at larger scales where extended hold times may be required.

Scheme 4. Formation of Degradant 18 Annotated With ¹H NMR Shift for the Suspected Dichloromethane Adduct

2-Methyltetrahydrofuran (2-MeTHF) has been previously suggested as a good substitute for dichloromethane in biphasic aqueous workups. (53) We found that freebase 6 was highly soluble, and 2-MeTHF formed a clean phase split with the acidic aqueous crude reaction mixture without the need for distillation of the acetonitrile cosolvent. Additionally, 2-MeTHF represented a greener solvent choice for process chemistry, as it is produced industrially by biorenewable processes. On smaller scales, the acetonitrile cosolvent was distilled prior to workup. On larger scales, this distillation was avoided and the workup proceeded directly into a liquid–liquid washing step. Subsequent data would indicate that some product loss occurred in the first washing step by being extracted into the organic phase, possibly related to increased partitioning due to the acetonitrile present.

Freebase Purification

Analysis of the crude freebase extract by LC–UV–high-resolution mass spectrometry (HRMS) revealed the presence of several isomeric dimer-like products representing approximately 8% combined peak area for the crude reaction mixture. HRMS analysis provided m/z 534.3803 with MS/MS fragmentation to m/z 316.2383 for each of the isomers, supporting the putative structure 19 (Scheme 5 and Supporting Information S15), although different attachment points (denoted by red circles) for the dimer are also possible. Regardless of connectivity, the HRMS data supported the identity of a triamine for the isometric impurities corresponding to m/z 534.3803. Though ethanol was initially identified as a suitable recrystallization solvent for the succinate salt of 6, the isomeric dimers were found to co-crystallize with 6 at levels that exceeded impurity specifications. Alternatively, we speculated that a significant differential in retention would exist between monoamine 6 and triamine isomers of 19 on silica gel, such that a filtration through a small silica plug would be sufficient to remove the polar impurities while allowing the product 6 to readily elute. Mobile phase screening experiments with thin-layer chromatography revealed that 10% methanol in acetone provided such separation, with polar dimer impurities remaining adhered to the baseline and migration of the product spot for 6 with a retention factor (R_f) of about 0.3 (Supporting Information S16). While methanol/acetone is an atypical eluent with silica gel, dichloromethane, which is commonly used in separations with polar amines, was unacceptable given the reactivity concerns outlined above. On the preparative scale, filtration through a 5 wt % silica pad and washing the pad with 100 vol of 10% methanol in acetone was sufficient to recover 80–90% mass of the input crude freebase, while the polar dimeric impurities remained adhered to the baseline and were effectively removed.

Scheme 5. Putative Dimer Impurity Structure and MS/MS Fragmentation^a

Following the silica filtration step during concentration of the resulting eluent, a previously unobserved degradant appeared in up to 3% peak area by HPLC. The degradant was conclusively identified as oxidation degradant 21, the N-oxide of 6. The structure was supported by HRMS initially (Supporting Information S17) and later chemical synthesis with additional characterization by ¹H and ¹³C NMR (Scheme 6 and Supporting Information S18 and S19) conclusively characterized 21. Previous in vitro and in vivo metabolism data has indicated that N-oxide 21 is a metabolite of 6 (54) and would therefore afford some flexibility in the allowable levels of this degradant in the API.

Succinate Salt Formation

With smaller-scale development reactions, the succinic acid salt of 6 was readily isolated by adding 1 equiv of succinic acid to a solution of freebase 6 in acetone and collecting the resulting insoluble crystalline precipitate by filtration. We later found that the inclusion of a washing step using activated charcoal helped to minimize slight variability in color observed in the final isolated product. The color variation was found to be correlated with the use of different commercial sources of phenylhydrazine 13, even though all lots were tested upon receipt to >98% purity. The procedure was modified to form the succinate salt in a solution of methanol at a volume that did not initially induce precipitation. The resulting solution was stirred with activated charcoal, filtered, and then concentrated. The resulting solid succinate salt was slurried in acetone, filtered, and dried to provide a crystalline solid consistent with the desired polymorphic form. The process provided a net yield of 49% to produce 136 g of isolated succinic acid salt of 6 with HPLC purity of 99.86% peak area. The identified N-oxide degradant 21 was the only detectable impurity at 0.14% peak area. Though not reported in the larger-scale synthesis, as the required purity specifications were met, following salt formation, ethanol was found to perform well as a recrystallization solvent for further purification of the succinate salt of 6 if necessary.

Future Optimization

The Fischer indole reaction to 6 readily provided API that met all set specifications. Achieving a high-purity product was the initial focus, and further optimization could improve the final yield without compromising final product purity. HPLC data indicated that product conversion was as high as 90%, yet isolated freebase recovery was 57%. Additionally, in the smaller-scale development reaction (Table 1, entry 9), an isolated yield of 80% was achieved. The key difference between the two processes was the distillation of the cosolvent prior to workup and much of the yield loss that occurred at the first liquid–liquid washing step, where approximately 10–20% of the product was extracted from the acidic aqueous layer in the first wash. In the future, the washes could potentially be back-extracted to recover this loss. With further scale-up, the elimination of the silica pad filtration step would be desirable. Vacuum distillation of the crude freebase could be an acceptable alternative for the separation of the freebase product from high-MW dimers such as 19. Though dimer impurities present in succinate salt were not readily purged by recrystallization approaches, exploration of the recrystallization of alternate salt forms prior to generation of the succinate salt may also circumvent the silica pad filtration. As an alternative to purification approaches, additional optimization of reaction conditions could be explored to further improve the specificity of the reaction toward formation of 6 and minimize side reactions.

Conclusions

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The first production run has provided sufficient API to meet current clinical and nonclinical needs to enable first-in-human clinical trials with 6. The key features of the developed process were an optimized Fischer indole reaction with advantageous inclusion of acetonitrile cosolvent to provide crude freebase 6. The workup featured greener solvent choices with an intermediate purification via filtration through a silica pad. The 1:1 succinic acid salt was subsequently prepared from methanol with an activated charcoal decolorizing step followed by final purification by acetone slurry. A minor API degradation product, the corresponding N-oxide 21, was identified, synthesized, and characterized. The final product was isolated in 49% overall yield to provide 136 g of API with 99.86% HPLC purity. The controllability and scalability inherent to the developed process will ensure that current and future clinical demands for 6 are met.

Experimental Section

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General Experimental Methods

Reactions were performed using commercially obtained raw materials and solvents. Unless otherwise stated, all commercially obtained reagents were identity tested and used as received. Reactions were conducted in a Borosilicate Glass 3.3 jacketed glass reactor (5 L) with a Julabo FPW91-SL Ultra-Low Refrigerated-Heating circulator for temperature control. Distillations (>5 L) were performed with a Buchi Rotavapor R-220 Pro. Reactions were monitored by thin-layer chromatography (TLC) using EMD/Merck silica gel 60 F254-precoated plates (0.25 mm). Flash column chromatography was performed using prepackaged RediSepRf columns on a CombiFlash Rf system (Teledyne ISCO Inc.). ¹H and ¹³C NMR spectra were recorded on a Bruker Avance 400 (at 400 and 101 MHz, respectively) and a Bruker Avance 500 (at 500 and 126 MHz, respectively). Process development and reaction monitoring was performed with a Waters Acquity I-Class UPLC utilizing a Waters HSS T3 column (2.5 μm, 2.1 mm × 30 mm) run in gradient mode with H₂O (0.1% formic acid) and acetonitrile (0.1% formic acid) mobile phases at 0.6 mL/min. Samples were diluted in acetonitrile or water to approximately 1 mg/mL and 0.1 μL was injected. Chromatographic peaks were detected by a diode array detector at 269 nm. High-resolution mass spectra were acquired in line with UV on a Waters Xevo G2-XS QTof in ESI-positive mode. Low and high collision energy mass spectra were acquired using a Waters MSe experiment.

2-(5-Methoxy-1H-indol-3-yl)-N,N-dimethylethanamine (6-freebase)

To a clean and dry 5 L reactor was charged 4-methoxyphenylhydrazine hydrochloride (145.0 g; 0.83 mol, 1.0 equiv, purity >98% confirmed by HPLC) followed by water (1.45 L, 10 vol) under a nitrogen atmosphere at 20–25 °C. The contents of the reactor were then stirred at 30–35 °C and a dark red colored suspension was observed. To the suspension, concentrated H₂SO₄ (47.7 mL, 0.91 mol, 1.1 equiv) was cautiously added dropwise under a nitrogen atmosphere over 10 min while maintaining the temperature below 40 °C. (Note: This addition is slightly exothermic.) The brown/red solution was heated to 35–40 °C (with a target temperature of 37 °C) and stirred for an additional 10 min. A solution of 4,4-diethoxy-N,N-dimethylbutan-1-amine (14) (165.0 g, 0.87 mol, 1.05 equiv) was prepared in acetonitrile (0.58 L, 4.0 vol) and added dropwise to the reactor under a nitrogen atmosphere over approximatively 60 min while maintaining the temperature between 35 and 40 °C. The addition funnel was rinsed with acetonitrile (145 mL, 1.0 vol) and added dropwise to the reactor. The temperature was maintained at 40 °C and the contents were agitated for an additional 4 h. A sample of the reaction mixture was aliquoted for HPLC analysis and reaction completion with a target limit of ≤2% peak area for the limiting reagent. (Result: 4-Methoxyphenylhydrazine: 1.86% area.) The mixture was cooled to 20–25 °C and the contents were transferred to a 10 L reactor. The acidic aqueous solution was washed with 2-MeTHF (2 × 2.03 L, 14.0 vol). After each wash, the layers were allowed to settle for 15 min. The lower acidic aqueous layer was collected and the upper 2-MeTHF wash was discarded. The acidic aqueous layer was recharged to the reactor and sodium hydroxide solution (4 M, 0.65 L, 4.5 vol) was added dropwise while maintaining the temperature at 20–25 °C to bring the pH to 11–12 providing a milky suspension. The suspension was extracted with 2-MeTHF (3 × 1.45 L, 10.0 vol); following each extraction, the layers were allowed to settle for 15 min, the lower alkaline water layer was separated into a drum, and the upper organic layer was collected. The lower aqueous layer was discarded and the combined 2-MeTHF organic layers were transferred to a 20 L-flask. The solution was concentrated in vacuo to an oily amber residue. Residual water was removed azeotropically by redissolving the residue with fresh 2-MeTHF (1.45 L, 10 vol) and repeating the concentration step. This oily residue was dried on the rotatory evaporator under vacuum (10–20 mbar) for 1 h at 40–45 °C to provide 117.68 g (64.9% theoretical yield) of crude 5-MeO-DMT freebase. The crude freebase was dissolved in acetone (1.45 L, 10.0 vol) and poured through a pad of silica (230–400 mesh, 725 g, 5 wt). The pad was eluted with acetone/MeOH (9:1, v-v, 14.5 L, 100.0 vol). The combined filtrates were concentrated to provide 102.94 g of purified 5-MeO-DMT freebase (56.8% yield, 98.27% area by HPLC) as a pale clear orange oil that slowly solidified on standing.

2-(5-Methoxy-1H-indol-3-yl)-N,N-dimethylethanamine (6-succinate (1:1))

To the 20 L-flask containing purified 5-MeO-DMT freebase from the previous step (101.1 g, 0.46 mol, 1.0 equiv) was charged fresh MeOH (1.01 L, 10.0 vol). The flask was attached to a rotary evaporator and rotation was started without applying vacuum until the material dissolved. The methanolic solution was then transferred to a 5 L-RBF fitted with an overhead mechanical stirrer. Additional MeOH (2.02 L, 20.0 vol) was charged to the RBF, under a nitrogen atmosphere, at 20–25 °C. Succinic acid (57.4 g, 0.48 mol, 1.05 equiv) was added portion wise and the solution was stirred at 20–25 °C for 48 h under a nitrogen atmosphere. Charcoal (NORIT SX1, 31.2 g, ∼20% w/w) was charged to the flask, under a nitrogen atmosphere, at 20–25 °C. The resulting dark suspension was stirred at 20–25 °C for 2.5 h under a nitrogen atmosphere and then filtered on a Celite pad. The Celite pad was rinsed with additional MeOH (3.03 L, 30.0 vol). The collected filtrate (5.05 L) was then concentrated under reduced pressure. Acetone was charged in portions to the rotatory evaporator containing the solid 5-MeO-DMT succinate salt and the solvent concentrated until no more distillate was observed to ensure that most of the residual MeOH had been distilled. Fresh acetone (505.5 mL, 5.0 vol) was added to the flask and the resulting suspension was slurried at ambient temperature for 1 h. The suspension was cooled to 0–5 °C on an ice bath and was filtered over a sintered funnel. The filter cake was washed with ice-cold acetone (2 × 101.1 mL, 1.0 vol) and the solids were pulled dry on the filter for approximately 30 min. The solid was dried in a vacuum oven at 40–45 °C to a constant weight to provide 136.0 g (86.0% yield, 48.8% overall yield, 99.86% area) of 5-MeO-DMT succinate salt (6). TG/DTA Melt onset: 140 °C; ¹H NMR (500 MHz, DMSO-d₆): δ 10.66 (s, 1H), 7.22 (d, J = 9 Hz, 1H), 7.06 (d, J = 2 Hz, 1H), 7.00 (d, J = 2.5 Hz, 1H), 6.72 (dd, J = 9 Hz, 2 Hz, 1H), 3.76 (s, 3H), 2.85 (m, 2H), 2.77 (m, 2H), 2.42 (s, 6H), 2.34 (s, 4H); ¹³C NMR (126 MHz, DMSO-d₆): δ 175.1, 153.5, 131.8, 127.8, 123.9, 112.5, 111.5, 111.2, 100.7, 58.8, 55.8, 44.1, 30.9, 22.2.

2-(5-Methoxy-1H-indol-3-yl)-N,N-dimethylethan-1-amine oxide (21)

Freebase 6 (500 mg, 2.3 mmol) was suspended in 30% w/w H₂O₂ (1.2 mL, 11.5 mmol, 5 equiv) and stirred. Ethanol (ca. 3 mL) was added dropwise to the suspension until a homogeneous solution was achieved. Stirring continued for 48 h whereupon thin-layer chromatography (100:10:1; CHCl₃/MeOH/NH₄OH) indicated complete conversion of the starting material to a new slightly more polar spot. Without concentration, the reaction mixture was applied directly to a preparative C18 column (130 g) and gradient eluted at 85 mL/min with MeOH and H₂O, both containing 1% NH₄OH. Collected fractions were combined and concentrated to provide the target compound as a yellow deliquescent solid, (470 mg, 88%). HRMS (ESI+): calcd for [C₁₃H₁₈N₂O₂] [M+H]⁺: 235.1441; found: 235.1426. ¹H NMR (400 MHz, DMSO-d₆): δ 11.29 (s, 1H), 7.24 (d, 1H, J = 8.7 Hz), 7.13 (s, 1H), 7.05 (1H, s), 6.71 (d, 1H, J = 8.7 Hz), 3.75 (s, 3H), 3.45–3.36 (m, 2H), 3.25–3.16 (m, 2H), 3.12 (s, 6H); ¹³C NMR (101 MHz, DMSO-d₆): δ 153.0, 131.5, 127.4, 123.6, 112.1, 111.1, 109.9, 100.2, 69.9, 58.5, 55.4, 19.1.

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Certificate of analysis for 5-MeO-DMT succinate salt; solubility data; characterization data; polymorph screen summary and results; HPLC methodology and chromatograms; impurity identification and characterization (PDF)

ao0c05099_si_001.pdf (1.21 MB)

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Corresponding Author
- Alexander M. Sherwood - Usona Institute, 2800 Woods Hollow Road, Madison, Wisconsin 53711, United States; http://orcid.org/0000-0003-0895-0791; Email: [email protected]
Authors
- Romain Claveau - Almac Sciences, 20 Seagoe Industrial Estate, Craigavon BT63 5QD, United Kingdom
- Rafael Lancelotta - Habituating to Wholeness, 6500 W 13th Avenue, Lakewood, Colorado 80214, United States
- Kristi W. Kaylo - Usona Institute, 2800 Woods Hollow Road, Madison, Wisconsin 53711, United States
- Kelsey Lenoch - Usona Institute, 2800 Woods Hollow Road, Madison, Wisconsin 53711, United States
Notes
The authors declare no competing financial interest.

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The authors wish to thank William Linton for his vision and support.

References

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This article references 54 other publications.

