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The Subjective Effects of Psychedelics May Not Be Necessary for Their Enduring Therapeutic EffectsClick to copy article linkArticle link copied!
- David E. Olson*David E. Olson*Email: [email protected]Department of Chemistry, University of California, Davis, One Shields Avenue, Davis, California 95616, United StatesDepartment of Biochemistry & Molecular Medicine, School of Medicine, University of California, Davis, 2700 Stockton Blvd, Suite 2102, Sacramento, California 95817, United StatesCenter for Neuroscience, University of California, Davis, 1544 Newton Court, Davis, California 95618, United StatesMore by David E. Olson
Abstract
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Psychedelics represent one of the most promising classes of experimental medicines for the treatment of neuropsychiatric disorders due to their ability to promote neural plasticity and produce both rapid and sustained therapeutic effects following a single administration. Conventional wisdom holds that peak mystical experiences induced by psychedelics are a critical component of their therapeutic mechanisms of action, though evidence supporting that claim is largely correlational. Here, I present data suggesting that the subjective effects induced by psychedelics may not be necessary to produce long-lasting changes in mood and behavior. Understanding the role of subjective effects in the therapeutic mechanisms of psychedelics will have important implications for both basic neuroscience and for increasing patient access to the next generation of medicines developed as a result of psychedelic research.
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Neuropsychiatric diseases such as depression, post-traumatic stress disorder (PTSD), and addiction are among the greatest contributors to disability worldwide, (1) but unfortunately, traditional treatments have proven largely ineffective with long therapeutic lag times and a significant portion of the patient population remaining treatment-resistant. (2) The advent of psychoplastogens (3)—compounds with the abilities to rapidly rewire neural circuitry by engaging plasticity mechanisms—represents a new era in the development of neurotherapeutics focused on fixing neural circuits rather than rectifying chemical imbalances. Because psychoplastogens are quite effective at promoting the growth of cortical pyramidal neurons, they are particularly well suited to treat illnesses characterized by the atrophy of neurons in the prefrontal cortex (PFC) such as stress-related neuropsychiatric diseases.
Ketamine is one of the best known psychoplastogens, and the recent approval of esketamine (the S-enantiomer of ketamine) for treatment-resistant depression represents an important milestone for psychiatry given that ketamine’s mechanism of action is unlike anything previously found in psychiatry’s arsenal. By producing long-lasting changes in neuronal structure and function, psychoplastogens have the potential to produce sustained behavioral effects after a single administration.
Dissociative, deliriant, and hallucinogenic drugs have emerged as some of the most effective psychoplastogens. (3) Among these mind-altering substances, psychedelics have distinguished themselves by their dramatic, long-lasting effects on cortical neuron structure and function (4) and sustained (>6 months) antidepressant, anxiolytic, and antiaddictive effects in the clinic. (5) A critical question for the field to address is whether or not the acute subjective effects of these drugs are necessary to produce long-lasting therapeutic responses. Not only will research in this area help us to better understand their psychological and neurobiological mechanisms of action, it has the potential to have real world consequences for how we might treat patients in the future.
While psilocybin treatment is demonstrating impressive clinical efficacy across a broad range of stress-related neuropsychiatric diseases, (5) this treatment strategy is limited by the significant healthcare costs associated with it. Due to the powerful subjective effects of the drug, healthcare professionals must provide support before, during, and after treatment to prepare patients for the subjective effects of the drug, ensure that no harm comes to them during the altered state of consciousness, and help them integrate their experience. Psilocybin induces subjective effects that last for several hours, prompting the exploration of shorter-acting psychedelics to minimize the time patients must spend in the clinic. (6)
In addition to the substantial healthcare costs associated with using psychedelics as medicines, many patients may be reluctant to participate in psychedelic-assisted therapy given that there is a risk for short-term anxiety and/or psychological distress. Moreover, psychedelic-assisted therapy is contraindicated for those with a family history of psychotic disorders, which is problematic given the overlapping genetics and comorbidity of neuropsychiatric diseases. Patient throughput is an important consideration given the prevalence of mental illness, with some estimates suggesting that roughly 20% of the population suffers from a neuropsychiatric disease at any given time. (2) If the subjective effects of psychedelics are not necessary for their long-lasting antidepressant, anxiolytic, and antiaddictive properties, new medicines and/or treatment approaches could potentially be devised to greatly improve patient access to therapies inspired by psychedelic research.
Clinical studies on psychedelics have been challenged by the unique ability of these drugs to induce profound altered states of consciousness, making the design of truly double-blind, placebo-controlled studies exceedingly difficult. Though modern clinical studies on psychedelics have made the admirable attempt to mitigate this issue and reduce expectations by incorporating “active placebos” (e.g., niacin or a low-dose of a psychedelic) into their designs, (7,8) a large proportion of both patients and clinicians are still able to correctly distinguish between a high dose of a psychedelic drug and an active placebo. Thus, it is still unclear what role placebo effects play in the overall efficacy of psychedelic-assisted therapy.
Patients who are treated with psychedelic-assisted therapy often attribute the amelioration of their symptoms to a psychological breakthrough achieved during a psychedelic-induced altered state of consciousness. This is not surprising given that many people rate psychedelic experiences as being among the most profound and meaningful events in their lives that can lead to long-lasting changes in their worldviews. (9) Research has consistently shown that the intensity of “mystical” or “peak” experiences induced by psychedelics positively correlates with therapeutic responses. (7,8,10−12) Similar results have been reported for ketamine. (13−15)
While studies associating mystical experiences with improved patient outcomes are quite intriguing, it is important to remember that correlation does not imply causation, and thus, we cannot definitively say that the subjective effects induced by psychedelics cause therapeutic responses. These experiences might contribute to therapeutic responses, but they may not be necessary to produce antidepressant, anxiolytic, and antiaddictive effects. In fact, many patients treated with psychedelics who do not have full mystical experiences still find psychedelic treatment to be beneficial, while others who do have full mystical experiences do not necessarily experience substantial reduction in disease symptoms. (11,16)
Perhaps one