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Carhart-Harris, R. L.; Bolstridge, M.; Day, C. M. J.; Rucker, J.; Watts, R.; Erritzoe, D. E.; Kaelen, M.; Giribaldi, B.; Bloomfield, M.; Pilling, S.; Rickard, J. A.; Forbes, B.; Feilding, A.; Taylor, D.; Curran, H. V.; Nutt, D. J. Psilocybin with Psychological Support for Treatment-Resistant Depression: Six-Month Follow-Up. Psychopharmacology 2018, 235, 399– 408, DOI: 10.1007/s00213-017-4771-x
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Rationale: Recent clin. trials are reporting marked improvements in mental health outcomes with psychedelic drug-assisted psychotherapy. Objectives: Here, we report on safety and efficacy outcomes for up to 6 mo in an open-label trial of psilocybin for treatment-resistant depression. Methods: Twenty patients (six females) with (mostly) severe, unipolar, treatment-resistant major depression received two oral doses of psilocybin (10 and 25 mg, 7 days apart) in a supportive setting. Depressive symptoms were assessed from 1 wk to 6 mo post-treatment, with the self-rated QIDS-SR16 as the primary outcome measure. Results: Treatment was generally well tolerated. Relative to baseline, marked redns. in depressive symptoms were obsd. for the first 5 wk post-treatment (Cohen's d = 2.2 at week 1 and 2.3 at week 5, both p < 0.001); nine and four patients met the criteria for response and remission at week 5. Results remained pos. at 3 and 6 mo (Cohen's d = 1.5 and 1.4, resp., both p < 0.001). No patients sought conventional antidepressant treatment within 5 wk of psilocybin. Redns. in depressive symptoms at 5 wk were predicted by the quality of the acute psychedelic experience. Conclusions: Although limited conclusions can be drawn about treatment efficacy from open-label trials, tolerability was good, effect sizes large and symptom improvements appeared rapidly after just two psilocybin treatment sessions and remained significant 6 mo post-treatment in a treatment-resistant cohort. Psilocybin represents a promising paradigm for unresponsive depression that warrants further research in double-blind randomized control trials.
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Griffiths, R. R.; Johnson, M. W.; Carducci, M. A.; Umbricht, A.; Richards, W. A.; Richards, B. D.; Cosimano, M. P.; Klinedinst, M. A. Psilocybin Produces Substantial and Sustained Decreases in Depression and Anxiety in Patients with Life-Threatening Cancer: A Randomized Double-Blind Trial. J. Psychopharmacol. 2016, 30, 1181– 1197, DOI: 10.1177/0269881116675513
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Cancer patients often develop chronic, clin. significant symptoms of depression and anxiety. Previous studies suggest that psilocybin may decrease depression and anxiety in cancer patients. The effects of psilocybin were studied in 51 cancer patients with life-threatening diagnoses and symptoms of depression and/or anxiety. This randomized, double-blind, cross-over trial investigated the effects of a very low (placebo-like) dose (1 or 3 mg/70 kg) vs. a high dose (22 or 30 mg/70 kg) of psilocybin administered in counterbalanced sequence with 5 wk between sessions and a 6-mo follow-up. Instructions to participants and staff minimized expectancy effects. High-dose psilocybin produced large decreases in clinician- and self-rated measures of depressed mood and anxiety, along with increases in quality of life, life meaning, and optimism, and decreases in death anxiety. At 6-mo follow-up, these changes were sustained, with about 80% of participants continuing to show clin. significant decreases in depressed mood and anxiety. Participants attributed improvements in attitudes about life/self, mood, relationships, and spirituality to the high-dose experience, with >80% endorsing moderately or greater increased well-being/life satisfaction. Community observer ratings showed corresponding changes. Mystical-type psilocybin experience on session day mediated the effect of psilocybin dose on therapeutic outcomes.
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Ot’alora G, M.; Grigsby, J.; Poulter, B.; Van Derveer, J. W.; Giron, S. G.; Jerome, L.; Feduccia, A. A.; Hamilton, S.; Yazar-Klosinski, B.; Emerson, A.; Mithoefer, M. C.; Doblin, R. 3,4-Methylenedioxymethamphetamine-Assisted Psychotherapy for Treatment of Chronic Posttraumatic Stress Disorder: A Randomized Phase 2 Controlled Trial. J. Psychopharmacol. 2018, 32, 1295– 1307, DOI: 10.1177/0269881118806297
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Posttraumatic stress disorder often does not resolve after conventional psychotherapies or pharmacotherapies. Pilot studies have reported that 3,4-methylenedioxymethamphetamine (MDMA) combined with psychotherapy reduces posttraumatic stress disorder symptoms. This pilot dose response trial assessed efficacy and safety of MDMA-assisted psychotherapy across multiple therapy teams. Twenty-eight people with chronic posttraumatic stress disorder were randomized in a double-blind dose response comparison of two active doses (100 and 125 mg) with a low dose (40 mg) of MDMA administered during eight-hour psychotherapy sessions. Change in the Clinician-Administered PTSD Scale total scores one month after two sessions of MDMA served as the primary outcome. Active dose groups had one addnl. open-label session; the low dose group crossed over for three open-label active dose sessions. A 12-mo follow-up assessment occurred after the final MDMA session. In the intent-to-treat set, the active groups had the largest redn. in Clinician-Administered PTSD Scale total scores at the primary endpoint, with mean (std. deviation) changes of -26.3 (29.5) for 125 mg, -24.4 (24.2) for 100 mg, and -11.5 (21.2) for 40 mg, though statistical significance was reached only in the per protocol set (p = 0.03). Posttraumatic stress disorder symptoms remained lower than baseline at 12-mo follow-up (p<0.001) with 76% (n = 25) not meeting posttraumatic stress disorder criteria. There were no drug-related serious adverse events, and the treatment was well-tolerated. Our findings support previous investigations of MDMA-assisted psychotherapy as an innovative, efficacious treatment for posttraumatic stress disorder.
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Ross, S.; Bossis, A.; Guss, J.; Agin-Liebes, G.; Malone, T.; Cohen, B.; Mennenga, S. E.; Belser, A.; Kalliontzi, K.; Babb, J.; Su, Z.; Corby, P.; Schmidt, B. L. Rapid and Sustained Symptom Reduction Following Psilocybin Treatment for Anxiety and Depression in Patients with Life-Threatening Cancer: A Randomized Controlled Trial. J. Psychopharmacol. 2016, 30, 1165– 1180, DOI: 10.1177/0269881116675512
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Background: Clin. significant anxiety and depression are common in patients with cancer, and are assocd. with poor psychiatric and medical outcomes. Historical and recent research suggests a role for psilocybin to treat cancer-related anxiety and depression. Methods: In this double-blind, placebo-controlled, crossover trial, 29 patients with cancer-related anxiety and depression were randomly assigned and received treatment with single-dose psilocybin (0.3 mg/kg) or niacin, both in conjunction with psychotherapy. The primary outcomes were anxiety and depression assessed between groups prior to the crossover at 7 wk. Results: Prior to the crossover, psilocybin produced immediate, substantial, and sustained improvements in anxiety and depression and led to decreases in cancer-related demoralization and hopelessness, improved spiritual wellbeing, and increased quality of life. At the 6.5-mo follow-up, psilocybin was assocd. with enduring anxiolytic and anti-depressant effects (approx. 60-80% of participants continued with clin. significant redns. in depression or anxiety), sustained benefits in existential distress and quality of life, as well as improved attitudes towards death. The psilocybin-induced mystical experience mediated the therapeutic effect of psilocybin on anxiety and depression. Conclusions: In conjunction with psychotherapy, single moderate-dose psilocybin produced rapid, robust and enduring anxiolytic and anti-depressant effects in patients with cancer-related psychol. distress.
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Research into the basic effects and therapeutic applications of psychedelic drugs has grown considerably in recent years. Yet, pressing questions remain regarding the substances' lasting effects. Although individual studies have begun monitoring sustained changes, no study to-date has synthesized this information. Therefore, this systematic review aims to fill this important gap in the literature by synthesizing results from 34 contemporary exptl. studies which included classic psychedelics, human subjects, and follow-up latencies of at least two weeks. The bulk of this work was published in the last five years, with psilocybin being the most frequently administered drug. Enduring changes in personality/attitudes, depression, spirituality, anxiety, wellbeing, substance misuse, meditative practices, and mindfulness were documented. Mystical experiences, connectedness, emotional breakthrough, and increased neural entropy were related to these long-term changes in psychol. functioning. Finally, with proper screening, prepn., supervision, and integration, limited aversive side effects were noted by study participants. Future researchers should focus on including larger and more diverse samples, lengthier longitudinal designs, stronger control conditions, and standardized dosages.
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Barsuglia, J.; Davis, A. K.; Palmer, R.; Lancelotta, R.; Windham-Herman, A. M.; Peterson, K.; Polanco, M.; Grant, R.; Griffiths, R. R. Intensity of Mystical Experiences Occasioned by 5-MeO-DMT and Comparison with a Prior Psilocybin Study. Front. Psychol. 2018, 9, 2459 DOI: 10.3389/fpsyg.2018.02459
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Intensity of Mystical Experiences Occasioned by 5-MeO-DMT and Comparison With a Prior Psilocybin Study
Barsuglia Joseph; Polanco Martin; Barsuglia Joseph; Barsuglia Joseph; Barsuglia Joseph; Polanco Martin; Davis Alan K; Griffiths Roland R; Palmer Robert; Windham-Herman Austin-Marley; Lancelotta Rafael; Peterson Kristel; Grant Robert; Griffiths Roland R
Frontiers in psychology (2018), 9 (), 2459 ISSN:1664-1078.
5-MeO-DMT is a psychoactive substance found in high concentrations in the bufotoxin of the Colorado River Toad (Bufo alvarius). Emerging evidence suggests that vaporized 5-MeO-DMT may occasion mystical experiences of comparable intensity to those occasioned by more widely studied psychedelics such as psilocybin, but no empirical study has tested this hypothesis. Data was obtained from 20 individuals (Mage = 38.9, ± 10.7; male = 55%, Caucasian = 85%) who were administered 5-MeO-DMT as part of a psychospiritual retreat program in Mexico. All participants received 50 mg of inhaled vaporized toad bufotoxin which contains 5-MeO-DMT and completed the Mystical Experience Questionnaire (MEQ30) approximately 4-6 h after their session. Administration of 5-MeO-DMT occasioned strong mystical experiences (MEQ30 Overall Mintensity = 4.17, ± 0.64, range 0-5) and the majority (n = 15, 75%) had "a complete mystical experience" (≥60% on all MEQ30 subscales). Compared to a prior laboratory-based psilocybin study, there were no differences in the intensity of mystical effects between 5-MeO-DMT and a high dose (30 mg/70 kg) of psilocybin, but the intensity of mystical effects was significantly higher in the 5-MeO-DMT sample compared to moderate/high dose (20 mg/70 kg) of psilocybin (MEQ30 Total Score: p = 0.02, d = 0.81). Administration of vaporized 5-MeO-DMT reliably occasioned complete mystical experiences in 75% of individuals and was similar in intensity to high dose psilocybin administered in a laboratory setting. The short duration of action may be advantageous for clinical interventions and for studying mystical-type experiences.
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Davis, A. K.; So, S.; Lancelotta, R.; Barsuglia, J. P.; Griffiths, R. R. 5-Methoxy-N,N-Dimethyltryptamine (5-MeO-DMT) Used in a Naturalistic Group Setting Is Associated with Unintended Improvements in Depression and Anxiety. Am. J. Drug Alcohol Abuse 2019, 45, 161– 169, DOI: 10.1080/00952990.2018.1545024
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5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) used in a naturalistic group setting is associated with unintended improvements in depression and anxiety
Davis Alan K; Griffiths Roland R; So Sara; Lancelotta Rafael; Barsuglia Joseph P; Griffiths Roland R
The American journal of drug and alcohol abuse (2019), 45 (2), 161-169 ISSN:.
BACKGROUND: A recent epidemiological study suggested that 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) used for spiritual and recreational reasons is associated with subjective improvement in depression and anxiety. Further exploration of the potential psychotherapeutic effects of 5-MeO-DMT could inform future clinical trials. OBJECTIVES: We examined self-reported improvement in depression and anxiety among people who use 5-MeO-DMT in a group setting with structured procedures guiding dose and administration of 5-MeO-DMT. Such procedures also include activities for the preparation of, and support during/following sessions, which are similar to procedures used in clinical trials of hallucinogen administration. Next, we examined whether depression or anxiety were improved following use, and whether the acute subjective effects (mystical/challenging) or beliefs about the 5-MeO-DMT experience were associated with improvements in these conditions. METHODS: Respondents (n = 362; Mage = 47.7; Male = 55%; White/Caucasian = 84%) completed an anonymous web-based survey. RESULTS: Of those reporting having been diagnosed with depression (41%) or anxiety (48%), most reported these conditions were improved (depression = 80%; anxiety = 79%) following 5-MeO-DMT use, and fewer reported they were unchanged (depression = 17%; anxiety = 19%) or worsened (depression = 3%; anxiety = 2%). Improvement in depression/anxiety conditions were associated with greater intensity of mystical experiences and higher ratings of the spiritual significance and personal meaning of the 5-MeO-DMT experience. There were no associations between depression or anxiety improvement and the intensity of acute challenging physical/psychological effects during the 5-MeO-DMT experience. CONCLUSIONS: Future prospective controlled clinical pharmacology studies should examine the safety and efficacy of 5-MeO-DMT administration for relieving depression and anxiety.
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Griffiths, R. R.; Johnson, M. W.; Richards, W. A.; Richards, B. D.; McCann, U.; Jesse, R. Psilocybin Occasioned Mystical-Type Experiences: Immediate and Persisting Dose-Related Effects. Psychopharmacology 2011, 218, 649– 665, DOI: 10.1007/s00213-011-2358-5
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Psilocybin occasioned mystical-type experiences: immediate and persisting dose-related effects
Griffiths, Roland R.; Johnson, Matthew W.; Richards, William A.; Richards, Brian D.; McCann, Una; Jesse, Robert
Psychopharmacology (Heidelberg, Germany) (2011), 218 (4), 649-665CODEN: PSCHDL; ISSN:0033-3158. (Springer)
Rationale: This dose-effect study extends previous observations showing that psilocybin can occasion mystical-type experiences having persisting pos. effects on attitudes, mood, and behavior. Objectives: This double-blind study evaluated psilocybin (0, 5, 10, 20, 30 mg/70 kg, p.o.) administered under supportive conditions. Methods: Participants were 18 adults (17 hallucinogen-naive). Five 8-h sessions were conducted individually for each participant at 1-mo intervals. Participants were randomized to receive the four active doses in either ascending or descending order (nine participants each). Placebo was scheduled quasi-randomly. During sessions, volunteers used eyeshades and were instructed to direct their attention inward. Volunteers completed questionnaires assessing effects immediately after and 1 mo after each session, and at 14 mo follow-up. Results: Psilocybin produced acute perceptual and subjective effects including, at 20 and/or 30 mg/70 kg, extreme anxiety/fear (39% of volunteers) and/or mystical-type experience (72% of volunteers). One month after sessions at the two highest doses, volunteers rated the psilocybin experience as having substantial personal and spiritual significance, and attributed to the experience sustained pos. changes in attitudes, mood, and behavior, with the ascending dose sequence showing greater pos. effects. At 14 mo, ratings were undiminished and were consistent with changes rated by community observers. Both the acute and persisting effects of psilocybin were generally a monotonically increasing function of dose, with the lowest dose showing significant effects. Conclusions: Under supportive conditions, 20 and 30 mg/70 kg psilocybin occasioned mystical-type experiences having persisting pos. effects on attitudes, mood, and behavior. Implications for therapeutic trials are discussed.
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Weil, A. T.; Davis, W. Bufo alvarius: A Potent Hallucinogen of Animal Origin. J. Ethnopharmacol. 1994, 41, 1– 8, DOI: 10.1016/0378-8741(94)90051-5
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Bufo alvarius: A potent hallucinogen of animal origin
Weil, Andrew T.; Davis, Wade
Journal of Ethnopharmacology (1994), 41 (1-2), 1-8CODEN: JOETD7; ISSN:0378-8741.
The authors demonstrate that the venom of B. alvarius, although known to be toxic when consumed orally, may be safely smoked and is powerfully psychoactive by that route of administration. These expts. are the first documentation of an hallucinogenic agent from the animal kingdom, and they provide clear evidence of a psychoactive toad that could have been employed by Precolumbian peoples of the New World.
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Agurell, S.; Holmstedt, B.; Lindgren, J. E.; Schultes, R. E. Alkaloids in Certain Species of Virola and Other South American Plants of Ethnopharmacologic Interest. Acta Chem. Scand. 1969, 23, 903– 916, DOI: 10.3891/acta.chem.scand.23-0903
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Alkaloids in certain species of Virola and other south American plants of ethnopharmacologic interest
Agurell, Stig; Holmstedt, Bo; Lindgren, Jan E.; Schultes, Richard E.
Acta Chemica Scandinavica (1947-1973) (1969), 23 (3), 903-16CODEN: ACSAA4; ISSN:0001-5393.
V. theiodora, a botanical source of intoxicating snuffs used by certain South American Indian tribes, contained the hallucinogen 5-methoxy-N,N-dimethyltryptamine (I) as well as a no. of other indoles. One indian snuff proved to be unusually high in alkaloid content (11%). Considerable differences in the alkaloid compn. of different parts of single plants were encountered, N,N-dimethyltryptamine being the major component in the leaves and I in the bark of Virola theiodora. Of other species of Virola investigated V. rufula contained substantial amts. of tryptamines, whereas V. multinervia and V. venosa were almost devoid of alkaloids. V. calophylla contained high amts. of alkaloids only in the leaves. Two new β-carbolines of a type carrying the substituents in the 6-position of the β-carboline nucleus were found in V. theiodora, V. rufula, and Anadenanthera (Pipatadenia) peregrina. By spectrometric and other data their structures have been shown to be 2-methyl-6-methoxy-1,2,3,4-tetrahydro-β-carboline and 1,2-dimethyl-6-methoxy-1,2,3,4-tetrahydro-β-carboline.
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Mckenna, D. J.; Towers, G. H. N.; Abbott, F. S. Monoamine Oxidase Inhibitors in South American Hallucinogenic Plants Part 2: Constituents of Orally-Active Myristicaceous hallucinogens. J. Ethnopharmacol. 1984, 12, 179– 211, DOI: 10.1016/0378-8741(84)90048-5
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Monoamine oxidase inhibitors in South American hallucinogenic plants. Part 2: constituents of orally-active Myristicaceous hallucinogens
McKenna, Dennis J.; Towers, G. H. N.; Abbott, F. S.
Journal of Ethnopharmacology (1984), 12 (2), 179-211CODEN: JOETD7; ISSN:0378-8741.
Alkaloid constituents in Myristicaceous bark and leaf samples and in purportedly hallucinogenic prepns. derived from Myristicaceous sources were qual. and quant. analyzed using TLC/gas chromatog. (GC), alkaloid pptn. tests and GC/MS. Fourteen of the 27 bark and leaf samples analyzed contained detectable amts. of alkaloids. The major bases were N,N-dimethyltryptamine [61-50-7] and/or 5-methoxy-N,N-dimethyltryptamine [1019-45-0]; much smaller amts. of tryptamine [61-54-1] and/or N-methyltryptamine [61-49-4] were also usually present. β-Carbolines were not detected in the bark or leaf samples. Considerable variation in alkaloid profiles was found, extending to different collections of the same species. Fourteen of the 20 Virola samples contained alkaloids; none of the 6 Iryanthera species had alkaloids. Osteophloem platyspermum Contained N-methyltryptophan Me ester [32164-04-8]. Seven samples of an orally-ingested drug made from Virola were analyzed. All except one contained substantial amts. of tryptamines; the types and proportions of tryptamines present varied greatly between samples. Samples of Yanomama snuff including various admixts. were analyzed and all components but one contained tryptamines. The drug samples having the highest concns. of alkaloids contained 15-20 mg/g dry wt. while the Myristicaceous bark and leaf samples had much lower concns. ranging from 0.04 to 0.25 mg/g dry wt. β-Carbolines were detected as trace constituents in only two of the Myristicaceous drug samples. Four Myristicaceous paste samples were bioassayed in self-expts. Two of the samples were devoid of hallucinogenic or physiol. activity, while some degree of oral activity was detected in two other samples. The activity of a no. of tryptamine derivs. as monoamine oxidase [9001-66-5] inhibitors (MAOI) was investigated using an in vitro enzyme assay. Activity was measured using single compds. and mixts. of compds. and the results were compared to the activity of samples of orally-ingested Myristicaceous pastes. Tryptamine derivs. had significantly less MAOI activity than the activity of β-carboline derivs. measured in a previous study (McKenna, D. J., et al., 1984). Some structural correlations for MAOI activity were found for the tryptamine derivs. Samples of orally-ingested Myristicaceous pastes were assayed for MAOI activity. The inhibition elicited by the paste samples was closely matched by mixts. of tryptamine stds. having comparable proportions and concns. These observations indicate that the MAOI activity of the pastes is due mainly to the high concns. of tryptamines; the traces of β-carbolines or non-N inhibitors present probably do not contribute significantly to the total inhibition. Thus, it appears unlikely that the oral activity of the Myristicaceous pastes is due to the potentiation of the tryptamines via inhibition of MAO by β-carbolines; some mechanism other than MAO inhibition must be sought to account for the oral hallucinogenic activity of the Myristicaceous pastes if they are, in fact, orally active.
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Schultes, R. E. Fifteen Years of Study of Psychoactive Snuffs of South America: 1967-1982- a Review. J. Ethnopharmacol. 1984, 11, 17– 32, DOI: 10.1016/0378-8741(84)90093-X
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Fifteen years of study of psychoactive snuffs of South America: 1967-1982--a review
Schultes R E
Journal of ethnopharmacology (1984), 11 (1), 17-32 ISSN:0378-8741.
Much has been learned concerning psychoactive snuffs in South America in the past 15 years since I delivered a review paper in the now famous symposium "Ethnopharmacologic Search for Psychoactive Drugs" held in San Francisco in 1967 (Efron et al., 1967; Schultes, 1967). There is still much to be investigated, but it seems that a recapitulation at this time may be warranted. The advances in our knowledge have come about as a result of field work as well as laboratory research and have been effected by investigators in several disciplines: archaeology, ethnobotany, ethnology and phytochemistry.
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Torres, C. M.; Repke, D. B. Anadenanthera: Visionary Plant of Ancient South America; Haworth Herbal Press: New York, 2014.
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Davis, A. K.; Barsuglia, J. P.; Lancelotta, R.; Grant, R. M.; Renn, E. The Epidemiology of 5-Methoxy-N, N-Dimethyltryptamine (5-MeO-DMT) Use: Benefits, Consequences, Patterns of Use, Subjective Effects, and Reasons for Consumption. J. Psychopharmacol. 2018, 32, 779– 792, DOI: 10.1177/0269881118769063
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The epidemiology of 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT) use: Benefits, consequences, patterns of use, subjective effects, and reasons for consumption
Davis, Alan K.; Barsuglia, Joseph P.; Lancelotta, Rafael; Grant, Robert M.; Renn, Elise
Journal of Psychopharmacology (London, United Kingdom) (2018), 32 (7), 779-792CODEN: JOPSEQ; ISSN:0269-8811. (Sage Publications Ltd.)
Background/aim:: 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a psychoactive compd. found in several plants and in high concns. in Bufo alvarius toad venom. Synthetic, toad, and plant-sourced 5-MeO-DMT are used for spiritual and recreational purposes and may have psychotherapeutic effects. However, the use of 5-MeO-DMT is not well understood. Therefore, we examd. patterns of use, motivations for consumption, subjective effects, and potential benefits and consequences assocd. with 5-MeO-DMT use. Methods:: Using internet-based advertisements, 515 respondents (Mage=35.4. SD=11.7; male=79%; White/Caucasian=86%; United States resident=42%) completed a web-based survey. Results:: Most respondents consumed 5-MeO-DMT infrequently (< once/yr), for spiritual exploration, and had used less than four times in their lifetime. The majority (av. of 90%) reported moderate-to-strong mystical-type experiences (Mintensity=3.64, SD=1.11; range 0-5; e.g., ineffability, timelessness, awe/amazement, experience of pure being/awareness), and relatively fewer (av. of 37%) experienced very slight challenging experiences (Mintensity=0.95, SD=0.91; range 0-5; e.g., anxiousness, fear). Less than half (39%) reported repeated consumption during the same session, and very few reported drug craving/desire (8%), or legal (1%), medical (1%), or psychiatric (1%) problems related to use. Furthermore, of those who reported being diagnosed with psychiatric disorders, the majority reported improvements in symptoms following 5-MeO-DMT use, including improvements related to post-traumatic stress disorder (79%), depression (77%), anxiety (69%), and alcoholism (66%) or drug use disorder (60%). Conclusion:: Findings suggest that 5-MeO-DMT is used infrequently, predominantly for spiritual exploration, has low potential for addiction, and might have psychotherapeutic effects. Future research should examine the safety and pharmacokinetics of 5-MeO-DMT administration in humans using rigorous exptl. designs.
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Uthaug, M. V.; Lancelotta, R.; van Oorsouw, K.; Kuypers, K. P. C.; Mason, N.; Rak, J.; Šuláková, A.; Jurok, R.; Maryška, M.; Kuchař, M.; Páleníček, T.; Riba, J.; Ramaekers, J. G. A Single Inhalation of Vapor from Dried Toad Secretion Containing 5-Methoxy-N,N-Dimethyltryptamine (5-MeO-DMT) in a Naturalistic Setting Is Related to Sustained Enhancement of Satisfaction with Life, Mindfulness-Related Capacities, and a Decrement of Psyc. Psychopharmacology 2019, 236, 2653– 2666, DOI: 10.1007/s00213-019-05236-w
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A single inhalation of vapor from dried toad secretion containing 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) in a naturalistic setting is related to sustained enhancement of satisfaction with life, mindfulness-related capacities, and a decrement of psychopathological symptoms
Uthaug, M. V.; Lancelotta, R.; van Oorsouw, K.; Kuypers, K. P. C.; Mason, N.; Rak, J.; Sulakova, A.; Jurok, R.; Maryska, M.; Kuchar, M.; Palenicek, T.; Riba, J.; Ramaekers, J. G.
Psychopharmacology (Heidelberg, Germany) (2019), 236 (9), 2653-2666CODEN: PSCHDL; ISSN:0033-3158. (Springer)
Background: 5-methoxy-N,N-dimethyltryptamine (hereinafter referred to as 5-MeO-DMT) is a psychedelic substance found in the secretion from the parotoid glands of the Bufo alvarius toad. Aims: The first objective of this study was to assess sub-acute and long-term effects of inhaling vapor from dried toad secretion contg. 5-MeO-DMT on affect and cognition. The second objective was to assess whether any changes were assocd. with the psychedelic experience. Methods: Assessments at baseline, within 24 h and 4 wk following intake, were made in 42 individuals who inhaled vapor from dried toad secretion at several European locations. Results: Relative to baseline, ratings of satisfaction with life and convergent thinking significantly increased right after intake and were maintained at follow-up 4 wk later. Ratings of mindfulness also increased over time and reached statistical significance at 4 wk. Ratings of depression, anxiety, and stress decreased after the session, and reached significance at 4 wk. Participants that experienced high levels of ego dissoln. or oceanic boundlessness during the session displayed higher ratings of satisfaction with life and lower ratings of depression and stress. Conclusion: A single inhalation of vapor from dried toad secretion contg. 5-MeO-DMT produces sub-acute and long-term changes in affect and cognition in volunteers. These results warrant exploratory research into therapeutic applications of 5-MeO-DMT.
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Metzner, R. The Toad and the Jaguar: A Field Report of Underground Research on a Visionary Medicine: Bufo alvarius and 5-Methoxy-Dimethyltryptamine, 1st ed.; Regent Press: Berkeley, CA, 2013.
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Uthaug, M. V.; Lancelotta, R.; Ortiz Bernal, A. M.; Davis, A. K.; Ramaekers, J. G. A Comparison of Reactivation Experiences Following Vaporization and Intramuscular Injection (IM) of Synthetic 5-Methoxy-N,N-Dimethyltryptamine (5-MeO-DMT) in a Naturalistic Setting. J. Psychedelic Stud. 2020, 4, 104– 113, DOI: 10.1556/2054.2020.00123
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Sepeda, N. D.; Clifton, J. M.; Doyle, L. Y.; Lancelotta, R.; Griffiths, R. R.; Davis, A. K. Inhaled 5-Methoxy-N,N-Dimethyltryptamine: Supportive Context Associated with Positive Acute and Enduring Effects. J. Psychedelic Stud. 2019, 4, 114– 122, DOI: 10.1556/2054.2019.033
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Lancelotta, R. L.; Davis, A. K. Use of Benefit Enhancement Strategies among 5-Methoxy-N,N-Dimethyltryptamine (5-MeO-DMT) Users: Associations with Mystical, Challenging, and Enduring Effects. J. Psychoact. Drugs 2020, 52, 273– 281, DOI: 10.1080/02791072.2020.1737763
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Use of Benefit Enhancement Strategies among 5-Methoxy-N,N-Dimethyltryptamine (5-MeO-DMT) Users: Associations with Mystical, Challenging, and Enduring Effects
Lancelotta Rafael L; Lancelotta Rafael L; Davis Alan K; Davis Alan K
Journal of psychoactive drugs (2020), 52 (3), 273-281 ISSN:.
5-Methoxy-N,N-Dimethyltryptamine (5-MeO-DMT) is a potent, fast-acting psychedelic. Anecdotal reports from 5-MeO-DMT users suggest that they employ a variety of benefit enhancement (BE) strategies aimed to increase positive effects and decrease any potential challenging effects of the substance, but no empirical study has investigated this claim. We examined the prevalence of BE strategy use using secondary data from a survey of 5-MeO-DMT users (n = 515; Mage = 35.4, SD = 11.7; Male = 79%; White/Caucasian = 86%). Results indicated that BE strategy use was common in this sample. As a secondary aim, we assessed whether the use of BE strategies was associated with acute subjective (i.e., mystical-type, challenging) and persisting effects of 5-MeO-DMT among a subset of respondents who reported using 5-MeO-DMT once in their lifetime (n = 116). Results showed that the use of several BE strategies were associated with significantly more intense mystical-type effects and enduring beliefs about the personal meaning and spiritual significance of their experience, and some BE strategies were associated with less intense or challenging experiences. Data suggests that BE strategies are commonly used, and that the use of BE strategies may be associated with increases in positive mystical-type and enduring effects. The causal influence of BE strategies on acute/persisting effects of 5-MeO-DMT should be examined in longitudinal research.
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Nichols, D. E. Psychedelics. Pharmacol. Rev. 2016, 68, 264– 355, DOI: 10.1124/pr.115.011478
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Psychedelics
Nichols, David E.
Pharmacological Reviews (2016), 68 (2), 264-355CODEN: PAREAQ; ISSN:1521-0081. (American Society for Pharmacology and Experimental Therapeutics)
Psychedelics (serotonergic hallucinogens) are powerful psychoactive substances that alter perception and mood and affect numerous cognitive processes. They are generally considered physiol. safe and do not lead to dependence or addiction. Their origin predates written history, and they were employed by early cultures in many sociocultural and ritual contexts. After the virtually contemporaneous discovery of (5R,8R)-(+)-lysergic acid-N,N-diethylamide (LSD)-25 and the identification of serotonin in the brain, early research focused intensively on the possibility that LSD and other psychedelics had a serotonergic basis for their action. Today there is a consensus that psychedelics are agonists or partial agonists at brain serotonin 5-hydroxytryptamine 2A receptors, with particular importance on those expressed on apical dendrites of neocortical pyramidal cells in layer V. Several useful rodent models have been developed over the years to help unravel the neurochem. correlates of serotonin 5-hydroxytryptamine 2A receptor activation in the brain, and a variety of imaging techniques have been employed to identify key brain areas that are directly affected by psychedelics. Recent and exciting developments in the field have occurred in clin. research, where several double-blind placebo-controlled phase 2 studies of psilocybin-assisted psychotherapy in patients with cancer-related psychosocial distress have demonstrated unprecedented pos. relief of anxiety and depression. Two small pilot studies of psilocybin-assisted psychotherapy also have shown pos. benefit in treating both alc. and nicotine addiction. Recently, blood oxygen level-dependent functional magnetic resonance imaging and magnetoencephalog. have been employed for in vivo brain imaging in humans after administration of a psychedelic, and results indicate that i.v. administered psilocybin and LSD produce decreases in oscillatory power in areas of the brain's default mode network.
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Nichols, D. E. Hallucinogens. Pharmacol. Ther. 2004, 101, 131– 181, DOI: 10.1016/j.pharmthera.2003.11.002
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Hallucinogens
Nichols, David E.
Pharmacology & Therapeutics (2004), 101 (2), 131-181CODEN: PHTHDT; ISSN:0163-7258. (Elsevier Science B.V.)
A review. Hallucinogens (psychedelics) are psychoactive substances that powerfully alter perception, mood, and a host of cognitive processes. They are considered physiol. safe and do not produce dependence or addiction. Their origin predates written history, and they were employed by early cultures in a variety of sociocultural and ritual contexts. In the 1950s, after the virtually contemporaneous discovery of both serotonin (5-HT) and lysergic acid diethylamide (LSD-25), early brain research focused intensely on the possibility that LSD or other hallucinogens had a serotonergic basis of action and reinforced the idea that 5-HT was an important neurotransmitter in brain. These ideas were eventually proven, and today it is believed that hallucinogens stimulate 5-HT2A receptors, esp. those expressed on neocortical pyramidal cells. Activation of 5-HT2A receptors also leads to increased cortical glutamate levels presumably by a presynaptic receptor-mediated release from thalamic afferents. These findings have led to comparisons of the effects of classical hallucinogens with certain aspects of acute psychosis and to a focus on thalamocortical interactions as key to understanding both the action of these substances and the neuroanatomical sites involved in altered states of consciousness (ASC). In vivo brain imaging in humans using [18F]fluorodeoxyglucose has shown that hallucinogens increase prefrontal cortical metab., and correlations have been developed between activity in specific brain areas and psychol. elements of the ASC produced by hallucinogens. The 5-HT2A receptor clearly plays an essential role in cognitive processing, including working memory, and ligands for this receptor may be extremely useful tools for future cognitive neuroscience research. In addn., it appears entirely possible that utility may still emerge for the use of hallucinogens in treating alcoholism, substance abuse, and certain psychiatric disorders.
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Halberstadt, A. L.; Geyer, M. A. Multiple Receptors Contribute to the Behavioral Effects of Indoleamine Hallucinogens. Neuropharmacology 2011, 61, 364– 381, DOI: 10.1016/j.neuropharm.2011.01.017
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Multiple receptors contribute to the behavioral effects of indoleamine hallucinogens
Halberstadt, Adam L.; Geyer, Mark A.
Neuropharmacology (2011), 61 (3), 364-381CODEN: NEPHBW; ISSN:0028-3908. (Elsevier B.V.)
A review. Serotonergic hallucinogens produce profound changes in perception, mood, and cognition. These drugs include phenylalkylamines such as mescaline and 2,5-dimethoxy-4-methylamphetamine (DOM), and indoleamines such as (+)-lysergic acid diethylamide (LSD) and psilocybin. Despite their differences in chem. structure, the two classes of hallucinogens produce remarkably similar subjective effects in humans, and induce cross-tolerance. The phenylalkylamine hallucinogens are selective 5-HT2 receptor agonists, whereas the indoleamines are relatively non-selective for serotonin (5-HT) receptors. There is extensive evidence, from both animal and human studies, that the characteristic effects of hallucinogens are mediated by interactions with the 5-HT2A receptor. Nevertheless, there is also evidence that interactions with other receptor sites contribute to the psychopharmacol. and behavioral effects of the indoleamine hallucinogens. This article reviews the evidence demonstrating that the effects of indoleamine hallucinogens in a variety of animal behavioral paradigms are mediated by both 5-HT2 and non-5-HT2 receptors.
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Halberstadt, A. L.; Nichols, D. E.; Geyer, M. A. Behavioral Effects of α,α,β,β-Tetradeutero-5-MeO-DMT in Rats: Comparison with 5-MeO-DMT Administered in Combination with a Monoamine Oxidase Inhibitor. Psychopharmacology 2012, 221, 709– 718, DOI: 10.1007/s00213-011-2616-6
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Behavioral effects of α,α,β,β-tetradeutero-5-MeO-DMT in rats: comparison with 5-MeO-DMT administered in combination with a monoamine oxidase inhibitor
Halberstadt, Adam L.; Nichols, David E.; Geyer, Mark A.
Psychopharmacology (Heidelberg, Germany) (2012), 221 (4), 709-718CODEN: PSCHDL; ISSN:0033-3158. (Springer)
Ayahuasca is a psychoactive tea prepd. from a combination of plants that contain a hallucinogenic tryptamine and monoamine oxidase inhibitors (MAOIs). Behavioral pattern monitor (BPM) expts. demonstrated that the combination of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and a behaviorally inactive dose of an MAOA inhibitor such as harmaline or clorgyline induces biphasic effects on locomotor activity in rats, initially reducing locomotion and then increasing activity as time progresses. The present study investigated whether the biphasic locomotor profile induced by the combination of 5-MeO-DMT and an MAOI is a consequence of a redn. in the rate of 5-MeO-DMT metab. This hypothesis was tested using a deuterated deriv. of 5-MeO-DMT (α,α,β,β-tetradeutero-5-MeO-DMT) that is resistant to metab. by MAO. Confirming our previous findings, 1.0 mg/kg 5-MeO-DMT (s.c.) had biphasic effects on locomotor activity in rats pretreated with a behaviorally inactive dose of the nonselective MAOI pargyline (10 mg/kg). Administration of 5-MeO-DMT alone, even at doses > 1.0 mg/kg, produced only redns. in locomotor activity. Although low doses of α,α,β,β-tetradeutero-5-MeO-DMT (0.3 and 1.0 mg/kg, s.c.) produced only hypoactivity in the BPM, a dose of 3.0 mg/kg induced a biphasic locomotor profile similar to that produced by the combination of 5-MeO-DMT and an MAOI. Receptor binding studies demonstrated that deuterium substitution had little effect on the affinity of 5-MeO-DMT for a wide variety of neurotransmitter binding sites. The finding with α,α,β,β-tetradeutero-5-MeO-DMT indicates that the hyperactivity induced by 5-MeO-DMT after MAO inhibition is a consequence of reduced metab. of 5-MeO-DMT, leading to prolonged occupation of central serotonin receptors. These results demonstrate that deuterated tryptamines may be useful in behavioral and pharmacol. studies to mimic the effects of tryptamine/MAOI combinations.
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Krebs-Thomson, K.; Ruiz, E. M.; Masten, V.; Buell, M.; Geyer, M. A. The Roles of 5-HT1A and 5-HT2 Receptors in the Effects of 5-MeO-DMT on Locomotor Activity and Prepulse Inhibition in Rats. Psychopharmacology 2006, 189, 319– 329, DOI: 10.1007/s00213-006-0566-1
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The roles of 5-HT1A and 5-HT2 receptors in the effects of 5-MeO-DMT on locomotor activity and prepulse inhibition in rats
Krebs-Thomson, Kirsten; Ruiz, Erbert M.; Masten, Virginia; Buell, Mahalah; Geyer, Mark A.
Psychopharmacology (Berlin, Germany) (2006), 189 (3), 319-329CODEN: PSCHDL; ISSN:0033-3158. (Springer GmbH)
The hallucinogen 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is structurally similar to other indoleamine hallucinogens such as LSD. The present study examd. the effects of 5-MeO-DMT in rats using the Behavioral Pattern Monitor (BPM), which enables analyses of patterns of locomotor activity and exploration, and the prepulse inhibition of startle (PPI) paradigm. A series of interaction studies using the serotonin (5-HT)1A antagonist WAY-100635 (1.0 mg/kg), the 5-HT2A antagonist M100907 (1.0 mg/kg), and the 5-HT2C antagonist SER-082 (0.5 mg/kg) were performed to assess the resp. contributions of these receptors to the behavioral effects of 5-MeO-DMT (0.01, 0.1, and 1.0 mg/kg) in the BPM and PPI paradigms. 5-MeO-DMT decreased locomotor activity, investigatory behavior, the time spent in the center of the BPM chamber, and disrupted PPI. All of these effects were antagonized by WAY-100635 pretreatment. M100907 pretreatment failed to attenuate any of these effects, while SER-082 pretreatment only antagonized the PPI disruption produced by 5-MeO-DMT. While the prevailing view was that the activation of 5-HT2 receptors is solely responsible for hallucinogenic drug effects, these results support a role for 5-HT1A receptors in the effects of the indoleamine hallucinogen 5-MeO-DMT on locomotor activity and PPI in rats.
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Krebs-Thomson, K.; Geyer, M. A. Evidence for a Functional Interaction between 5-HT(1A) and 5-HT2 Receptors in Rats. Psychopharmacology 1998, 140, 69– 74, DOI: 10.1007/s002130050740
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Evidence for a functional interaction between 5-HT1a and 5-HT2 receptors in rats
Krebs-Thomson, Kirsten; Geyer, Mark A.
Psychopharmacology (Berlin) (1998), 140 (1), 69-74CODEN: PSCHDL; ISSN:0033-3158. (Springer-Verlag)
Evidence of a functional interaction between serotonin 5-HT1A and 5-HT2 receptor subtypes has been compromised by incomplete exptl. designs and conflicting data. To test for such an interaction, combinations of the 5-HT1A agonist 8-OH-DPAT and the 5-HT2 agonist DOI were administered to rats prior to testing of locomotor activity in the Behavioral Pattern Monitor (BPM). The BPM is an activity and holeboard chamber that enables analyses of quant. and qual. changes in locomotor and investigatory activity. Dose-response studies of 8-OH-DPAT and DOI alone and in the presence of selected doses of the other drug were performed in order to allow isobolog. anal., which characterizes the relationship of two drugs as either additive (no interaction), supra-additive, or infra-additive. Rats treated with saline, 8-OH-DPAT (6.25, 12.5, 25, or 50 μg/kg SC), DOI (0.15, 0.3, or 0.6 mg/kg SC), or selected combinations of both drugs were tested in the BPM for 1 h. Isobolog. anal. of the effects on locomotor activity revealed that 8-OH-DPAT and DOI interact in an infra-additive manner. Thus, at a functional level, 5-HT1A and 5-HT2 receptors interact antagonistically in the modulation of locomotor activity.
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Krebs, K. M.; Geyer, M. A. Cross-Tolerance Studies of Serotonin Receptors Involved in Behavioral Effects of LSD in Rats. Psychopharmacology 1994, 113, 429– 437, DOI: 10.1007/BF02245219
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Cross-tolerance studies of serotonin receptors involved in behavioral effects of LSD in rats
Krebs, Kirsten M.; Geyer, Mark A.
Psychopharmacology (Berlin, Germany) (1994), 113 (3-4), 429-37CODEN: PSCHDL; ISSN:0033-3158.
Like hallucinogenic 5-HT2 agonists, LSD (d-lysergic acid diethylamide) produces characteristic decreases in locomotor activity and investigatory behaviors of rats tested in a novel environment. Because LSD is an agonist at both 5-HT1A and 5-HT2 receptors, however, the resp. influences of these different receptors in the behavioral effects of LSD remain unclear. In particular, the paucity of selective 5-HT1A antagonists has made it difficult to assess the specific contribution of 5-HT1A receptors to the effects of LSD. An alternative approach to the delineation of receptor-specific effects is the use of cross-tolerance regimens. In the present studies, rats were pretreated with saline, 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT) (0.5 mg/kg SC), 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (1.0 mg/kg SC), or LSD (60 μg/kg SC), every 12 h for 5 or 8 days. Thirty-six hours later, rats were tested in a behavioral pattern monitor 10 min after injection of saline, 0.5 mg/kg 8-OH-DPAT, 1.0 mg/kg DOI, or 60 μg/kg LSD. As expected, tolerance to the decreases in locomotor activity produced by acute administrations of 8-OH-DPAT, DOI, or LSD occurred when rats were pretreated chronically with 8-OH-DPAT, DOI, or LSD resp. Furthermore, pretreatment with either 8-OH-DPAT or DOI produced cross-tolerance to LSD. These results support the hypothesis that the effects of LSD in this model reflect a combination of 5-HT1A and 5-HT2 effects and support the view that there is an interaction between 5-HT1A and 5-HT2 receptors.
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Data from the NIMH Psychoactive Drug Screening Program.
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Pokorny, T.; Preller, K. H.; Kraehenmann, R.; Vollenweider, F. X. Modulatory Effect of the 5-HT1A Agonist Buspirone and the Mixed Non-Hallucinogenic 5-HT1A/2A Agonist Ergotamine on Psilocybin-Induced Psychedelic Experience. Eur. Neuropsychopharmacol. 2016, 26, 756– 766, DOI: 10.1016/j.euroneuro.2016.01.005
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Modulatory effect of the 5-HT1A agonist buspirone and the mixed non-hallucinogenic 5-HT1A/2A agonist ergotamine on psilocybin-induced psychedelic experience
Pokorny, Thomas; Preller, Katrin H.; Kraehenmann, Rainer; Vollenweider, Franz X.
European Neuropsychopharmacology (2016), 26 (4), 756-766CODEN: EURNE8; ISSN:0924-977X. (Elsevier B.V.)
The mixed serotonin (5-HT) 1A/2A/2B/2C/6/7 receptor agonist psilocybin dose-dependently induces an altered state of consciousness (ASC) that is characterized by changes in sensory perception, mood, thought, and the sense of self. The psychol. effects of psilocybin are primarily mediated by 5-HT2A receptor activation. However, accumulating evidence suggests that 5-HT1A or an interaction between 5-HT1A and 5-HT2A receptors may contribute to the overall effects of psilocybin. Therefore, we used a double-blind, counterbalanced, within-subject design to investigate the modulatory effects of the partial 5-HT1A agonist buspirone (20 mg p.o.) and the non-hallucinogenic 5-HT2A/1A agonist ergotamine (3 mg p.o.) on psilocybin-induced (170 μg/kg p.o.) psychol. effects in two groups (n=19, n=17) of healthy human subjects. Psychol. effects were assessed using the Altered State of Consciousness (5D-ASC) rating scale. Buspirone significantly reduced the 5D-ASC main scale score for Visionary Restructuralization (VR) (p<0.001), which was mostly driven by a redn. of the VR item cluster scores for elementary and complex visual hallucinations. Further, buspirone also reduced the main scale score for Oceanic Boundlessness (OB) including derealization and depersonalization phenomena at a trend level (p=0.062), whereas ergotamine did not show any effects on the psilocybin-induced 5D-ASC main scale scores. The present finding demonstrates that buspirone exerts inhibitory effects on psilocybin-induced effects, presumably via 5-HT1A receptor activation, an interaction between 5-HT1A and 5-HT2A receptors, or both. The data suggest that the modulation of 5-HT1A receptor activity may be a useful target in the treatment of visual hallucinations in different psychiatric and neurol. diseases.
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Shulgin, A.; Shulgin, A. TIHKAL: The Continuation; Transform Press: Berkeley, CA, 1997.
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Ly, C.; Greb, A. C.; Cameron, L. P.; Wong, J. M.; Barragan, E. V.; Wilson, P. C.; Burbach, K. F.; Soltanzadeh Zarandi, S.; Sood, A.; Paddy, M. R.; Duim, W. C.; Dennis, M. Y.; McAllister, A. K.; Ori-McKenney, K. M.; Gray, J. A.; Olson, D. E. Psychedelics Promote Structural and Functional Neural Plasticity. Cell Rep. 2018, 23, 3170– 3182, DOI: 10.1016/j.celrep.2018.05.022
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Psychedelics Promote Structural and Functional Neural Plasticity
Ly, Calvin; Greb, Alexandra C.; Cameron, Lindsay P.; Wong, Jonathan M.; Barragan, Eden V.; Wilson, Paige C.; Burbach, Kyle F.; Soltanzadeh Zarandi, Sina; Sood, Alexander; Paddy, Michael R.; Duim, Whitney C.; Dennis, Megan Y.; McAllister, A. Kimberley; Ori-McKenney, Kassandra M.; Gray, John A.; Olson, David E.
Cell Reports (2018), 23 (11), 3170-3182CODEN: CREED8; ISSN:2211-1247. (Cell Press)
Atrophy of neurons in the prefrontal cortex (PFC) plays a key role in the pathophysiol. of depression and related disorders. The ability to promote both structural and functional plasticity in the PFC has been hypothesized to underlie the fast-acting antidepressant properties of the dissociative anesthetic ketamine. Here, we report that, like ketamine, serotonergic psychedelics are capable of robustly increasing neuritogenesis and/or spinogenesis both in vitro and in vivo. These changes in neuronal structure are accompanied by increased synapse no. and function, as measured by fluorescence microscopy and electrophysiol. The structural changes induced by psychedelics appear to result from stimulation of the TrkB, mTOR, and 5-HT2A signaling pathways and could possibly explain the clin. effectiveness of these compds. Our results underscore the therapeutic potential of psychedelics and, importantly, identify several lead scaffolds for medicinal chem. efforts focused on developing plasticity-promoting compds. as safe, effective, and fast-acting treatments for depression and related disorders.
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Nutt, D.; Erritzoe, D.; Carhart-Harris, R. Psychedelic Psychiatry’s Brave New World. Cell 2020, 181, 24– 28, DOI: 10.1016/j.cell.2020.03.020
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Psychedelic Psychiatry's Brave New World
Nutt, David; Erritzoe, David; Carhart-Harris, Robin
Cell (Cambridge, MA, United States) (2020), 181 (1), 24-28CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
A review. After a legally mandated, decades-long global arrest of research on psychedelic drugs, investigation of psychedelics in the context of psychiatric disorders is yielding exciting results. Outcomes of neuroscience and clin. research into 5-Hydroxytryptamine 2A (5-HT2A) receptor agonists, such as psilocybin, show promise for addressing a range of serious disorders, including depression and addiction.
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Davis, A. K.; Barrett, F. S.; May, D. G.; Cosimano, M. P.; Sepeda, N. D.; Johnson, M. W.; Finan, P. H.; Griffiths, R. R. Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder A Randomized Clinical Trial. JAMA Psychiatry 2020, DOI: 10.1001/jamapsychiatry.2020.3285
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Gupta, D.; Bhatia, D.; Dave, V.; Sutariya, V.; Gupta, S. V. Salts of Therapeutic Agents: Chemical, Physicochemical, and Biological Considerations. Molecules 2018, 23, 1719 DOI: 10.3390/molecules23071719
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Salts of therapeutic agents: chemical, physicochemical, and biological considerations
Gupta, Deepak; Bhatia, Deepak; Dave, Vivek; Sutariya, Vijaykumar; Gupta, Sheeba Varghese
Molecules (2018), 23 (7), 1719/1-1719/15CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)
The physicochem. and biol. properties of active pharmaceutical ingredients (APIs) are greatly affected by their salt forms. The choice of a particular salt formulation is based on numerous factors such as API chem., intended dosage form, pharmacokinetics, and pharmacodynamics. The appropriate salt can improve the overall therapeutic and pharmaceutical effects of an API. However, the incorrect salt form can have the opposite effect, and can be quite detrimental for overall drug development. This review summarizes several criteria for choosing the appropriate salt forms, along with the effects of salt forms on the pharmaceutical properties of APIs. In addn. to a comprehensive review of the selection criteria, this review also gives a brief historic perspective of the salt selection processes.
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Chadeayne, A. R.; Golen, J. A.; Manke, D. R. Bis(4-Acetoxy- N, N -Dimethyltryptammonium) Fumarate: A New Crystalline Form of Psilacetin, an Alternative to Psilocybin as a Psilocin Prodrug. Acta Crystallogr., Sect. E 2019, 75, 900– 902, DOI: 10.1107/S2056989019007370
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Bis(4-acetoxy-N,N-dimethyltryptammonium) fumarate: a new crystalline form of psilacetin, an alternative to psilocybin as a psilocin prodrug
Chadeayne, Andrew R.; Golen, James A.; Manke, David R.
Acta Crystallographica, Section E: Crystallographic Communications (2019), 75 (6), 900-902CODEN: ACSECI; ISSN:2056-9890. (International Union of Crystallography)
The title compd. (systematic name: bis{2-[4-(acetyloxy)-1H-indol-3-yl]ethan-1-aminium} but-2-enedioate), 2C14H19N2O2+·C4H2O42-, has a single protonated psilacetin cation and one half of a fumarate dianion in the asym. unit. There are N-H···O hydrogen bonds between the ammonium H atoms and the fumarate O atoms, as well as N-H···O hydrogen bonds between the indole H atoms and the fumarate O atoms. The hydrogen bonds hold the ions together in infinite one-dimensional chains along [111].
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Strassman, R. J.; Qualls, C. R.; Berg, L. M. Differential Tolerance to Biological and Subjective Effects of Four Closely Spaced Doses of N,N-Dimethyltryptamine in Humans. Biol. Psychiatry 1996, 39, 784– 795, DOI: 10.1016/0006-3223(95)00200-6
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Differential tolerance to biological and subjective effects of four closely spaced doses of N,N-dimethyltryptamine in humans
Strassman, Rick J.; Qualls, Clifford R.; Berg, Laura M.
Biological Psychiatry (1996), 39 (9), 784-795CODEN: BIPCBF; ISSN:0006-3223. (Elsevier)
Tolerance to the behavioral effects of the short-acting, endogenous hallucinogen, N,N-dimethyltryptamine (DMT) is seen inconsistently in animals, and has not been produced in humans. The nature and time course of responses to repetitive, closely spaced administrations of an hallucinogenic dose of DMT were characterized. Thirteen experienced hallucinogen users received i.v. 0.3 mg/kg DMT fumarate, or saline placebo, four times, at 30 min intervals, on 2 sep. days, in a randomized, double-blind, design. Tolerance to "psychedelic" subjective effects did not occur according to either clin. interview or Hallucinogen Rating Scale scores. Adrenocorticotropic hormone (ACTH), prolactin, cortisol, and heart rate responses decreased with repeated DMT administration, although blood pressure did not. These data demonstrate the unique properties of DMT relative to other hallucinogens and underscore the differential regulation of the multiple processes mediating the effects of DMT.
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Ludvigsson, J. W.; Wikström, H.; Andersson, T.; Norrby, P. O. Degradation Caused by Incompatibility between Sodium Stearyl Fumarate (PRUV) and AZD7986 in the Drug Product. J. Pharm. Biomed. Anal. 2018, 158, 82– 87, DOI: 10.1016/j.jpba.2018.05.036
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Degradation caused by incompatibility between sodium stearyl fumarate (PRUV) and AZD7986 in the drug product
Ludvigsson, Jufang Wu; Wikstroem, Haakan; Andersson, Thomas; Norrby, Per-Ola
Journal of Pharmaceutical and Biomedical Analysis (2018), 158 (), 82-87CODEN: JPBADA; ISSN:0731-7085. (Elsevier B.V.)
During compatibility study of the AZD7986 project, a peak of 3 area% at the tail (RRT 1.03) of the active pharmaceutical ingredient (API) was discovered for all tablets contg. sodium stearyl fumarate (PRUV) under humid condition (e.g. 50 °C/75% RH), regardless of choice of disintegrant or filler combination. The degradant was needed to be identified to understand the corresponding reaction mechanism and help the final formulation design. Structure elucidation was therefore done by anal. using high resoln. mass spectrometry. The degradant was found to be a Michael addn. product of the API and fumaric acid. Reaction between deuterated fumaric acid and the API was carried to confirm the proposed structure and reaction mechanism. Fumaric acid was a degradant product of PRUV in the presence of other excipients, revealed by the stability study. The Michael addn. reaction needs facilitation by water and basic conditions. The result from this study should serve as a precaution note for projects using PRUV as one of excipients where the API could act as a nucleophile. In such cases the microenvironment should be optimized to minimize the reaction, such as pH adjustment and incorporating protection from moisture.
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Do, J.; Kang, J.; Lee, Y.; Ok, K. M.; Jacobson, A. J. Copper(II) Complexes with N-Substituted Aspartic Acids: A New One-Pot Synthesis Method via in Situ Michael Addition of Amines to Fumaric Acid. Inorg. Chim. Acta 2015, 430, 280– 287, DOI: 10.1016/j.ica.2015.03.020
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Copper(II) complexes with N-substituted aspartic acids: A new one-pot synthesis method via in situ Michael addition of amines to fumaric acid
Do, Junghwan; Kang, Jaeun; Lee, Yumi; Ok, Kang Min; Jacobson, Allan J.
Inorganica Chimica Acta (2015), 430 (), 280-287CODEN: ICHAA3; ISSN:0020-1693. (Elsevier B.V.)
The hydrothermal reaction of fumaric acid, benzylamine and cuprous chloride yielded Cu[(rac-N-benzyl-Asp)(benzylamine)(H2O)] (1), while ethylenediamine, 1,3-diaminopropane and piperazine produced Cu[rac-N-aminoethyl-Asp] (2), Cu[rac-N-aminopropyl-Asp] (3) and Cu[rac-piperazinyl succinate]2 (4), resp. Under mild hydrothermal conditions, Michael addn. of benzylamine, ethylenediamine, 1,3-diaminopropane and piperazine to fumaric acid gave racemic mixts. of N-benzyl aspartic acid, N-aminoethyl aspartic acid, N-aminopropyl aspartic acid and piperazinyl succinic acid, resp. The structure of 1 consists of 1-dimensional polymeric chains in which copper cations are bridged by D- and L-N-benzyl aspartate anions alternatively along the chain. Addnl. benzylamine and water mols. bond to copper cations to complete the Cu[(rac-N-benzyl-Asp)(benzylamine)(H2O)] chain. The structures of 2 and 3 consist of 1-dimensional polymeric chains in which copper cations are bridged by D- and L-N-aminoethyl and aminopropyl aspartate anions alternatively along the chains. The structure of 4 is composed of discrete Cu[rac-piperazinyl succinate]2 units that are connected by hydrogen bonds.
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Brandt, S. D.; Moore, S. A.; Freeman, S.; Kanu, A. B. Characterization of the Synthesis of N,N-Dimethyltryptamine by Reductive Amination Using Gas Chromatography Ion Trap Mass Spectrometry. Drug Test. Anal. 2010, 2, 330– 338, DOI: 10.1002/dta.142
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Characterization of the synthesis of N,N-dimethyltryptamine by reductive amination using gas chromatography ion trap mass spectrometry
Brandt, Simon D.; Moore, Sharon A.; Freeman, Sally; Kanu, Abu B.
Drug Testing and Analysis (2010), 2 (7), 330-338CODEN: DTARBG; ISSN:1942-7603. (John Wiley & Sons Ltd.)
The present study established an impurity profile of a synthetic route to the hallucinogenic N,N-dimethyltryptamine (DMT). The synthesis was carried out under reductive amination conditions between tryptamine and aq. formaldehyde in the presence of acetic acid followed by redn. with sodium cyanoborohydride. Anal. characterization of this synthetic route was carried out by gas chromatog. ion trap mass spectrometry using electron- and chem.-ionization modes. Methanol was employed as a liq. Cl reagent and the impact of stoichiometric modifications on side-products formation was also investigated. Tryptamine 1, DMT 2, 2-methyltetrahydro-β-carboline (2-Me-THBC, 3), N-methyl-N-cyanomethyltryptamine (MCMT, 4), N-methyltryptamine (NMT, 5), 2-cyanomethyl-tetrahydro-β-carboline (2-CM-THBC, 6) and tetrahydro-β-carboline (THBC, 7) have been detected under a variety of conditions. Replacement of formaldehyde soln. with paraformaldehyde resulted in incomplete conversion of the starting material whereas a similar replacement of sodium cyanoborohydride with sodium borohydride almost exclusively produced THBC instead of the expected DMT. Compds. 1 to 7 were quantified and the limits of detection were 28.4, 87.7, 21.5, 23.4, 41.1, 36.6, and 34.9 ng mL-1, resp. The limits of quantification for compds. 1 to 7 were 32.4, 88.3, 25.4, 24.6, 41.4, 39.9, and 37.0 μg mL-1, resp. Linearity was obsd. in the range of 20.8-980 μg mL-1 with correlation coeffs. >0.99. The application holds great promise in the area of forensic chem. where development of reliable anal. methods for the detection, identification, and quantification of DMT are crucial and also in pharmaceutical anal. where DMT might be prepd. for use in human clin. studies.
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Speeter, M. E.; Anthony, W. C. The Action of Oxalyl Chloride on Indoles: A New Approach to Tryptamines. J. Am. Chem. Soc. 1954, 76, 6208– 6210, DOI: 10.1021/ja01652a113
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The action of oxalyl chloride on indoles: a new approach to tryptamines
Speeter, Merrill E.; Anthony, Wm. C.
Journal of the American Chemical Society (1954), 76 (), 6208-10CODEN: JACSAT; ISSN:0002-7863.
cf. C.A. 46, 9544i. To obtain bufotenine and its relatives in quantity for study of their central nervous system effects, a new tryptamine synthesis was developed which is of wide scope and general application. The reaction of (COCl)2 (I) with indole yields 3-indoleglyoxylyl chloride (II) instead of the 2-isomer as reported by Giua (C.A. 19, 280). II with NH3 yielded the amide, which with LiAlH4 gave tryptamine. LiAlH4 and Et 3-indoleglyoxalate (III) yielded tryptophol. Indolemagnesium iodide and EtO2CCOCl yielded III, m. 183-5°. I with indoles can be used to prep. a variety of cryst. glyoxylyl chloride derivs., e.g., from 2-methylindole, 2-phenylindole, 5,6-dimethoxyindole, 5-acetoxyindole, 5-benzyloxyindole, 6-acetoxy-7-methoxyindole, and 1-benz(g)indole. LiAlH4 and the amides from the preceding glyoxylyl chlorides gave tryptamines in good yield. Crude 5-benzyloxy-3-indoleglyoxylyl chloride (IIIA), m. 146-50° (decompn.), and (PhCH2)2NH yielded 91% 5-benzyloxy-3-indole-N,N-dibenzylglyoxylamide (IV), m. 150-1°. IV with LiAlH4 yielded 92% 5-benzyloxy-3-(2-dibenzylaminoethyl)indole (V); HCl salt, m. 232-3°. V was catalytically debenzylated to serotonin. The creatinine sulfate complex prepd. from this serotonin was identical with that prepd. from serotonin previously. IIIA with Me2NH yielded 5-benzyloxy-N,N-dimethyl-3-indoleglyoxylamide (VI), m. 178-80.5°. VI with LiAlH4 gave 5-benzyloxy-3-(2-dimethylaminoethyl)indole (VII); HCl salt, m. 154-5°. Debenzylation of VII gave bufotenine, m. 146-7°; picrate identical with the natural picrate.
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Kargbo, R. B.; Sherwood, A.; Walker, A.; Cozzi, N. V.; Dagger, R. E.; Sable, J.; O’Hern, K.; Kaylo, K.; Patterson, T.; Tarpley, G.; Meisenheimer, P. Direct Phosphorylation of Psilocin Enables Optimized CGMP Kilogram-Scale Manufacture of Psilocybin. ACS Omega 2020, 5, 16959– 16966, DOI: 10.1021/acsomega.0c02387
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Direct Phosphorylation of Psilocin Enables Optimized cGMP Kilogram-Scale Manufacture of Psilocybin
Kargbo, Robert B.; Sherwood, Alexander; Walker, Andrew; Cozzi, Nicholas V.; Dagger, Raymond E.; Sable, Jessica; O'Hern, Kelsey; Kaylo, Kristi; Patterson, Tura; Tarpley, Gary; Meisenheimer, Poncho
ACS Omega (2020), 5 (27), 16959-16966CODEN: ACSODF; ISSN:2470-1343. (American Chemical Society)
A second-generation kilogram-scale synthesis of the psychedelic tryptamine psilocybin has been developed. The synthesis was designed to address several challenges first encountered with the scale-up of previously described literature procedures, which were not optimized for providing consistent yield and purity of products, atom economy, or being run in pilot plant-scale reactors. These challenges were addressed and circumvented with the design of the second-generation route, which featured an optimized cGMP large-scale Speeter-Anthony tryptamine synthesis to the intermediate psilocin with improved in-process control and impurity removal over the three steps. Psilocin was subsequently phosphorylated directly with phosphorous oxychloride for the first time, avoiding a tedious and poor atom economy benzyl-protecting group strategy common to all previously described methods for producing psilocybin. In this report, the challenges encountered in a 100 g scale first-generation literature-based synthesis are highlighted, followed by a detailed description of the newly developed second-generation synthesis to provide over one kilogram of high-purity psilocybin under cGMP.
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Shirota, O.; Hakamata, W.; Goda, Y. Concise Large-Scale Synthesis of Psilocin and Psilocybin, Principal Hallucinogenic Constituents of “Magic Mushroom. J. Nat. Prod. 2003, 66, 885– 887, DOI: 10.1021/np030059u
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Concise Large-Scale Synthesis of Psilocin and Psilocybin, Principal Hallucinogenic Constituents of "Magic Mushroom"
Shirota, Osamu; Hakamata, Wataru; Goda, Yukihiro
Journal of Natural Products (2003), 66 (6), 885-887CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society)
The concise large-scale syntheses of psilocin and psilocybin, the principal hallucinogenic constituents of "magic mushroom", were achieved without chromatog. purifn. The key step in the synthesis of psilocybin was the isolation of the dibenzyl-protected intermediate as a zwitterionic deriv. I, which was completely identified by means of 2D NMR analyses.
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Nichols, D. E. Improvements to the Synthesis of Psilocybin and a Facile Method for Preparing the O-Acetyl Prodrug of Psilocin. Synthesis 1999, 1999, 935– 938, DOI: 10.1055/s-1999-3490
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Crookes, D. L.; Parry, K. P.; Smith, G. F. 2-(Indol-3′-Yl)-2-Hydroxy-N,N-Dimethylethylamine and 2-(Indol-3′-Yl)-2[3″-[2’’’-(N,N-Dimethylamino) Ethyl]Indol-2″-Yl]-N,N-Dimethylethylamine, by-Products in the LAH Reduction of 3-Indoleglyoxyl- N,N-Dimethylamide. Pol. J. Chem. 1979, 53, 73– 78
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2-(Indol-3'-yl)-2-hydroxy-N,N-dimethylethylamine and 2-(indol-3'-yl)-2[3''-[2'''-(N,N-dimethylamino)ethyl]indol-2''-yl]-N,N-dimethylethylamine, by-products in the LAH reduction of 3-indoleglyoxyl-N,N-dimethylamide
Crookes, D. L.; Parry, K. P.; Smith, G. F.
Polish Journal of Chemistry (1979), 53 (1), 73-8CODEN: PJCHDQ; ISSN:0137-5083.
LiAlH4 redn. of RCOCONMe2 (R = 3-indolyl) gave RCH2CH2NMe2 and RCH(OH)CH2NMe2, which reacted together to give dimer I.
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Chen, C.-y.; Senanayake, C. H.; Bill, T. J.; Larsen, R. D.; Verhoeven, T. R.; Reider, P. J. Improved Fischer Indole Reaction for the Preparation of N,N-Dimethyltryptamines: Synthesis of L-695,894, a Potent 5-HT1D Receptor Agonist. J. Org. Chem. 1994, 59, 3738– 3741, DOI: 10.1021/jo00092a046
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Improved Fischer Indole Reaction for the Preparation of N,N-Dimethyltryptamines: Synthesis of L-695,894, a Potent 5-HT1D Receptor Agonist
Chen, Cheng-yi; Senanayake, Chris H.; Bill, Timothy J.; Larsen, Robert D.; Verhoeven, Thomas R.; Reider, Paul J.
Journal of Organic Chemistry (1994), 59 (13), 3738-41CODEN: JOCEAH; ISSN:0022-3263.
A facile prepn. of 5-substituted-N,N-dimethyltryptamines using an improved Fischer indole reaction is described. This methodol. has been applied to the synthesis of the novel 5-HT1D agonist L-695,894 (I), a potential antimigraine drug.
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Baumann, M.; Baxendale, I. R.; Ley, S. V.; Nikbin, N. An Overview of the Key Routes to the Best Selling 5-Membered Ring Heterocyclic Pharmaceuticals. Beilstein J. Org. Chem. 2011, 7, 442– 495, DOI: 10.3762/bjoc.7.57
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An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals
Baumann, Marcus; Baxendale, Ian R.; Ley, Steven V.; Nikbin, Nikzad
Beilstein Journal of Organic Chemistry (2011), 7 (), 442-495, No. 57CODEN: BJOCBH; ISSN:1860-5397. (Beilstein-Institut zur Foerderung der Chemischen Wissenschaften)
This review presents a comprehensive overview on selected synthetic routes towards com. drug compds. as published in both journal and patent literature. Owing to the vast no. of potential structures, we have concd. only on those drugs contg. five-membered heterocycles and focused principally on the assembly of the heterocyclic core. In order to target the most representative chem. entities, the examples discussed have been selected from the top 200 best selling drugs of recent years.
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Brandt, S. D.; Martins, C. P. B.; Freeman, S.; Dempster, N.; Riby, P. G.; Gartz, J.; Alder, J. F. Halogenated Solvent Interactions with N,N-Dimethyltryptamine: Formation of Quaternary Ammonium Salts and Their Artificially Induced Rearrangements during Analysis. Forensic Sci. Int. 2008, 178, 162– 170, DOI: 10.1016/j.forsciint.2008.03.013
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Halogenated solvent interactions with N,N-dimethyltryptamine: Formation of quaternary ammonium salts and their artificially induced rearrangements during analysis
Brandt, Simon D.; Martins, Claudia P. B.; Freeman, Sally; Dempster, Nicola; Riby, Philip G.; Gartz, Jochen; Alder, John F.
Forensic Science International (2008), 178 (2-3), 162-170CODEN: FSINDR; ISSN:0379-0738. (Elsevier Ltd.)
The psychoactive properties of N,N-dimethyltryptamine (DMT) 1a are known to induce altered states of consciousness in humans. This particular attribute attracts great interest from a variety of scientific and also clandestine communities. Our recent research has confirmed that DMT reacts with dichloromethane (DCM), either as a result of work-up or storage to give a quaternary N-chloromethyl ammonium salt. Furthermore, this was obsd. to undergo rearrangement during anal. using gas chromatog.-mass spectrometry (GC-MS) with products including 3-(2-chloroethyl)indole and 2-methyltetrahydro-β-carboline (2-Me-THBC). This study further investigates this so far unexplored area of solvent interactions by the exposure of DMT to other halogenated solvents including dibromomethane and 1,2-dichloroethane (DCE). The N-bromomethyl- and N-chloroethyl quaternary ammonium derivs. were subsequently characterized by ion trap GC-MS in electron and chem. ionization tandem MS mode and by NMR spectroscopy. The DCE-derived deriv. formed at least six rearrangement products in the total ion chromatogram. Identification of mass spectrometry generated byproducts was verified by conventional or microwave-accelerated synthesis. The use of deuterated DCM and deuterated DMT provided insights into the mechanism of the rearrangements. The presence of potentially characteristic marker mols. may allow the identification of solvents used during the manuf. of controlled substances, which is often neglected since these are considered inert.
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Dunlap, L. E.; Olson, D. E. Reaction of N, N-Dimethyltryptamine with Dichloromethane under Common Experimental Conditions. ACS Omega 2018, 3, 4968– 4973, DOI: 10.1021/acsomega.8b00507
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Reaction of N,N-Dimethyltryptamine with Dichloromethane Under Common Experimental Conditions
Dunlap, Lee E.; Olson, David E.
ACS Omega (2018), 3 (5), 4968-4973CODEN: ACSODF; ISSN:2470-1343. (American Chemical Society)
A large no. of clin. used drugs and exptl. pharmaceuticals possess the N,N-dimethyltryptamine (DMT) structural core. Previous reports have described the reaction of this motif with dichloromethane (DCM), a common lab. solvent used during extn. and purifn., leading to the formation of an undesired quaternary ammonium salt byproduct. However, the kinetics of this reaction under various conditions have not been thoroughly described. Here, we report a series of expts. designed to simulate the exposure of DMT to DCM that would take place during extn. from plant material, biphasic aq. work-up, or column chromatog. purifn. We find that the quaternary ammonium salt byproduct forms at an exceedingly slow rate, only accumulates to a significant extent upon prolonged exposure of DMT to DCM, and is readily extd. into water. Our results suggest that DMT can be exposed to DCM under conditions where contact times are limited (<30 min) with minimal risk of degrdn. and that this byproduct is not obsd. following aq. extn. However, alternative solvents should be considered when the exptl. conditions require longer contact times. Our work has important implications for prepg. a wide-range of pharmaceuticals bearing the DMT structural motif in high yields and purities.
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El Jaber-Vazdekis, N.; Gutierrez-Nicolás, F.; Ravelo, Á. G.; Zárate, R. Studies on Tropane Alkaloid Extraction by Volatile Organic Solvents: Dichloromethane vs. Chloroform. Phytochem. Anal. 2006, 17, 107– 113, DOI: 10.1002/pca.893
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Studies on tropane alkaloid extraction by volatile organic solvents: dichloromethane vs. chloroform
El Jaber-Vazdekis, Nabil; Gutierrez-Nicolas, Fatima; Ravelo, Angel G.; Zarate, Rafael
Phytochemical Analysis (2006), 17 (2), 107-113CODEN: PHANEL; ISSN:0958-0344. (John Wiley & Sons Ltd.)
In order to investigate the prodn. of tropane alkaloids by hairy roots of Atropa baetica, transgenic for the gene h6h encoding the enzyme hyoscyamine 6β-hydroxylase, solvent extn. with chloroform and with dichloromethane of the metabolites present in the liq. medium and in the root tissue was compared. The extn. of scopolamine from the liq. medium was equally effective with either solvent, giving max. values of around 850 μg/flask. For the roots, 3 different extn. methods were employed: A, employing chloroform:methanol: (25%) ammonia (15:5:1) for initial extn., followed by treatment with sulfuric acid and ammonia, and using chloroform for the final extn. and washes: B, as A but using dichloromethane for extn. and washes: and C, as B but substituting chloroform for dichloromethane in the extn. cocktail. Scopolamine was the most abundant metabolite (present in amts. of 3250-3525 μg/g dry wt.) and presented similar extn. efficiencies with all of the extn. methods employed. The highest amts. of hyoscyamine and the intermediate 6β-hydroxyhyoscyamine were present on day 31 (800 and 975 μg/g dry wt., resp.) and no statistical differences between the 3 extn. methods employed were detected. This study confirms that, for the extn. of tropane alkaloids, dichloromethane can replace the commonly employed chloroform, the use of which incurs major health, security and regulation problems.
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Brandt, S. D.; Martins, C. P. B.; Freeman, S.; Dempster, N.; Wainwright, M.; Riby, P. G.; Alder, J. F. N,N-Dimethyltryptamine and Dichloromethane: Rearrangement of Quaternary Ammonium Salt Product during GC-EI and CI-MS-MS Analysis. J. Pharm. Biomed. Anal. 2008, 47, 207– 212, DOI: 10.1016/j.jpba.2007.12.024
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N,N-Dimethyltryptamine and dichloromethane: Rearrangement of quaternary ammonium salt product during GC-EI and CI-MS-MS analysis
Brandt, Simon D.; Martins, Claudia P. B.; Freeman, Sally; Dempster, Nicola; Wainwright, Mark; Riby, Philip G.; Alder, John F.
Journal of Pharmaceutical and Biomedical Analysis (2008), 47 (1), 207-212CODEN: JPBADA; ISSN:0731-7085. (Elsevier B.V.)
N,N-Dimethyltryptamine (DMT) is a simple tryptamine deriv. with powerful psychoactive properties. It is abundant in nature and easily accessible through a variety of synthetic routes. Most work-up procedures require the use of org. solvents and halogenated representatives are often employed. DMT was found to be reactive towards dichloromethane, either during work-up or long term storage therein, which led to the formation of the quaternary ammonium salt N-chloromethyl-DMT chloride (I). Anal. of this side-product by gas chromatog. ion trap mass spectrometry (GC-MS), both in electron and chem. ionization tandem MS modes, gave only degrdn. products. For example, I could not be detected but appeared to have rearranged to 3-(2-chloroethyl)indole (II) and 2-methyltetrahydro-β-carboline (III), whereas HPLC anal. enabled the detection of I. GC-MS is a std. tool for the fingerprinting of drug products. The identification of a particular synthetic route is based on the anal. of impurities, provided these side products can be established to be route-specific. The in situ detection of both II and III within a DMT sample may have led to erroneous conclusions with regards to the identification of the synthetic route.
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Nevstad, G. O.; Songstad, J.; Rodriguez, B.; Mörch, L.; Norin, T. Solvent Properties of Dichloromethane. II. The Reactivity of Dichloromethane Toward Amines. Acta Chem. Scand. 1984, 38b, 469– 477, DOI: 10.3891/acta.chem.scand.38b-0469
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Aycock, D. F. Solvent Applications of 2-Methyltetrahydrofuran in Organometallic and Biphasic Reactions. Org. Process Res. Dev. 2007, 11, 156– 159, DOI: 10.1021/op060155c
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Solvent Applications of 2-Methyltetrahydrofuran in Organometallic and Biphasic Reactions
Aycock, David F.
Organic Process Research & Development (2007), 11 (1), 156-159CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
2-Methyltetrahydrofuran (MeTHF) is a com. available solvent that is produced from renewable resources. The properties of MeTHF place it between THF and Et2O in solvent polarity and Lewis base strength. In many cases, MeTHF can replace THF in organometallic reactions. The formation and reaction of Grignard reagents in MeTHF and THF are similar. MeTHF can be used as a solvent for low-temp. lithiation, for lithium aluminum hydride redns., for the Reformatskii reaction, and for metal-catalyzed coupling reactions. MeTHF is also a good substitute for dichloromethane in biphasic reactions.
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Shen, H.-W.; Jiang, X.-L.; C. Winter, J.; Yu, A.-M. Psychedelic 5-Methoxy-N,N-Dimethyltryptamine: Metabolism, Pharmacokinetics, Drug Interactions, and Pharmacological Actions. Curr. Drug Metab. 2010, 11, 659– 666, DOI: 10.2174/138920010794233495
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Psychedelic 5-methoxy-N,N-dimethyltryptamine: metabolism, pharmacokinetics, drug interactions, and pharmacological actions
Shen, Hong-Wu; Jiang, Xi-Ling; Winter, Jerrold C.; Yu, Ai-Ming
Current Drug Metabolism (2010), 11 (8), 659-666CODEN: CDMUBU; ISSN:1389-2002. (Bentham Science Publishers Ltd.)
A review. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) belongs to a group of naturally-occurring psychoactive indolealkylamine drugs. It acts as a nonselective serotonin (5-HT) agonist and causes many physiol. and behavioral changes. 5-MeO-DMT is O-demethylated by polymorphic cytochrome P 450 2D6 (CYP2D6) to an active metabolite, bufotenine, while it is mainly inactivated through the deamination pathway mediated by monoamine oxidase A (MAO-A). 5-MeO-DMT is often used with MAO-A inhibitors such as harmaline. Concurrent use of harmaline reduces 5-MeO-DMT deamination metab. and leads to a prolonged and increased exposure to the parent drug 5-MeO-DMT, as well as the active metabolite bufotenine. Harmaline, 5-MeO-DMT and bufotenine act agonistically on serotonergic systems and may result in hyperserotonergic effects or serotonin toxicity. Interestingly, CYP2D6 also has important contribution to harmaline metab., and CYP2D6 genetic polymorphism may cause considerable variability in the metab., pharmacokinetics and dynamics of harmaline and its interaction with 5-MeO-DMT. Therefore, this review summarizes recent findings on biotransformation, pharmacokinetics, and pharmacol. actions of 5-MeO-DMT. In addn., the pharmacokinetic and pharmacodynamic drug-drug interactions between harmaline and 5-MeO-DMT, potential involvement of CYP2D6 pharmacogenetics, and risks of 5-MeO-DMT intoxication are discussed.
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Abstract
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Figure 1
Figure 1. Structures of clinically explored psychedelic, entactogenic, and dissociative psychoactive drugs.
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Figure 2
Figure 2. (Left) I. alvarius (image courtesy of Holger Krisp, Ulm, Germany, 2011 under CC BY 3.0) with the parotid gland highlighted. (Right) Structure of 5-MeO-DMT (6).
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Scheme 1
Scheme 1. Eschweiler–Clarke Reaction to 6 and Mechanism of Pictet–Spengler Byproduct Formation
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Scheme 2
Scheme 2. Speeter–Anthony Tryptamine Synthesis and Byproduct Formation via Reactive Impurity 11
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Scheme 3
Scheme 3. (A) Fischer Indole Reaction in the preparation of 6 and (B) Approved Antimigraine Medications Prepared by the Analogous Process
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Scheme 4
Scheme 4. Formation of Degradant 18 Annotated With ¹H NMR Shift for the Suspected Dichloromethane Adduct
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Scheme 5
Scheme 5. Putative Dimer Impurity Structure and MS/MS Fragmentation^a
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^aRed circles indicate alternate attachment points.
Scheme 6
Scheme 6. Synthesis of N-Oxide 21
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  Clinical applications of hallucinogens: a review
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  Hallucinogens fall into several different classes, as broadly defined by pharmacol. mechanism of action, and chem. structure. These include psychedelics, entactogens, dissociatives, and other atypical hallucinogens. Although these classes do not share a common primary mechanism of action, they do exhibit important similarities in their ability to occasion temporary but profound alterations of consciousness, involving acute changes in somatic, perceptual, cognitive, and affective processes. Such effects likely contribute to their recreational use. However, a growing body of evidence indicates that these drugs may have therapeutic applications beyond their potential for abuse. This review will present data on several classes of hallucinogens with a particular focus on psychedelics, entactogens, and dissociatives, for which clin. utility has been most extensively documented. Information on each class is presented in turn, tracing relevant historical insights, highlighting similarities and differences between the classes from the mol. to the behavioral level, and presenting the most up-to-date information on clin. oriented research with these substances, with important ramifications for their potential therapeutic value.
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2. 2
  Sherwood, A. M.; Prisinzano, T. E. Novel Psychotherapeutics–a Cautiously Optimistic Focus on Hallucinogens. Expert Rev. Clin. Pharmacol. 2018, 11, 1– 3, DOI: 10.1080/17512433.2018.1415755
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  2
  Novel psychotherapeutics - a cautiously optimistic focus on Hallucinogens
  Sherwood, Alexander M.; Prisinzano, Thomas E.
  Expert Review of Clinical Pharmacology (2018), 11 (1), 1-3CODEN: ERCPAG; ISSN:1751-2433. (Taylor & Francis Ltd.)
  A review. This review discusses the role of hallucinogens for treating mental illness. This development of novel approaches to treating mental illness is discussed. The hallucinogens are used to treat diseases such as severe post-traumatic stress disorder, depression, anxiety, etc. The success of hallucinogen-based therapies will depend on the application of ethically sound and rigorous scientific methods towards the continued demonstration of significant clin. outcomes combined with rethinking how we perceive and regulate these compds.ods toward the continued demonstration of significant clinicaloutcomes combined with rethinking how we perceive andregulate these compds.
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3. 3
  Carhart-Harris, R. L.; Bolstridge, M.; Day, C. M. J.; Rucker, J.; Watts, R.; Erritzoe, D. E.; Kaelen, M.; Giribaldi, B.; Bloomfield, M.; Pilling, S.; Rickard, J. A.; Forbes, B.; Feilding, A.; Taylor, D.; Curran, H. V.; Nutt, D. J. Psilocybin with Psychological Support for Treatment-Resistant Depression: Six-Month Follow-Up. Psychopharmacology 2018, 235, 399– 408, DOI: 10.1007/s00213-017-4771-x
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  3
  Psilocybin with psychological support for treatment-resistant depression: six-month follow-up
  Carhart-Harris, R. L.; Bolstridge, M.; Day, C. M. J.; Rucker, J.; Watts, R.; Erritzoe, D. E.; Kaelen, M.; Giribaldi, B.; Bloomfield, M.; Pilling, S.; Rickard, J. A.; Forbes, B.; Feilding, A.; Taylor, D.; Curran, H. V.; Nutt, D. J.
  Psychopharmacology (Heidelberg, Germany) (2018), 235 (2), 399-408CODEN: PSCHDL; ISSN:0033-3158. (Springer)
  Rationale: Recent clin. trials are reporting marked improvements in mental health outcomes with psychedelic drug-assisted psychotherapy. Objectives: Here, we report on safety and efficacy outcomes for up to 6 mo in an open-label trial of psilocybin for treatment-resistant depression. Methods: Twenty patients (six females) with (mostly) severe, unipolar, treatment-resistant major depression received two oral doses of psilocybin (10 and 25 mg, 7 days apart) in a supportive setting. Depressive symptoms were assessed from 1 wk to 6 mo post-treatment, with the self-rated QIDS-SR16 as the primary outcome measure. Results: Treatment was generally well tolerated. Relative to baseline, marked redns. in depressive symptoms were obsd. for the first 5 wk post-treatment (Cohen's d = 2.2 at week 1 and 2.3 at week 5, both p < 0.001); nine and four patients met the criteria for response and remission at week 5. Results remained pos. at 3 and 6 mo (Cohen's d = 1.5 and 1.4, resp., both p < 0.001). No patients sought conventional antidepressant treatment within 5 wk of psilocybin. Redns. in depressive symptoms at 5 wk were predicted by the quality of the acute psychedelic experience. Conclusions: Although limited conclusions can be drawn about treatment efficacy from open-label trials, tolerability was good, effect sizes large and symptom improvements appeared rapidly after just two psilocybin treatment sessions and remained significant 6 mo post-treatment in a treatment-resistant cohort. Psilocybin represents a promising paradigm for unresponsive depression that warrants further research in double-blind randomized control trials.
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4. 4
  Griffiths, R. R.; Johnson, M. W.; Carducci, M. A.; Umbricht, A.; Richards, W. A.; Richards, B. D.; Cosimano, M. P.; Klinedinst, M. A. Psilocybin Produces Substantial and Sustained Decreases in Depression and Anxiety in Patients with Life-Threatening Cancer: A Randomized Double-Blind Trial. J. Psychopharmacol. 2016, 30, 1181– 1197, DOI: 10.1177/0269881116675513
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  4
  Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: a randomized double-blind trial
  Griffiths, Roland R.; Johnson, Matthew W.; Carducci, Michael A.; Umbricht, Annie; Richards, William A.; Richards, Brian D.; Cosimano, Mary P.; Klinedinst, Margaret A.
  Journal of Psychopharmacology (London, United Kingdom) (2016), 30 (12), 1181-1197CODEN: JOPSEQ; ISSN:0269-8811. (Sage Publications Ltd.)
  Cancer patients often develop chronic, clin. significant symptoms of depression and anxiety. Previous studies suggest that psilocybin may decrease depression and anxiety in cancer patients. The effects of psilocybin were studied in 51 cancer patients with life-threatening diagnoses and symptoms of depression and/or anxiety. This randomized, double-blind, cross-over trial investigated the effects of a very low (placebo-like) dose (1 or 3 mg/70 kg) vs. a high dose (22 or 30 mg/70 kg) of psilocybin administered in counterbalanced sequence with 5 wk between sessions and a 6-mo follow-up. Instructions to participants and staff minimized expectancy effects. High-dose psilocybin produced large decreases in clinician- and self-rated measures of depressed mood and anxiety, along with increases in quality of life, life meaning, and optimism, and decreases in death anxiety. At 6-mo follow-up, these changes were sustained, with about 80% of participants continuing to show clin. significant decreases in depressed mood and anxiety. Participants attributed improvements in attitudes about life/self, mood, relationships, and spirituality to the high-dose experience, with >80% endorsing moderately or greater increased well-being/life satisfaction. Community observer ratings showed corresponding changes. Mystical-type psilocybin experience on session day mediated the effect of psilocybin dose on therapeutic outcomes.
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5. 5
  Ot’alora G, M.; Grigsby, J.; Poulter, B.; Van Derveer, J. W.; Giron, S. G.; Jerome, L.; Feduccia, A. A.; Hamilton, S.; Yazar-Klosinski, B.; Emerson, A.; Mithoefer, M. C.; Doblin, R. 3,4-Methylenedioxymethamphetamine-Assisted Psychotherapy for Treatment of Chronic Posttraumatic Stress Disorder: A Randomized Phase 2 Controlled Trial. J. Psychopharmacol. 2018, 32, 1295– 1307, DOI: 10.1177/0269881118806297
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  5
  3,4-Methylenedioxymethamphetamine-assisted psychotherapy for treatment of chronic posttraumatic stress disorder: A randomized phase 2 controlled trial
  Ot'alora G, Marcela; Grigsby, Jim; Poulter, Bruce; Van Derveer, Joseph W.; Giron, Sara Gael; Jerome, Lisa; Feduccia, Allison A.; Hamilton, Scott; Yazar-Klosinski, Berra; Emerson, Amy; Mithoefer, Michael C.; Doblin, Rick
  Journal of Psychopharmacology (London, United Kingdom) (2018), 32 (12), 1295-1307CODEN: JOPSEQ; ISSN:0269-8811. (Sage Publications Ltd.)
  Posttraumatic stress disorder often does not resolve after conventional psychotherapies or pharmacotherapies. Pilot studies have reported that 3,4-methylenedioxymethamphetamine (MDMA) combined with psychotherapy reduces posttraumatic stress disorder symptoms. This pilot dose response trial assessed efficacy and safety of MDMA-assisted psychotherapy across multiple therapy teams. Twenty-eight people with chronic posttraumatic stress disorder were randomized in a double-blind dose response comparison of two active doses (100 and 125 mg) with a low dose (40 mg) of MDMA administered during eight-hour psychotherapy sessions. Change in the Clinician-Administered PTSD Scale total scores one month after two sessions of MDMA served as the primary outcome. Active dose groups had one addnl. open-label session; the low dose group crossed over for three open-label active dose sessions. A 12-mo follow-up assessment occurred after the final MDMA session. In the intent-to-treat set, the active groups had the largest redn. in Clinician-Administered PTSD Scale total scores at the primary endpoint, with mean (std. deviation) changes of -26.3 (29.5) for 125 mg, -24.4 (24.2) for 100 mg, and -11.5 (21.2) for 40 mg, though statistical significance was reached only in the per protocol set (p = 0.03). Posttraumatic stress disorder symptoms remained lower than baseline at 12-mo follow-up (p<0.001) with 76% (n = 25) not meeting posttraumatic stress disorder criteria. There were no drug-related serious adverse events, and the treatment was well-tolerated. Our findings support previous investigations of MDMA-assisted psychotherapy as an innovative, efficacious treatment for posttraumatic stress disorder.
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6. 6
  Ross, S.; Bossis, A.; Guss, J.; Agin-Liebes, G.; Malone, T.; Cohen, B.; Mennenga, S. E.; Belser, A.; Kalliontzi, K.; Babb, J.; Su, Z.; Corby, P.; Schmidt, B. L. Rapid and Sustained Symptom Reduction Following Psilocybin Treatment for Anxiety and Depression in Patients with Life-Threatening Cancer: A Randomized Controlled Trial. J. Psychopharmacol. 2016, 30, 1165– 1180, DOI: 10.1177/0269881116675512
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  6
  Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial
  Ross, Stephen; Bossis, Anthony; Guss, Jeffrey; Agin-Liebes, Gabrielle; Malone, Tara; Cohen, Barry; Mennenga, Sarah E.; Belser, Alexander; Kalliontzi, Krystallia; Babb, James; Su, Zhe; Corby, Patricia; Schmidt, Brian L.
  Journal of Psychopharmacology (London, United Kingdom) (2016), 30 (12), 1165-1180CODEN: JOPSEQ; ISSN:0269-8811. (Sage Publications Ltd.)
  Background: Clin. significant anxiety and depression are common in patients with cancer, and are assocd. with poor psychiatric and medical outcomes. Historical and recent research suggests a role for psilocybin to treat cancer-related anxiety and depression. Methods: In this double-blind, placebo-controlled, crossover trial, 29 patients with cancer-related anxiety and depression were randomly assigned and received treatment with single-dose psilocybin (0.3 mg/kg) or niacin, both in conjunction with psychotherapy. The primary outcomes were anxiety and depression assessed between groups prior to the crossover at 7 wk. Results: Prior to the crossover, psilocybin produced immediate, substantial, and sustained improvements in anxiety and depression and led to decreases in cancer-related demoralization and hopelessness, improved spiritual wellbeing, and increased quality of life. At the 6.5-mo follow-up, psilocybin was assocd. with enduring anxiolytic and anti-depressant effects (approx. 60-80% of participants continued with clin. significant redns. in depression or anxiety), sustained benefits in existential distress and quality of life, as well as improved attitudes towards death. The psilocybin-induced mystical experience mediated the therapeutic effect of psilocybin on anxiety and depression. Conclusions: In conjunction with psychotherapy, single moderate-dose psilocybin produced rapid, robust and enduring anxiolytic and anti-depressant effects in patients with cancer-related psychol. distress.
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7. 7
  Aday, J. S.; Mitzkovitz, C. M.; Bloesch, E. K.; Davoli, C. C.; Davis, A. K. Long-Term Effects of Psychedelic Drugs: A Systematic Review. Neurosci. Biobehav. Rev. 2020, 113, 179– 189, DOI: 10.1016/j.neubiorev.2020.03.017
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  7
  Long-term effects of psychedelic drugs: A systematic review
  Aday, Jacob S.; Mitzkovitz, Cayla M.; Bloesch, Emily K.; Davoli, Christopher C.; Davis, Alan K.
  Neuroscience & Biobehavioral Reviews (2020), 113 (), 179-189CODEN: NBREDE; ISSN:0149-7634. (Elsevier Ltd.)
  Research into the basic effects and therapeutic applications of psychedelic drugs has grown considerably in recent years. Yet, pressing questions remain regarding the substances' lasting effects. Although individual studies have begun monitoring sustained changes, no study to-date has synthesized this information. Therefore, this systematic review aims to fill this important gap in the literature by synthesizing results from 34 contemporary exptl. studies which included classic psychedelics, human subjects, and follow-up latencies of at least two weeks. The bulk of this work was published in the last five years, with psilocybin being the most frequently administered drug. Enduring changes in personality/attitudes, depression, spirituality, anxiety, wellbeing, substance misuse, meditative practices, and mindfulness were documented. Mystical experiences, connectedness, emotional breakthrough, and increased neural entropy were related to these long-term changes in psychol. functioning. Finally, with proper screening, prepn., supervision, and integration, limited aversive side effects were noted by study participants. Future researchers should focus on including larger and more diverse samples, lengthier longitudinal designs, stronger control conditions, and standardized dosages.
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8. 8
  Barsuglia, J.; Davis, A. K.; Palmer, R.; Lancelotta, R.; Windham-Herman, A. M.; Peterson, K.; Polanco, M.; Grant, R.; Griffiths, R. R. Intensity of Mystical Experiences Occasioned by 5-MeO-DMT and Comparison with a Prior Psilocybin Study. Front. Psychol. 2018, 9, 2459 DOI: 10.3389/fpsyg.2018.02459
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  8
  Intensity of Mystical Experiences Occasioned by 5-MeO-DMT and Comparison With a Prior Psilocybin Study
  Barsuglia Joseph; Polanco Martin; Barsuglia Joseph; Barsuglia Joseph; Barsuglia Joseph; Polanco Martin; Davis Alan K; Griffiths Roland R; Palmer Robert; Windham-Herman Austin-Marley; Lancelotta Rafael; Peterson Kristel; Grant Robert; Griffiths Roland R
  Frontiers in psychology (2018), 9 (), 2459 ISSN:1664-1078.
  5-MeO-DMT is a psychoactive substance found in high concentrations in the bufotoxin of the Colorado River Toad (Bufo alvarius). Emerging evidence suggests that vaporized 5-MeO-DMT may occasion mystical experiences of comparable intensity to those occasioned by more widely studied psychedelics such as psilocybin, but no empirical study has tested this hypothesis. Data was obtained from 20 individuals (Mage = 38.9, ± 10.7; male = 55%, Caucasian = 85%) who were administered 5-MeO-DMT as part of a psychospiritual retreat program in Mexico. All participants received 50 mg of inhaled vaporized toad bufotoxin which contains 5-MeO-DMT and completed the Mystical Experience Questionnaire (MEQ30) approximately 4-6 h after their session. Administration of 5-MeO-DMT occasioned strong mystical experiences (MEQ30 Overall Mintensity = 4.17, ± 0.64, range 0-5) and the majority (n = 15, 75%) had "a complete mystical experience" (≥60% on all MEQ30 subscales). Compared to a prior laboratory-based psilocybin study, there were no differences in the intensity of mystical effects between 5-MeO-DMT and a high dose (30 mg/70 kg) of psilocybin, but the intensity of mystical effects was significantly higher in the 5-MeO-DMT sample compared to moderate/high dose (20 mg/70 kg) of psilocybin (MEQ30 Total Score: p = 0.02, d = 0.81). Administration of vaporized 5-MeO-DMT reliably occasioned complete mystical experiences in 75% of individuals and was similar in intensity to high dose psilocybin administered in a laboratory setting. The short duration of action may be advantageous for clinical interventions and for studying mystical-type experiences.
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9. 9
  Davis, A. K.; So, S.; Lancelotta, R.; Barsuglia, J. P.; Griffiths, R. R. 5-Methoxy-N,N-Dimethyltryptamine (5-MeO-DMT) Used in a Naturalistic Group Setting Is Associated with Unintended Improvements in Depression and Anxiety. Am. J. Drug Alcohol Abuse 2019, 45, 161– 169, DOI: 10.1080/00952990.2018.1545024
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  9
  5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) used in a naturalistic group setting is associated with unintended improvements in depression and anxiety
  Davis Alan K; Griffiths Roland R; So Sara; Lancelotta Rafael; Barsuglia Joseph P; Griffiths Roland R
  The American journal of drug and alcohol abuse (2019), 45 (2), 161-169 ISSN:.
  BACKGROUND: A recent epidemiological study suggested that 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) used for spiritual and recreational reasons is associated with subjective improvement in depression and anxiety. Further exploration of the potential psychotherapeutic effects of 5-MeO-DMT could inform future clinical trials. OBJECTIVES: We examined self-reported improvement in depression and anxiety among people who use 5-MeO-DMT in a group setting with structured procedures guiding dose and administration of 5-MeO-DMT. Such procedures also include activities for the preparation of, and support during/following sessions, which are similar to procedures used in clinical trials of hallucinogen administration. Next, we examined whether depression or anxiety were improved following use, and whether the acute subjective effects (mystical/challenging) or beliefs about the 5-MeO-DMT experience were associated with improvements in these conditions. METHODS: Respondents (n = 362; Mage = 47.7; Male = 55%; White/Caucasian = 84%) completed an anonymous web-based survey. RESULTS: Of those reporting having been diagnosed with depression (41%) or anxiety (48%), most reported these conditions were improved (depression = 80%; anxiety = 79%) following 5-MeO-DMT use, and fewer reported they were unchanged (depression = 17%; anxiety = 19%) or worsened (depression = 3%; anxiety = 2%). Improvement in depression/anxiety conditions were associated with greater intensity of mystical experiences and higher ratings of the spiritual significance and personal meaning of the 5-MeO-DMT experience. There were no associations between depression or anxiety improvement and the intensity of acute challenging physical/psychological effects during the 5-MeO-DMT experience. CONCLUSIONS: Future prospective controlled clinical pharmacology studies should examine the safety and efficacy of 5-MeO-DMT administration for relieving depression and anxiety.
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10. 10
  Griffiths, R. R.; Johnson, M. W.; Richards, W. A.; Richards, B. D.; McCann, U.; Jesse, R. Psilocybin Occasioned Mystical-Type Experiences: Immediate and Persisting Dose-Related Effects. Psychopharmacology 2011, 218, 649– 665, DOI: 10.1007/s00213-011-2358-5
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  10
  Psilocybin occasioned mystical-type experiences: immediate and persisting dose-related effects
  Griffiths, Roland R.; Johnson, Matthew W.; Richards, William A.; Richards, Brian D.; McCann, Una; Jesse, Robert
  Psychopharmacology (Heidelberg, Germany) (2011), 218 (4), 649-665CODEN: PSCHDL; ISSN:0033-3158. (Springer)
  Rationale: This dose-effect study extends previous observations showing that psilocybin can occasion mystical-type experiences having persisting pos. effects on attitudes, mood, and behavior. Objectives: This double-blind study evaluated psilocybin (0, 5, 10, 20, 30 mg/70 kg, p.o.) administered under supportive conditions. Methods: Participants were 18 adults (17 hallucinogen-naive). Five 8-h sessions were conducted individually for each participant at 1-mo intervals. Participants were randomized to receive the four active doses in either ascending or descending order (nine participants each). Placebo was scheduled quasi-randomly. During sessions, volunteers used eyeshades and were instructed to direct their attention inward. Volunteers completed questionnaires assessing effects immediately after and 1 mo after each session, and at 14 mo follow-up. Results: Psilocybin produced acute perceptual and subjective effects including, at 20 and/or 30 mg/70 kg, extreme anxiety/fear (39% of volunteers) and/or mystical-type experience (72% of volunteers). One month after sessions at the two highest doses, volunteers rated the psilocybin experience as having substantial personal and spiritual significance, and attributed to the experience sustained pos. changes in attitudes, mood, and behavior, with the ascending dose sequence showing greater pos. effects. At 14 mo, ratings were undiminished and were consistent with changes rated by community observers. Both the acute and persisting effects of psilocybin were generally a monotonically increasing function of dose, with the lowest dose showing significant effects. Conclusions: Under supportive conditions, 20 and 30 mg/70 kg psilocybin occasioned mystical-type experiences having persisting pos. effects on attitudes, mood, and behavior. Implications for therapeutic trials are discussed.
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11. 11
  Weil, A. T.; Davis, W. Bufo alvarius: A Potent Hallucinogen of Animal Origin. J. Ethnopharmacol. 1994, 41, 1– 8, DOI: 10.1016/0378-8741(94)90051-5
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  11
  Bufo alvarius: A potent hallucinogen of animal origin
  Weil, Andrew T.; Davis, Wade
  Journal of Ethnopharmacology (1994), 41 (1-2), 1-8CODEN: JOETD7; ISSN:0378-8741.
  The authors demonstrate that the venom of B. alvarius, although known to be toxic when consumed orally, may be safely smoked and is powerfully psychoactive by that route of administration. These expts. are the first documentation of an hallucinogenic agent from the animal kingdom, and they provide clear evidence of a psychoactive toad that could have been employed by Precolumbian peoples of the New World.
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12. 12
  Agurell, S.; Holmstedt, B.; Lindgren, J. E.; Schultes, R. E. Alkaloids in Certain Species of Virola and Other South American Plants of Ethnopharmacologic Interest. Acta Chem. Scand. 1969, 23, 903– 916, DOI: 10.3891/acta.chem.scand.23-0903
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  12
  Alkaloids in certain species of Virola and other south American plants of ethnopharmacologic interest
  Agurell, Stig; Holmstedt, Bo; Lindgren, Jan E.; Schultes, Richard E.
  Acta Chemica Scandinavica (1947-1973) (1969), 23 (3), 903-16CODEN: ACSAA4; ISSN:0001-5393.
  V. theiodora, a botanical source of intoxicating snuffs used by certain South American Indian tribes, contained the hallucinogen 5-methoxy-N,N-dimethyltryptamine (I) as well as a no. of other indoles. One indian snuff proved to be unusually high in alkaloid content (11%). Considerable differences in the alkaloid compn. of different parts of single plants were encountered, N,N-dimethyltryptamine being the major component in the leaves and I in the bark of Virola theiodora. Of other species of Virola investigated V. rufula contained substantial amts. of tryptamines, whereas V. multinervia and V. venosa were almost devoid of alkaloids. V. calophylla contained high amts. of alkaloids only in the leaves. Two new β-carbolines of a type carrying the substituents in the 6-position of the β-carboline nucleus were found in V. theiodora, V. rufula, and Anadenanthera (Pipatadenia) peregrina. By spectrometric and other data their structures have been shown to be 2-methyl-6-methoxy-1,2,3,4-tetrahydro-β-carboline and 1,2-dimethyl-6-methoxy-1,2,3,4-tetrahydro-β-carboline.
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13. 13
  Mckenna, D. J.; Towers, G. H. N.; Abbott, F. S. Monoamine Oxidase Inhibitors in South American Hallucinogenic Plants Part 2: Constituents of Orally-Active Myristicaceous hallucinogens. J. Ethnopharmacol. 1984, 12, 179– 211, DOI: 10.1016/0378-8741(84)90048-5
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  13
  Monoamine oxidase inhibitors in South American hallucinogenic plants. Part 2: constituents of orally-active Myristicaceous hallucinogens
  McKenna, Dennis J.; Towers, G. H. N.; Abbott, F. S.
  Journal of Ethnopharmacology (1984), 12 (2), 179-211CODEN: JOETD7; ISSN:0378-8741.
  Alkaloid constituents in Myristicaceous bark and leaf samples and in purportedly hallucinogenic prepns. derived from Myristicaceous sources were qual. and quant. analyzed using TLC/gas chromatog. (GC), alkaloid pptn. tests and GC/MS. Fourteen of the 27 bark and leaf samples analyzed contained detectable amts. of alkaloids. The major bases were N,N-dimethyltryptamine [61-50-7] and/or 5-methoxy-N,N-dimethyltryptamine [1019-45-0]; much smaller amts. of tryptamine [61-54-1] and/or N-methyltryptamine [61-49-4] were also usually present. β-Carbolines were not detected in the bark or leaf samples. Considerable variation in alkaloid profiles was found, extending to different collections of the same species. Fourteen of the 20 Virola samples contained alkaloids; none of the 6 Iryanthera species had alkaloids. Osteophloem platyspermum Contained N-methyltryptophan Me ester [32164-04-8]. Seven samples of an orally-ingested drug made from Virola were analyzed. All except one contained substantial amts. of tryptamines; the types and proportions of tryptamines present varied greatly between samples. Samples of Yanomama snuff including various admixts. were analyzed and all components but one contained tryptamines. The drug samples having the highest concns. of alkaloids contained 15-20 mg/g dry wt. while the Myristicaceous bark and leaf samples had much lower concns. ranging from 0.04 to 0.25 mg/g dry wt. β-Carbolines were detected as trace constituents in only two of the Myristicaceous drug samples. Four Myristicaceous paste samples were bioassayed in self-expts. Two of the samples were devoid of hallucinogenic or physiol. activity, while some degree of oral activity was detected in two other samples. The activity of a no. of tryptamine derivs. as monoamine oxidase [9001-66-5] inhibitors (MAOI) was investigated using an in vitro enzyme assay. Activity was measured using single compds. and mixts. of compds. and the results were compared to the activity of samples of orally-ingested Myristicaceous pastes. Tryptamine derivs. had significantly less MAOI activity than the activity of β-carboline derivs. measured in a previous study (McKenna, D. J., et al., 1984). Some structural correlations for MAOI activity were found for the tryptamine derivs. Samples of orally-ingested Myristicaceous pastes were assayed for MAOI activity. The inhibition elicited by the paste samples was closely matched by mixts. of tryptamine stds. having comparable proportions and concns. These observations indicate that the MAOI activity of the pastes is due mainly to the high concns. of tryptamines; the traces of β-carbolines or non-N inhibitors present probably do not contribute significantly to the total inhibition. Thus, it appears unlikely that the oral activity of the Myristicaceous pastes is due to the potentiation of the tryptamines via inhibition of MAO by β-carbolines; some mechanism other than MAO inhibition must be sought to account for the oral hallucinogenic activity of the Myristicaceous pastes if they are, in fact, orally active.
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14. 14
  Schultes, R. E. Fifteen Years of Study of Psychoactive Snuffs of South America: 1967-1982- a Review. J. Ethnopharmacol. 1984, 11, 17– 32, DOI: 10.1016/0378-8741(84)90093-X
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  14
  Fifteen years of study of psychoactive snuffs of South America: 1967-1982--a review
  Schultes R E
  Journal of ethnopharmacology (1984), 11 (1), 17-32 ISSN:0378-8741.
  Much has been learned concerning psychoactive snuffs in South America in the past 15 years since I delivered a review paper in the now famous symposium "Ethnopharmacologic Search for Psychoactive Drugs" held in San Francisco in 1967 (Efron et al., 1967; Schultes, 1967). There is still much to be investigated, but it seems that a recapitulation at this time may be warranted. The advances in our knowledge have come about as a result of field work as well as laboratory research and have been effected by investigators in several disciplines: archaeology, ethnobotany, ethnology and phytochemistry.
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15. 15
  Torres, C. M.; Repke, D. B. Anadenanthera: Visionary Plant of Ancient South America; Haworth Herbal Press: New York, 2014.
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16. 16
  Davis, A. K.; Barsuglia, J. P.; Lancelotta, R.; Grant, R. M.; Renn, E. The Epidemiology of 5-Methoxy-N, N-Dimethyltryptamine (5-MeO-DMT) Use: Benefits, Consequences, Patterns of Use, Subjective Effects, and Reasons for Consumption. J. Psychopharmacol. 2018, 32, 779– 792, DOI: 10.1177/0269881118769063
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  The epidemiology of 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT) use: Benefits, consequences, patterns of use, subjective effects, and reasons for consumption
  Davis, Alan K.; Barsuglia, Joseph P.; Lancelotta, Rafael; Grant, Robert M.; Renn, Elise
  Journal of Psychopharmacology (London, United Kingdom) (2018), 32 (7), 779-792CODEN: JOPSEQ; ISSN:0269-8811. (Sage Publications Ltd.)
  Background/aim:: 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a psychoactive compd. found in several plants and in high concns. in Bufo alvarius toad venom. Synthetic, toad, and plant-sourced 5-MeO-DMT are used for spiritual and recreational purposes and may have psychotherapeutic effects. However, the use of 5-MeO-DMT is not well understood. Therefore, we examd. patterns of use, motivations for consumption, subjective effects, and potential benefits and consequences assocd. with 5-MeO-DMT use. Methods:: Using internet-based advertisements, 515 respondents (Mage=35.4. SD=11.7; male=79%; White/Caucasian=86%; United States resident=42%) completed a web-based survey. Results:: Most respondents consumed 5-MeO-DMT infrequently (< once/yr), for spiritual exploration, and had used less than four times in their lifetime. The majority (av. of 90%) reported moderate-to-strong mystical-type experiences (Mintensity=3.64, SD=1.11; range 0-5; e.g., ineffability, timelessness, awe/amazement, experience of pure being/awareness), and relatively fewer (av. of 37%) experienced very slight challenging experiences (Mintensity=0.95, SD=0.91; range 0-5; e.g., anxiousness, fear). Less than half (39%) reported repeated consumption during the same session, and very few reported drug craving/desire (8%), or legal (1%), medical (1%), or psychiatric (1%) problems related to use. Furthermore, of those who reported being diagnosed with psychiatric disorders, the majority reported improvements in symptoms following 5-MeO-DMT use, including improvements related to post-traumatic stress disorder (79%), depression (77%), anxiety (69%), and alcoholism (66%) or drug use disorder (60%). Conclusion:: Findings suggest that 5-MeO-DMT is used infrequently, predominantly for spiritual exploration, has low potential for addiction, and might have psychotherapeutic effects. Future research should examine the safety and pharmacokinetics of 5-MeO-DMT administration in humans using rigorous exptl. designs.
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17. 17
  Uthaug, M. V.; Lancelotta, R.; van Oorsouw, K.; Kuypers, K. P. C.; Mason, N.; Rak, J.; Šuláková, A.; Jurok, R.; Maryška, M.; Kuchař, M.; Páleníček, T.; Riba, J.; Ramaekers, J. G. A Single Inhalation of Vapor from Dried Toad Secretion Containing 5-Methoxy-N,N-Dimethyltryptamine (5-MeO-DMT) in a Naturalistic Setting Is Related to Sustained Enhancement of Satisfaction with Life, Mindfulness-Related Capacities, and a Decrement of Psyc. Psychopharmacology 2019, 236, 2653– 2666, DOI: 10.1007/s00213-019-05236-w
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  17
  A single inhalation of vapor from dried toad secretion containing 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) in a naturalistic setting is related to sustained enhancement of satisfaction with life, mindfulness-related capacities, and a decrement of psychopathological symptoms
  Uthaug, M. V.; Lancelotta, R.; van Oorsouw, K.; Kuypers, K. P. C.; Mason, N.; Rak, J.; Sulakova, A.; Jurok, R.; Maryska, M.; Kuchar, M.; Palenicek, T.; Riba, J.; Ramaekers, J. G.
  Psychopharmacology (Heidelberg, Germany) (2019), 236 (9), 2653-2666CODEN: PSCHDL; ISSN:0033-3158. (Springer)
  Background: 5-methoxy-N,N-dimethyltryptamine (hereinafter referred to as 5-MeO-DMT) is a psychedelic substance found in the secretion from the parotoid glands of the Bufo alvarius toad. Aims: The first objective of this study was to assess sub-acute and long-term effects of inhaling vapor from dried toad secretion contg. 5-MeO-DMT on affect and cognition. The second objective was to assess whether any changes were assocd. with the psychedelic experience. Methods: Assessments at baseline, within 24 h and 4 wk following intake, were made in 42 individuals who inhaled vapor from dried toad secretion at several European locations. Results: Relative to baseline, ratings of satisfaction with life and convergent thinking significantly increased right after intake and were maintained at follow-up 4 wk later. Ratings of mindfulness also increased over time and reached statistical significance at 4 wk. Ratings of depression, anxiety, and stress decreased after the session, and reached significance at 4 wk. Participants that experienced high levels of ego dissoln. or oceanic boundlessness during the session displayed higher ratings of satisfaction with life and lower ratings of depression and stress. Conclusion: A single inhalation of vapor from dried toad secretion contg. 5-MeO-DMT produces sub-acute and long-term changes in affect and cognition in volunteers. These results warrant exploratory research into therapeutic applications of 5-MeO-DMT.
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18. 18
  Metzner, R. The Toad and the Jaguar: A Field Report of Underground Research on a Visionary Medicine: Bufo alvarius and 5-Methoxy-Dimethyltryptamine, 1st ed.; Regent Press: Berkeley, CA, 2013.
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19. 19
  Uthaug, M. V.; Lancelotta, R.; Ortiz Bernal, A. M.; Davis, A. K.; Ramaekers, J. G. A Comparison of Reactivation Experiences Following Vaporization and Intramuscular Injection (IM) of Synthetic 5-Methoxy-N,N-Dimethyltryptamine (5-MeO-DMT) in a Naturalistic Setting. J. Psychedelic Stud. 2020, 4, 104– 113, DOI: 10.1556/2054.2020.00123
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  There is no corresponding record for this reference.
20. 20
  Sepeda, N. D.; Clifton, J. M.; Doyle, L. Y.; Lancelotta, R.; Griffiths, R. R.; Davis, A. K. Inhaled 5-Methoxy-N,N-Dimethyltryptamine: Supportive Context Associated with Positive Acute and Enduring Effects. J. Psychedelic Stud. 2019, 4, 114– 122, DOI: 10.1556/2054.2019.033
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21. 21
  Lancelotta, R. L.; Davis, A. K. Use of Benefit Enhancement Strategies among 5-Methoxy-N,N-Dimethyltryptamine (5-MeO-DMT) Users: Associations with Mystical, Challenging, and Enduring Effects. J. Psychoact. Drugs 2020, 52, 273– 281, DOI: 10.1080/02791072.2020.1737763
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  Use of Benefit Enhancement Strategies among 5-Methoxy-N,N-Dimethyltryptamine (5-MeO-DMT) Users: Associations with Mystical, Challenging, and Enduring Effects
  Lancelotta Rafael L; Lancelotta Rafael L; Davis Alan K; Davis Alan K
  Journal of psychoactive drugs (2020), 52 (3), 273-281 ISSN:.
  5-Methoxy-N,N-Dimethyltryptamine (5-MeO-DMT) is a potent, fast-acting psychedelic. Anecdotal reports from 5-MeO-DMT users suggest that they employ a variety of benefit enhancement (BE) strategies aimed to increase positive effects and decrease any potential challenging effects of the substance, but no empirical study has investigated this claim. We examined the prevalence of BE strategy use using secondary data from a survey of 5-MeO-DMT users (n = 515; Mage = 35.4, SD = 11.7; Male = 79%; White/Caucasian = 86%). Results indicated that BE strategy use was common in this sample. As a secondary aim, we assessed whether the use of BE strategies was associated with acute subjective (i.e., mystical-type, challenging) and persisting effects of 5-MeO-DMT among a subset of respondents who reported using 5-MeO-DMT once in their lifetime (n = 116). Results showed that the use of several BE strategies were associated with significantly more intense mystical-type effects and enduring beliefs about the personal meaning and spiritual significance of their experience, and some BE strategies were associated with less intense or challenging experiences. Data suggests that BE strategies are commonly used, and that the use of BE strategies may be associated with increases in positive mystical-type and enduring effects. The causal influence of BE strategies on acute/persisting effects of 5-MeO-DMT should be examined in longitudinal research.
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22. 22
  Nichols, D. E. Psychedelics. Pharmacol. Rev. 2016, 68, 264– 355, DOI: 10.1124/pr.115.011478
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  Psychedelics
  Nichols, David E.
  Pharmacological Reviews (2016), 68 (2), 264-355CODEN: PAREAQ; ISSN:1521-0081. (American Society for Pharmacology and Experimental Therapeutics)
  Psychedelics (serotonergic hallucinogens) are powerful psychoactive substances that alter perception and mood and affect numerous cognitive processes. They are generally considered physiol. safe and do not lead to dependence or addiction. Their origin predates written history, and they were employed by early cultures in many sociocultural and ritual contexts. After the virtually contemporaneous discovery of (5R,8R)-(+)-lysergic acid-N,N-diethylamide (LSD)-25 and the identification of serotonin in the brain, early research focused intensively on the possibility that LSD and other psychedelics had a serotonergic basis for their action. Today there is a consensus that psychedelics are agonists or partial agonists at brain serotonin 5-hydroxytryptamine 2A receptors, with particular importance on those expressed on apical dendrites of neocortical pyramidal cells in layer V. Several useful rodent models have been developed over the years to help unravel the neurochem. correlates of serotonin 5-hydroxytryptamine 2A receptor activation in the brain, and a variety of imaging techniques have been employed to identify key brain areas that are directly affected by psychedelics. Recent and exciting developments in the field have occurred in clin. research, where several double-blind placebo-controlled phase 2 studies of psilocybin-assisted psychotherapy in patients with cancer-related psychosocial distress have demonstrated unprecedented pos. relief of anxiety and depression. Two small pilot studies of psilocybin-assisted psychotherapy also have shown pos. benefit in treating both alc. and nicotine addiction. Recently, blood oxygen level-dependent functional magnetic resonance imaging and magnetoencephalog. have been employed for in vivo brain imaging in humans after administration of a psychedelic, and results indicate that i.v. administered psilocybin and LSD produce decreases in oscillatory power in areas of the brain's default mode network.
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23. 23
  Nichols, D. E. Hallucinogens. Pharmacol. Ther. 2004, 101, 131– 181, DOI: 10.1016/j.pharmthera.2003.11.002
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  Hallucinogens
  Nichols, David E.
  Pharmacology & Therapeutics (2004), 101 (2), 131-181CODEN: PHTHDT; ISSN:0163-7258. (Elsevier Science B.V.)
  A review. Hallucinogens (psychedelics) are psychoactive substances that powerfully alter perception, mood, and a host of cognitive processes. They are considered physiol. safe and do not produce dependence or addiction. Their origin predates written history, and they were employed by early cultures in a variety of sociocultural and ritual contexts. In the 1950s, after the virtually contemporaneous discovery of both serotonin (5-HT) and lysergic acid diethylamide (LSD-25), early brain research focused intensely on the possibility that LSD or other hallucinogens had a serotonergic basis of action and reinforced the idea that 5-HT was an important neurotransmitter in brain. These ideas were eventually proven, and today it is believed that hallucinogens stimulate 5-HT2A receptors, esp. those expressed on neocortical pyramidal cells. Activation of 5-HT2A receptors also leads to increased cortical glutamate levels presumably by a presynaptic receptor-mediated release from thalamic afferents. These findings have led to comparisons of the effects of classical hallucinogens with certain aspects of acute psychosis and to a focus on thalamocortical interactions as key to understanding both the action of these substances and the neuroanatomical sites involved in altered states of consciousness (ASC). In vivo brain imaging in humans using [18F]fluorodeoxyglucose has shown that hallucinogens increase prefrontal cortical metab., and correlations have been developed between activity in specific brain areas and psychol. elements of the ASC produced by hallucinogens. The 5-HT2A receptor clearly plays an essential role in cognitive processing, including working memory, and ligands for this receptor may be extremely useful tools for future cognitive neuroscience research. In addn., it appears entirely possible that utility may still emerge for the use of hallucinogens in treating alcoholism, substance abuse, and certain psychiatric disorders.
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24. 24
  Halberstadt, A. L.; Geyer, M. A. Multiple Receptors Contribute to the Behavioral Effects of Indoleamine Hallucinogens. Neuropharmacology 2011, 61, 364– 381, DOI: 10.1016/j.neuropharm.2011.01.017
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  Multiple receptors contribute to the behavioral effects of indoleamine hallucinogens
  Halberstadt, Adam L.; Geyer, Mark A.
  Neuropharmacology (2011), 61 (3), 364-381CODEN: NEPHBW; ISSN:0028-3908. (Elsevier B.V.)
  A review. Serotonergic hallucinogens produce profound changes in perception, mood, and cognition. These drugs include phenylalkylamines such as mescaline and 2,5-dimethoxy-4-methylamphetamine (DOM), and indoleamines such as (+)-lysergic acid diethylamide (LSD) and psilocybin. Despite their differences in chem. structure, the two classes of hallucinogens produce remarkably similar subjective effects in humans, and induce cross-tolerance. The phenylalkylamine hallucinogens are selective 5-HT2 receptor agonists, whereas the indoleamines are relatively non-selective for serotonin (5-HT) receptors. There is extensive evidence, from both animal and human studies, that the characteristic effects of hallucinogens are mediated by interactions with the 5-HT2A receptor. Nevertheless, there is also evidence that interactions with other receptor sites contribute to the psychopharmacol. and behavioral effects of the indoleamine hallucinogens. This article reviews the evidence demonstrating that the effects of indoleamine hallucinogens in a variety of animal behavioral paradigms are mediated by both 5-HT2 and non-5-HT2 receptors.
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25. 25
  Halberstadt, A. L.; Nichols, D. E.; Geyer, M. A. Behavioral Effects of α,α,β,β-Tetradeutero-5-MeO-DMT in Rats: Comparison with 5-MeO-DMT Administered in Combination with a Monoamine Oxidase Inhibitor. Psychopharmacology 2012, 221, 709– 718, DOI: 10.1007/s00213-011-2616-6
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  25
  Behavioral effects of α,α,β,β-tetradeutero-5-MeO-DMT in rats: comparison with 5-MeO-DMT administered in combination with a monoamine oxidase inhibitor
  Halberstadt, Adam L.; Nichols, David E.; Geyer, Mark A.
  Psychopharmacology (Heidelberg, Germany) (2012), 221 (4), 709-718CODEN: PSCHDL; ISSN:0033-3158. (Springer)
  Ayahuasca is a psychoactive tea prepd. from a combination of plants that contain a hallucinogenic tryptamine and monoamine oxidase inhibitors (MAOIs). Behavioral pattern monitor (BPM) expts. demonstrated that the combination of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and a behaviorally inactive dose of an MAOA inhibitor such as harmaline or clorgyline induces biphasic effects on locomotor activity in rats, initially reducing locomotion and then increasing activity as time progresses. The present study investigated whether the biphasic locomotor profile induced by the combination of 5-MeO-DMT and an MAOI is a consequence of a redn. in the rate of 5-MeO-DMT metab. This hypothesis was tested using a deuterated deriv. of 5-MeO-DMT (α,α,β,β-tetradeutero-5-MeO-DMT) that is resistant to metab. by MAO. Confirming our previous findings, 1.0 mg/kg 5-MeO-DMT (s.c.) had biphasic effects on locomotor activity in rats pretreated with a behaviorally inactive dose of the nonselective MAOI pargyline (10 mg/kg). Administration of 5-MeO-DMT alone, even at doses > 1.0 mg/kg, produced only redns. in locomotor activity. Although low doses of α,α,β,β-tetradeutero-5-MeO-DMT (0.3 and 1.0 mg/kg, s.c.) produced only hypoactivity in the BPM, a dose of 3.0 mg/kg induced a biphasic locomotor profile similar to that produced by the combination of 5-MeO-DMT and an MAOI. Receptor binding studies demonstrated that deuterium substitution had little effect on the affinity of 5-MeO-DMT for a wide variety of neurotransmitter binding sites. The finding with α,α,β,β-tetradeutero-5-MeO-DMT indicates that the hyperactivity induced by 5-MeO-DMT after MAO inhibition is a consequence of reduced metab. of 5-MeO-DMT, leading to prolonged occupation of central serotonin receptors. These results demonstrate that deuterated tryptamines may be useful in behavioral and pharmacol. studies to mimic the effects of tryptamine/MAOI combinations.
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26. 26
  Krebs-Thomson, K.; Ruiz, E. M.; Masten, V.; Buell, M.; Geyer, M. A. The Roles of 5-HT1A and 5-HT2 Receptors in the Effects of 5-MeO-DMT on Locomotor Activity and Prepulse Inhibition in Rats. Psychopharmacology 2006, 189, 319– 329, DOI: 10.1007/s00213-006-0566-1
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  The roles of 5-HT1A and 5-HT2 receptors in the effects of 5-MeO-DMT on locomotor activity and prepulse inhibition in rats
  Krebs-Thomson, Kirsten; Ruiz, Erbert M.; Masten, Virginia; Buell, Mahalah; Geyer, Mark A.
  Psychopharmacology (Berlin, Germany) (2006), 189 (3), 319-329CODEN: PSCHDL; ISSN:0033-3158. (Springer GmbH)
  The hallucinogen 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is structurally similar to other indoleamine hallucinogens such as LSD. The present study examd. the effects of 5-MeO-DMT in rats using the Behavioral Pattern Monitor (BPM), which enables analyses of patterns of locomotor activity and exploration, and the prepulse inhibition of startle (PPI) paradigm. A series of interaction studies using the serotonin (5-HT)1A antagonist WAY-100635 (1.0 mg/kg), the 5-HT2A antagonist M100907 (1.0 mg/kg), and the 5-HT2C antagonist SER-082 (0.5 mg/kg) were performed to assess the resp. contributions of these receptors to the behavioral effects of 5-MeO-DMT (0.01, 0.1, and 1.0 mg/kg) in the BPM and PPI paradigms. 5-MeO-DMT decreased locomotor activity, investigatory behavior, the time spent in the center of the BPM chamber, and disrupted PPI. All of these effects were antagonized by WAY-100635 pretreatment. M100907 pretreatment failed to attenuate any of these effects, while SER-082 pretreatment only antagonized the PPI disruption produced by 5-MeO-DMT. While the prevailing view was that the activation of 5-HT2 receptors is solely responsible for hallucinogenic drug effects, these results support a role for 5-HT1A receptors in the effects of the indoleamine hallucinogen 5-MeO-DMT on locomotor activity and PPI in rats.
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  Krebs-Thomson, K.; Geyer, M. A. Evidence for a Functional Interaction between 5-HT(1A) and 5-HT2 Receptors in Rats. Psychopharmacology 1998, 140, 69– 74, DOI: 10.1007/s002130050740
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  27
  Evidence for a functional interaction between 5-HT1a and 5-HT2 receptors in rats
  Krebs-Thomson, Kirsten; Geyer, Mark A.
  Psychopharmacology (Berlin) (1998), 140 (1), 69-74CODEN: PSCHDL; ISSN:0033-3158. (Springer-Verlag)
  Evidence of a functional interaction between serotonin 5-HT1A and 5-HT2 receptor subtypes has been compromised by incomplete exptl. designs and conflicting data. To test for such an interaction, combinations of the 5-HT1A agonist 8-OH-DPAT and the 5-HT2 agonist DOI were administered to rats prior to testing of locomotor activity in the Behavioral Pattern Monitor (BPM). The BPM is an activity and holeboard chamber that enables analyses of quant. and qual. changes in locomotor and investigatory activity. Dose-response studies of 8-OH-DPAT and DOI alone and in the presence of selected doses of the other drug were performed in order to allow isobolog. anal., which characterizes the relationship of two drugs as either additive (no interaction), supra-additive, or infra-additive. Rats treated with saline, 8-OH-DPAT (6.25, 12.5, 25, or 50 μg/kg SC), DOI (0.15, 0.3, or 0.6 mg/kg SC), or selected combinations of both drugs were tested in the BPM for 1 h. Isobolog. anal. of the effects on locomotor activity revealed that 8-OH-DPAT and DOI interact in an infra-additive manner. Thus, at a functional level, 5-HT1A and 5-HT2 receptors interact antagonistically in the modulation of locomotor activity.
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28. 28
  Krebs, K. M.; Geyer, M. A. Cross-Tolerance Studies of Serotonin Receptors Involved in Behavioral Effects of LSD in Rats. Psychopharmacology 1994, 113, 429– 437, DOI: 10.1007/BF02245219
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  Cross-tolerance studies of serotonin receptors involved in behavioral effects of LSD in rats
  Krebs, Kirsten M.; Geyer, Mark A.
  Psychopharmacology (Berlin, Germany) (1994), 113 (3-4), 429-37CODEN: PSCHDL; ISSN:0033-3158.
  Like hallucinogenic 5-HT2 agonists, LSD (d-lysergic acid diethylamide) produces characteristic decreases in locomotor activity and investigatory behaviors of rats tested in a novel environment. Because LSD is an agonist at both 5-HT1A and 5-HT2 receptors, however, the resp. influences of these different receptors in the behavioral effects of LSD remain unclear. In particular, the paucity of selective 5-HT1A antagonists has made it difficult to assess the specific contribution of 5-HT1A receptors to the effects of LSD. An alternative approach to the delineation of receptor-specific effects is the use of cross-tolerance regimens. In the present studies, rats were pretreated with saline, 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT) (0.5 mg/kg SC), 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (1.0 mg/kg SC), or LSD (60 μg/kg SC), every 12 h for 5 or 8 days. Thirty-six hours later, rats were tested in a behavioral pattern monitor 10 min after injection of saline, 0.5 mg/kg 8-OH-DPAT, 1.0 mg/kg DOI, or 60 μg/kg LSD. As expected, tolerance to the decreases in locomotor activity produced by acute administrations of 8-OH-DPAT, DOI, or LSD occurred when rats were pretreated chronically with 8-OH-DPAT, DOI, or LSD resp. Furthermore, pretreatment with either 8-OH-DPAT or DOI produced cross-tolerance to LSD. These results support the hypothesis that the effects of LSD in this model reflect a combination of 5-HT1A and 5-HT2 effects and support the view that there is an interaction between 5-HT1A and 5-HT2 receptors.
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29. 29
  Data from the NIMH Psychoactive Drug Screening Program.
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30. 30
  Pokorny, T.; Preller, K. H.; Kraehenmann, R.; Vollenweider, F. X. Modulatory Effect of the 5-HT1A Agonist Buspirone and the Mixed Non-Hallucinogenic 5-HT1A/2A Agonist Ergotamine on Psilocybin-Induced Psychedelic Experience. Eur. Neuropsychopharmacol. 2016, 26, 756– 766, DOI: 10.1016/j.euroneuro.2016.01.005
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  30
  Modulatory effect of the 5-HT1A agonist buspirone and the mixed non-hallucinogenic 5-HT1A/2A agonist ergotamine on psilocybin-induced psychedelic experience
  Pokorny, Thomas; Preller, Katrin H.; Kraehenmann, Rainer; Vollenweider, Franz X.
  European Neuropsychopharmacology (2016), 26 (4), 756-766CODEN: EURNE8; ISSN:0924-977X. (Elsevier B.V.)
  The mixed serotonin (5-HT) 1A/2A/2B/2C/6/7 receptor agonist psilocybin dose-dependently induces an altered state of consciousness (ASC) that is characterized by changes in sensory perception, mood, thought, and the sense of self. The psychol. effects of psilocybin are primarily mediated by 5-HT2A receptor activation. However, accumulating evidence suggests that 5-HT1A or an interaction between 5-HT1A and 5-HT2A receptors may contribute to the overall effects of psilocybin. Therefore, we used a double-blind, counterbalanced, within-subject design to investigate the modulatory effects of the partial 5-HT1A agonist buspirone (20 mg p.o.) and the non-hallucinogenic 5-HT2A/1A agonist ergotamine (3 mg p.o.) on psilocybin-induced (170 μg/kg p.o.) psychol. effects in two groups (n=19, n=17) of healthy human subjects. Psychol. effects were assessed using the Altered State of Consciousness (5D-ASC) rating scale. Buspirone significantly reduced the 5D-ASC main scale score for Visionary Restructuralization (VR) (p<0.001), which was mostly driven by a redn. of the VR item cluster scores for elementary and complex visual hallucinations. Further, buspirone also reduced the main scale score for Oceanic Boundlessness (OB) including derealization and depersonalization phenomena at a trend level (p=0.062), whereas ergotamine did not show any effects on the psilocybin-induced 5D-ASC main scale scores. The present finding demonstrates that buspirone exerts inhibitory effects on psilocybin-induced effects, presumably via 5-HT1A receptor activation, an interaction between 5-HT1A and 5-HT2A receptors, or both. The data suggest that the modulation of 5-HT1A receptor activity may be a useful target in the treatment of visual hallucinations in different psychiatric and neurol. diseases.
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31. 31
  Shulgin, A.; Shulgin, A. TIHKAL: The Continuation; Transform Press: Berkeley, CA, 1997.
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  Ly, C.; Greb, A. C.; Cameron, L. P.; Wong, J. M.; Barragan, E. V.; Wilson, P. C.; Burbach, K. F.; Soltanzadeh Zarandi, S.; Sood, A.; Paddy, M. R.; Duim, W. C.; Dennis, M. Y.; McAllister, A. K.; Ori-McKenney, K. M.; Gray, J. A.; Olson, D. E. Psychedelics Promote Structural and Functional Neural Plasticity. Cell Rep. 2018, 23, 3170– 3182, DOI: 10.1016/j.celrep.2018.05.022
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  Psychedelics Promote Structural and Functional Neural Plasticity
  Ly, Calvin; Greb, Alexandra C.; Cameron, Lindsay P.; Wong, Jonathan M.; Barragan, Eden V.; Wilson, Paige C.; Burbach, Kyle F.; Soltanzadeh Zarandi, Sina; Sood, Alexander; Paddy, Michael R.; Duim, Whitney C.; Dennis, Megan Y.; McAllister, A. Kimberley; Ori-McKenney, Kassandra M.; Gray, John A.; Olson, David E.
  Cell Reports (2018), 23 (11), 3170-3182CODEN: CREED8; ISSN:2211-1247. (Cell Press)
  Atrophy of neurons in the prefrontal cortex (PFC) plays a key role in the pathophysiol. of depression and related disorders. The ability to promote both structural and functional plasticity in the PFC has been hypothesized to underlie the fast-acting antidepressant properties of the dissociative anesthetic ketamine. Here, we report that, like ketamine, serotonergic psychedelics are capable of robustly increasing neuritogenesis and/or spinogenesis both in vitro and in vivo. These changes in neuronal structure are accompanied by increased synapse no. and function, as measured by fluorescence microscopy and electrophysiol. The structural changes induced by psychedelics appear to result from stimulation of the TrkB, mTOR, and 5-HT2A signaling pathways and could possibly explain the clin. effectiveness of these compds. Our results underscore the therapeutic potential of psychedelics and, importantly, identify several lead scaffolds for medicinal chem. efforts focused on developing plasticity-promoting compds. as safe, effective, and fast-acting treatments for depression and related disorders.
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33. 33
  Nutt, D.; Erritzoe, D.; Carhart-Harris, R. Psychedelic Psychiatry’s Brave New World. Cell 2020, 181, 24– 28, DOI: 10.1016/j.cell.2020.03.020
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  Psychedelic Psychiatry's Brave New World
  Nutt, David; Erritzoe, David; Carhart-Harris, Robin
  Cell (Cambridge, MA, United States) (2020), 181 (1), 24-28CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
  A review. After a legally mandated, decades-long global arrest of research on psychedelic drugs, investigation of psychedelics in the context of psychiatric disorders is yielding exciting results. Outcomes of neuroscience and clin. research into 5-Hydroxytryptamine 2A (5-HT2A) receptor agonists, such as psilocybin, show promise for addressing a range of serious disorders, including depression and addiction.
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34. 34
  Davis, A. K.; Barrett, F. S.; May, D. G.; Cosimano, M. P.; Sepeda, N. D.; Johnson, M. W.; Finan, P. H.; Griffiths, R. R. Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder A Randomized Clinical Trial. JAMA Psychiatry 2020, DOI: 10.1001/jamapsychiatry.2020.3285
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  Gupta, D.; Bhatia, D.; Dave, V.; Sutariya, V.; Gupta, S. V. Salts of Therapeutic Agents: Chemical, Physicochemical, and Biological Considerations. Molecules 2018, 23, 1719 DOI: 10.3390/molecules23071719
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  Salts of therapeutic agents: chemical, physicochemical, and biological considerations
  Gupta, Deepak; Bhatia, Deepak; Dave, Vivek; Sutariya, Vijaykumar; Gupta, Sheeba Varghese
  Molecules (2018), 23 (7), 1719/1-1719/15CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)
  The physicochem. and biol. properties of active pharmaceutical ingredients (APIs) are greatly affected by their salt forms. The choice of a particular salt formulation is based on numerous factors such as API chem., intended dosage form, pharmacokinetics, and pharmacodynamics. The appropriate salt can improve the overall therapeutic and pharmaceutical effects of an API. However, the incorrect salt form can have the opposite effect, and can be quite detrimental for overall drug development. This review summarizes several criteria for choosing the appropriate salt forms, along with the effects of salt forms on the pharmaceutical properties of APIs. In addn. to a comprehensive review of the selection criteria, this review also gives a brief historic perspective of the salt selection processes.
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36. 36
  Chadeayne, A. R.; Golen, J. A.; Manke, D. R. Bis(4-Acetoxy- N, N -Dimethyltryptammonium) Fumarate: A New Crystalline Form of Psilacetin, an Alternative to Psilocybin as a Psilocin Prodrug. Acta Crystallogr., Sect. E 2019, 75, 900– 902, DOI: 10.1107/S2056989019007370
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  Bis(4-acetoxy-N,N-dimethyltryptammonium) fumarate: a new crystalline form of psilacetin, an alternative to psilocybin as a psilocin prodrug
  Chadeayne, Andrew R.; Golen, James A.; Manke, David R.
  Acta Crystallographica, Section E: Crystallographic Communications (2019), 75 (6), 900-902CODEN: ACSECI; ISSN:2056-9890. (International Union of Crystallography)
  The title compd. (systematic name: bis{2-[4-(acetyloxy)-1H-indol-3-yl]ethan-1-aminium} but-2-enedioate), 2C14H19N2O2+·C4H2O42-, has a single protonated psilacetin cation and one half of a fumarate dianion in the asym. unit. There are N-H···O hydrogen bonds between the ammonium H atoms and the fumarate O atoms, as well as N-H···O hydrogen bonds between the indole H atoms and the fumarate O atoms. The hydrogen bonds hold the ions together in infinite one-dimensional chains along [111].
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37. 37
  Strassman, R. J.; Qualls, C. R.; Berg, L. M. Differential Tolerance to Biological and Subjective Effects of Four Closely Spaced Doses of N,N-Dimethyltryptamine in Humans. Biol. Psychiatry 1996, 39, 784– 795, DOI: 10.1016/0006-3223(95)00200-6
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  Differential tolerance to biological and subjective effects of four closely spaced doses of N,N-dimethyltryptamine in humans
  Strassman, Rick J.; Qualls, Clifford R.; Berg, Laura M.
  Biological Psychiatry (1996), 39 (9), 784-795CODEN: BIPCBF; ISSN:0006-3223. (Elsevier)
  Tolerance to the behavioral effects of the short-acting, endogenous hallucinogen, N,N-dimethyltryptamine (DMT) is seen inconsistently in animals, and has not been produced in humans. The nature and time course of responses to repetitive, closely spaced administrations of an hallucinogenic dose of DMT were characterized. Thirteen experienced hallucinogen users received i.v. 0.3 mg/kg DMT fumarate, or saline placebo, four times, at 30 min intervals, on 2 sep. days, in a randomized, double-blind, design. Tolerance to "psychedelic" subjective effects did not occur according to either clin. interview or Hallucinogen Rating Scale scores. Adrenocorticotropic hormone (ACTH), prolactin, cortisol, and heart rate responses decreased with repeated DMT administration, although blood pressure did not. These data demonstrate the unique properties of DMT relative to other hallucinogens and underscore the differential regulation of the multiple processes mediating the effects of DMT.
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38. 38
  Ludvigsson, J. W.; Wikström, H.; Andersson, T.; Norrby, P. O. Degradation Caused by Incompatibility between Sodium Stearyl Fumarate (PRUV) and AZD7986 in the Drug Product. J. Pharm. Biomed. Anal. 2018, 158, 82– 87, DOI: 10.1016/j.jpba.2018.05.036
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  Degradation caused by incompatibility between sodium stearyl fumarate (PRUV) and AZD7986 in the drug product
  Ludvigsson, Jufang Wu; Wikstroem, Haakan; Andersson, Thomas; Norrby, Per-Ola
  Journal of Pharmaceutical and Biomedical Analysis (2018), 158 (), 82-87CODEN: JPBADA; ISSN:0731-7085. (Elsevier B.V.)
  During compatibility study of the AZD7986 project, a peak of 3 area% at the tail (RRT 1.03) of the active pharmaceutical ingredient (API) was discovered for all tablets contg. sodium stearyl fumarate (PRUV) under humid condition (e.g. 50 °C/75% RH), regardless of choice of disintegrant or filler combination. The degradant was needed to be identified to understand the corresponding reaction mechanism and help the final formulation design. Structure elucidation was therefore done by anal. using high resoln. mass spectrometry. The degradant was found to be a Michael addn. product of the API and fumaric acid. Reaction between deuterated fumaric acid and the API was carried to confirm the proposed structure and reaction mechanism. Fumaric acid was a degradant product of PRUV in the presence of other excipients, revealed by the stability study. The Michael addn. reaction needs facilitation by water and basic conditions. The result from this study should serve as a precaution note for projects using PRUV as one of excipients where the API could act as a nucleophile. In such cases the microenvironment should be optimized to minimize the reaction, such as pH adjustment and incorporating protection from moisture.
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39. 39
  Do, J.; Kang, J.; Lee, Y.; Ok, K. M.; Jacobson, A. J. Copper(II) Complexes with N-Substituted Aspartic Acids: A New One-Pot Synthesis Method via in Situ Michael Addition of Amines to Fumaric Acid. Inorg. Chim. Acta 2015, 430, 280– 287, DOI: 10.1016/j.ica.2015.03.020
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  Copper(II) complexes with N-substituted aspartic acids: A new one-pot synthesis method via in situ Michael addition of amines to fumaric acid
  Do, Junghwan; Kang, Jaeun; Lee, Yumi; Ok, Kang Min; Jacobson, Allan J.
  Inorganica Chimica Acta (2015), 430 (), 280-287CODEN: ICHAA3; ISSN:0020-1693. (Elsevier B.V.)
  The hydrothermal reaction of fumaric acid, benzylamine and cuprous chloride yielded Cu[(rac-N-benzyl-Asp)(benzylamine)(H2O)] (1), while ethylenediamine, 1,3-diaminopropane and piperazine produced Cu[rac-N-aminoethyl-Asp] (2), Cu[rac-N-aminopropyl-Asp] (3) and Cu[rac-piperazinyl succinate]2 (4), resp. Under mild hydrothermal conditions, Michael addn. of benzylamine, ethylenediamine, 1,3-diaminopropane and piperazine to fumaric acid gave racemic mixts. of N-benzyl aspartic acid, N-aminoethyl aspartic acid, N-aminopropyl aspartic acid and piperazinyl succinic acid, resp. The structure of 1 consists of 1-dimensional polymeric chains in which copper cations are bridged by D- and L-N-benzyl aspartate anions alternatively along the chain. Addnl. benzylamine and water mols. bond to copper cations to complete the Cu[(rac-N-benzyl-Asp)(benzylamine)(H2O)] chain. The structures of 2 and 3 consist of 1-dimensional polymeric chains in which copper cations are bridged by D- and L-N-aminoethyl and aminopropyl aspartate anions alternatively along the chains. The structure of 4 is composed of discrete Cu[rac-piperazinyl succinate]2 units that are connected by hydrogen bonds.
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40. 40
  Brandt, S. D.; Moore, S. A.; Freeman, S.; Kanu, A. B. Characterization of the Synthesis of N,N-Dimethyltryptamine by Reductive Amination Using Gas Chromatography Ion Trap Mass Spectrometry. Drug Test. Anal. 2010, 2, 330– 338, DOI: 10.1002/dta.142
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  Characterization of the synthesis of N,N-dimethyltryptamine by reductive amination using gas chromatography ion trap mass spectrometry
  Brandt, Simon D.; Moore, Sharon A.; Freeman, Sally; Kanu, Abu B.
  Drug Testing and Analysis (2010), 2 (7), 330-338CODEN: DTARBG; ISSN:1942-7603. (John Wiley & Sons Ltd.)
  The present study established an impurity profile of a synthetic route to the hallucinogenic N,N-dimethyltryptamine (DMT). The synthesis was carried out under reductive amination conditions between tryptamine and aq. formaldehyde in the presence of acetic acid followed by redn. with sodium cyanoborohydride. Anal. characterization of this synthetic route was carried out by gas chromatog. ion trap mass spectrometry using electron- and chem.-ionization modes. Methanol was employed as a liq. Cl reagent and the impact of stoichiometric modifications on side-products formation was also investigated. Tryptamine 1, DMT 2, 2-methyltetrahydro-β-carboline (2-Me-THBC, 3), N-methyl-N-cyanomethyltryptamine (MCMT, 4), N-methyltryptamine (NMT, 5), 2-cyanomethyl-tetrahydro-β-carboline (2-CM-THBC, 6) and tetrahydro-β-carboline (THBC, 7) have been detected under a variety of conditions. Replacement of formaldehyde soln. with paraformaldehyde resulted in incomplete conversion of the starting material whereas a similar replacement of sodium cyanoborohydride with sodium borohydride almost exclusively produced THBC instead of the expected DMT. Compds. 1 to 7 were quantified and the limits of detection were 28.4, 87.7, 21.5, 23.4, 41.1, 36.6, and 34.9 ng mL-1, resp. The limits of quantification for compds. 1 to 7 were 32.4, 88.3, 25.4, 24.6, 41.4, 39.9, and 37.0 μg mL-1, resp. Linearity was obsd. in the range of 20.8-980 μg mL-1 with correlation coeffs. >0.99. The application holds great promise in the area of forensic chem. where development of reliable anal. methods for the detection, identification, and quantification of DMT are crucial and also in pharmaceutical anal. where DMT might be prepd. for use in human clin. studies.
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41. 41
  Speeter, M. E.; Anthony, W. C. The Action of Oxalyl Chloride on Indoles: A New Approach to Tryptamines. J. Am. Chem. Soc. 1954, 76, 6208– 6210, DOI: 10.1021/ja01652a113
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  The action of oxalyl chloride on indoles: a new approach to tryptamines
  Speeter, Merrill E.; Anthony, Wm. C.
  Journal of the American Chemical Society (1954), 76 (), 6208-10CODEN: JACSAT; ISSN:0002-7863.
  cf. C.A. 46, 9544i. To obtain bufotenine and its relatives in quantity for study of their central nervous system effects, a new tryptamine synthesis was developed which is of wide scope and general application. The reaction of (COCl)2 (I) with indole yields 3-indoleglyoxylyl chloride (II) instead of the 2-isomer as reported by Giua (C.A. 19, 280). II with NH3 yielded the amide, which with LiAlH4 gave tryptamine. LiAlH4 and Et 3-indoleglyoxalate (III) yielded tryptophol. Indolemagnesium iodide and EtO2CCOCl yielded III, m. 183-5°. I with indoles can be used to prep. a variety of cryst. glyoxylyl chloride derivs., e.g., from 2-methylindole, 2-phenylindole, 5,6-dimethoxyindole, 5-acetoxyindole, 5-benzyloxyindole, 6-acetoxy-7-methoxyindole, and 1-benz(g)indole. LiAlH4 and the amides from the preceding glyoxylyl chlorides gave tryptamines in good yield. Crude 5-benzyloxy-3-indoleglyoxylyl chloride (IIIA), m. 146-50° (decompn.), and (PhCH2)2NH yielded 91% 5-benzyloxy-3-indole-N,N-dibenzylglyoxylamide (IV), m. 150-1°. IV with LiAlH4 yielded 92% 5-benzyloxy-3-(2-dibenzylaminoethyl)indole (V); HCl salt, m. 232-3°. V was catalytically debenzylated to serotonin. The creatinine sulfate complex prepd. from this serotonin was identical with that prepd. from serotonin previously. IIIA with Me2NH yielded 5-benzyloxy-N,N-dimethyl-3-indoleglyoxylamide (VI), m. 178-80.5°. VI with LiAlH4 gave 5-benzyloxy-3-(2-dimethylaminoethyl)indole (VII); HCl salt, m. 154-5°. Debenzylation of VII gave bufotenine, m. 146-7°; picrate identical with the natural picrate.
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42. 42
  Kargbo, R. B.; Sherwood, A.; Walker, A.; Cozzi, N. V.; Dagger, R. E.; Sable, J.; O’Hern, K.; Kaylo, K.; Patterson, T.; Tarpley, G.; Meisenheimer, P. Direct Phosphorylation of Psilocin Enables Optimized CGMP Kilogram-Scale Manufacture of Psilocybin. ACS Omega 2020, 5, 16959– 16966, DOI: 10.1021/acsomega.0c02387
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  Direct Phosphorylation of Psilocin Enables Optimized cGMP Kilogram-Scale Manufacture of Psilocybin
  Kargbo, Robert B.; Sherwood, Alexander; Walker, Andrew; Cozzi, Nicholas V.; Dagger, Raymond E.; Sable, Jessica; O'Hern, Kelsey; Kaylo, Kristi; Patterson, Tura; Tarpley, Gary; Meisenheimer, Poncho
  ACS Omega (2020), 5 (27), 16959-16966CODEN: ACSODF; ISSN:2470-1343. (American Chemical Society)
  A second-generation kilogram-scale synthesis of the psychedelic tryptamine psilocybin has been developed. The synthesis was designed to address several challenges first encountered with the scale-up of previously described literature procedures, which were not optimized for providing consistent yield and purity of products, atom economy, or being run in pilot plant-scale reactors. These challenges were addressed and circumvented with the design of the second-generation route, which featured an optimized cGMP large-scale Speeter-Anthony tryptamine synthesis to the intermediate psilocin with improved in-process control and impurity removal over the three steps. Psilocin was subsequently phosphorylated directly with phosphorous oxychloride for the first time, avoiding a tedious and poor atom economy benzyl-protecting group strategy common to all previously described methods for producing psilocybin. In this report, the challenges encountered in a 100 g scale first-generation literature-based synthesis are highlighted, followed by a detailed description of the newly developed second-generation synthesis to provide over one kilogram of high-purity psilocybin under cGMP.
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43. 43
  Shirota, O.; Hakamata, W.; Goda, Y. Concise Large-Scale Synthesis of Psilocin and Psilocybin, Principal Hallucinogenic Constituents of “Magic Mushroom. J. Nat. Prod. 2003, 66, 885– 887, DOI: 10.1021/np030059u
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  Concise Large-Scale Synthesis of Psilocin and Psilocybin, Principal Hallucinogenic Constituents of "Magic Mushroom"
  Shirota, Osamu; Hakamata, Wataru; Goda, Yukihiro
  Journal of Natural Products (2003), 66 (6), 885-887CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society)
  The concise large-scale syntheses of psilocin and psilocybin, the principal hallucinogenic constituents of "magic mushroom", were achieved without chromatog. purifn. The key step in the synthesis of psilocybin was the isolation of the dibenzyl-protected intermediate as a zwitterionic deriv. I, which was completely identified by means of 2D NMR analyses.
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44. 44
  Nichols, D. E. Improvements to the Synthesis of Psilocybin and a Facile Method for Preparing the O-Acetyl Prodrug of Psilocin. Synthesis 1999, 1999, 935– 938, DOI: 10.1055/s-1999-3490
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  Crookes, D. L.; Parry, K. P.; Smith, G. F. 2-(Indol-3′-Yl)-2-Hydroxy-N,N-Dimethylethylamine and 2-(Indol-3′-Yl)-2[3″-[2’’’-(N,N-Dimethylamino) Ethyl]Indol-2″-Yl]-N,N-Dimethylethylamine, by-Products in the LAH Reduction of 3-Indoleglyoxyl- N,N-Dimethylamide. Pol. J. Chem. 1979, 53, 73– 78
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  2-(Indol-3'-yl)-2-hydroxy-N,N-dimethylethylamine and 2-(indol-3'-yl)-2[3''-[2'''-(N,N-dimethylamino)ethyl]indol-2''-yl]-N,N-dimethylethylamine, by-products in the LAH reduction of 3-indoleglyoxyl-N,N-dimethylamide
  Crookes, D. L.; Parry, K. P.; Smith, G. F.
  Polish Journal of Chemistry (1979), 53 (1), 73-8CODEN: PJCHDQ; ISSN:0137-5083.
  LiAlH4 redn. of RCOCONMe2 (R = 3-indolyl) gave RCH2CH2NMe2 and RCH(OH)CH2NMe2, which reacted together to give dimer I.
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46. 46
  Chen, C.-y.; Senanayake, C. H.; Bill, T. J.; Larsen, R. D.; Verhoeven, T. R.; Reider, P. J. Improved Fischer Indole Reaction for the Preparation of N,N-Dimethyltryptamines: Synthesis of L-695,894, a Potent 5-HT1D Receptor Agonist. J. Org. Chem. 1994, 59, 3738– 3741, DOI: 10.1021/jo00092a046
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  Improved Fischer Indole Reaction for the Preparation of N,N-Dimethyltryptamines: Synthesis of L-695,894, a Potent 5-HT1D Receptor Agonist
  Chen, Cheng-yi; Senanayake, Chris H.; Bill, Timothy J.; Larsen, Robert D.; Verhoeven, Thomas R.; Reider, Paul J.
  Journal of Organic Chemistry (1994), 59 (13), 3738-41CODEN: JOCEAH; ISSN:0022-3263.
  A facile prepn. of 5-substituted-N,N-dimethyltryptamines using an improved Fischer indole reaction is described. This methodol. has been applied to the synthesis of the novel 5-HT1D agonist L-695,894 (I), a potential antimigraine drug.
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  Baumann, M.; Baxendale, I. R.; Ley, S. V.; Nikbin, N. An Overview of the Key Routes to the Best Selling 5-Membered Ring Heterocyclic Pharmaceuticals. Beilstein J. Org. Chem. 2011, 7, 442– 495, DOI: 10.3762/bjoc.7.57
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  An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals
  Baumann, Marcus; Baxendale, Ian R.; Ley, Steven V.; Nikbin, Nikzad
  Beilstein Journal of Organic Chemistry (2011), 7 (), 442-495, No. 57CODEN: BJOCBH; ISSN:1860-5397. (Beilstein-Institut zur Foerderung der Chemischen Wissenschaften)
  This review presents a comprehensive overview on selected synthetic routes towards com. drug compds. as published in both journal and patent literature. Owing to the vast no. of potential structures, we have concd. only on those drugs contg. five-membered heterocycles and focused principally on the assembly of the heterocyclic core. In order to target the most representative chem. entities, the examples discussed have been selected from the top 200 best selling drugs of recent years.
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48. 48
  Brandt, S. D.; Martins, C. P. B.; Freeman, S.; Dempster, N.; Riby, P. G.; Gartz, J.; Alder, J. F. Halogenated Solvent Interactions with N,N-Dimethyltryptamine: Formation of Quaternary Ammonium Salts and Their Artificially Induced Rearrangements during Analysis. Forensic Sci. Int. 2008, 178, 162– 170, DOI: 10.1016/j.forsciint.2008.03.013
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  Halogenated solvent interactions with N,N-dimethyltryptamine: Formation of quaternary ammonium salts and their artificially induced rearrangements during analysis
  Brandt, Simon D.; Martins, Claudia P. B.; Freeman, Sally; Dempster, Nicola; Riby, Philip G.; Gartz, Jochen; Alder, John F.
  Forensic Science International (2008), 178 (2-3), 162-170CODEN: FSINDR; ISSN:0379-0738. (Elsevier Ltd.)
  The psychoactive properties of N,N-dimethyltryptamine (DMT) 1a are known to induce altered states of consciousness in humans. This particular attribute attracts great interest from a variety of scientific and also clandestine communities. Our recent research has confirmed that DMT reacts with dichloromethane (DCM), either as a result of work-up or storage to give a quaternary N-chloromethyl ammonium salt. Furthermore, this was obsd. to undergo rearrangement during anal. using gas chromatog.-mass spectrometry (GC-MS) with products including 3-(2-chloroethyl)indole and 2-methyltetrahydro-β-carboline (2-Me-THBC). This study further investigates this so far unexplored area of solvent interactions by the exposure of DMT to other halogenated solvents including dibromomethane and 1,2-dichloroethane (DCE). The N-bromomethyl- and N-chloroethyl quaternary ammonium derivs. were subsequently characterized by ion trap GC-MS in electron and chem. ionization tandem MS mode and by NMR spectroscopy. The DCE-derived deriv. formed at least six rearrangement products in the total ion chromatogram. Identification of mass spectrometry generated byproducts was verified by conventional or microwave-accelerated synthesis. The use of deuterated DCM and deuterated DMT provided insights into the mechanism of the rearrangements. The presence of potentially characteristic marker mols. may allow the identification of solvents used during the manuf. of controlled substances, which is often neglected since these are considered inert.
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  Dunlap, L. E.; Olson, D. E. Reaction of N, N-Dimethyltryptamine with Dichloromethane under Common Experimental Conditions. ACS Omega 2018, 3, 4968– 4973, DOI: 10.1021/acsomega.8b00507
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  Reaction of N,N-Dimethyltryptamine with Dichloromethane Under Common Experimental Conditions
  Dunlap, Lee E.; Olson, David E.
  ACS Omega (2018), 3 (5), 4968-4973CODEN: ACSODF; ISSN:2470-1343. (American Chemical Society)
  A large no. of clin. used drugs and exptl. pharmaceuticals possess the N,N-dimethyltryptamine (DMT) structural core. Previous reports have described the reaction of this motif with dichloromethane (DCM), a common lab. solvent used during extn. and purifn., leading to the formation of an undesired quaternary ammonium salt byproduct. However, the kinetics of this reaction under various conditions have not been thoroughly described. Here, we report a series of expts. designed to simulate the exposure of DMT to DCM that would take place during extn. from plant material, biphasic aq. work-up, or column chromatog. purifn. We find that the quaternary ammonium salt byproduct forms at an exceedingly slow rate, only accumulates to a significant extent upon prolonged exposure of DMT to DCM, and is readily extd. into water. Our results suggest that DMT can be exposed to DCM under conditions where contact times are limited (<30 min) with minimal risk of degrdn. and that this byproduct is not obsd. following aq. extn. However, alternative solvents should be considered when the exptl. conditions require longer contact times. Our work has important implications for prepg. a wide-range of pharmaceuticals bearing the DMT structural motif in high yields and purities.
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  El Jaber-Vazdekis, N.; Gutierrez-Nicolás, F.; Ravelo, Á. G.; Zárate, R. Studies on Tropane Alkaloid Extraction by Volatile Organic Solvents: Dichloromethane vs. Chloroform. Phytochem. Anal. 2006, 17, 107– 113, DOI: 10.1002/pca.893
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  Phytochemical Analysis (2006), 17 (2), 107-113CODEN: PHANEL; ISSN:0958-0344. (John Wiley & Sons Ltd.)
  In order to investigate the prodn. of tropane alkaloids by hairy roots of Atropa baetica, transgenic for the gene h6h encoding the enzyme hyoscyamine 6β-hydroxylase, solvent extn. with chloroform and with dichloromethane of the metabolites present in the liq. medium and in the root tissue was compared. The extn. of scopolamine from the liq. medium was equally effective with either solvent, giving max. values of around 850 μg/flask. For the roots, 3 different extn. methods were employed: A, employing chloroform:methanol: (25%) ammonia (15:5:1) for initial extn., followed by treatment with sulfuric acid and ammonia, and using chloroform for the final extn. and washes: B, as A but using dichloromethane for extn. and washes: and C, as B but substituting chloroform for dichloromethane in the extn. cocktail. Scopolamine was the most abundant metabolite (present in amts. of 3250-3525 μg/g dry wt.) and presented similar extn. efficiencies with all of the extn. methods employed. The highest amts. of hyoscyamine and the intermediate 6β-hydroxyhyoscyamine were present on day 31 (800 and 975 μg/g dry wt., resp.) and no statistical differences between the 3 extn. methods employed were detected. This study confirms that, for the extn. of tropane alkaloids, dichloromethane can replace the commonly employed chloroform, the use of which incurs major health, security and regulation problems.
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  Brandt, S. D.; Martins, C. P. B.; Freeman, S.; Dempster, N.; Wainwright, M.; Riby, P. G.; Alder, J. F. N,N-Dimethyltryptamine and Dichloromethane: Rearrangement of Quaternary Ammonium Salt Product during GC-EI and CI-MS-MS Analysis. J. Pharm. Biomed. Anal. 2008, 47, 207– 212, DOI: 10.1016/j.jpba.2007.12.024
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  N,N-Dimethyltryptamine and dichloromethane: Rearrangement of quaternary ammonium salt product during GC-EI and CI-MS-MS analysis
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  Journal of Pharmaceutical and Biomedical Analysis (2008), 47 (1), 207-212CODEN: JPBADA; ISSN:0731-7085. (Elsevier B.V.)
  N,N-Dimethyltryptamine (DMT) is a simple tryptamine deriv. with powerful psychoactive properties. It is abundant in nature and easily accessible through a variety of synthetic routes. Most work-up procedures require the use of org. solvents and halogenated representatives are often employed. DMT was found to be reactive towards dichloromethane, either during work-up or long term storage therein, which led to the formation of the quaternary ammonium salt N-chloromethyl-DMT chloride (I). Anal. of this side-product by gas chromatog. ion trap mass spectrometry (GC-MS), both in electron and chem. ionization tandem MS modes, gave only degrdn. products. For example, I could not be detected but appeared to have rearranged to 3-(2-chloroethyl)indole (II) and 2-methyltetrahydro-β-carboline (III), whereas HPLC anal. enabled the detection of I. GC-MS is a std. tool for the fingerprinting of drug products. The identification of a particular synthetic route is based on the anal. of impurities, provided these side products can be established to be route-specific. The in situ detection of both II and III within a DMT sample may have led to erroneous conclusions with regards to the identification of the synthetic route.
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  Solvent Applications of 2-Methyltetrahydrofuran in Organometallic and Biphasic Reactions
  Aycock, David F.
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  2-Methyltetrahydrofuran (MeTHF) is a com. available solvent that is produced from renewable resources. The properties of MeTHF place it between THF and Et2O in solvent polarity and Lewis base strength. In many cases, MeTHF can replace THF in organometallic reactions. The formation and reaction of Grignard reagents in MeTHF and THF are similar. MeTHF can be used as a solvent for low-temp. lithiation, for lithium aluminum hydride redns., for the Reformatskii reaction, and for metal-catalyzed coupling reactions. MeTHF is also a good substitute for dichloromethane in biphasic reactions.
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54. 54
  Shen, H.-W.; Jiang, X.-L.; C. Winter, J.; Yu, A.-M. Psychedelic 5-Methoxy-N,N-Dimethyltryptamine: Metabolism, Pharmacokinetics, Drug Interactions, and Pharmacological Actions. Curr. Drug Metab. 2010, 11, 659– 666, DOI: 10.2174/138920010794233495
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  Psychedelic 5-methoxy-N,N-dimethyltryptamine: metabolism, pharmacokinetics, drug interactions, and pharmacological actions
  Shen, Hong-Wu; Jiang, Xi-Ling; Winter, Jerrold C.; Yu, Ai-Ming
  Current Drug Metabolism (2010), 11 (8), 659-666CODEN: CDMUBU; ISSN:1389-2002. (Bentham Science Publishers Ltd.)
  A review. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) belongs to a group of naturally-occurring psychoactive indolealkylamine drugs. It acts as a nonselective serotonin (5-HT) agonist and causes many physiol. and behavioral changes. 5-MeO-DMT is O-demethylated by polymorphic cytochrome P 450 2D6 (CYP2D6) to an active metabolite, bufotenine, while it is mainly inactivated through the deamination pathway mediated by monoamine oxidase A (MAO-A). 5-MeO-DMT is often used with MAO-A inhibitors such as harmaline. Concurrent use of harmaline reduces 5-MeO-DMT deamination metab. and leads to a prolonged and increased exposure to the parent drug 5-MeO-DMT, as well as the active metabolite bufotenine. Harmaline, 5-MeO-DMT and bufotenine act agonistically on serotonergic systems and may result in hyperserotonergic effects or serotonin toxicity. Interestingly, CYP2D6 also has important contribution to harmaline metab., and CYP2D6 genetic polymorphism may cause considerable variability in the metab., pharmacokinetics and dynamics of harmaline and its interaction with 5-MeO-DMT. Therefore, this review summarizes recent findings on biotransformation, pharmacokinetics, and pharmacol. actions of 5-MeO-DMT. In addn., the pharmacokinetic and pharmacodynamic drug-drug interactions between harmaline and 5-MeO-DMT, potential involvement of CYP2D6 pharmacogenetics, and risks of 5-MeO-DMT intoxication are discussed.
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- Certificate of analysis for 5-MeO-DMT succinate salt; solubility data; characterization data; polymorph screen summary and results; HPLC methodology and chromatograms; impurity identification and characterization (PDF)
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Synthesis and Characterization of 5-MeO-DMT Succinate for Clinical Use

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Abstract

Introduction

Figure 1

Figure 2

Results and Discussion

5-MeO-DMT Dosage and Salt Form Selection

5-MeO-DMT Route Scouting

Route 1

Scheme 1

Route 2

Scheme 2

Route 3

Scheme 3

Optimization of Workup, Isolation, and Salt Formation

Workup

Scheme 4

Freebase Purification

Scheme 5

Scheme 6

Succinate Salt Formation

Future Optimization

Conclusions

Experimental Section

General Experimental Methods

2-(5-Methoxy-1H-indol-3-yl)-N,N-dimethylethanamine (6-freebase)

2-(5-Methoxy-1H-indol-3-yl)-N,N-dimethylethanamine (6-succinate (1:1))

2-(5-Methoxy-1H-indol-3-yl)-N,N-dimethylethan-1-amine oxide (21)

Supporting Information

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Author Information

Acknowledgments

References

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Abstract

Figure 1

Figure 2

Scheme 1

Scheme 2

Scheme 3

Scheme 4

Scheme 5

Scheme 6

References

Supporting Information

Supporting Information

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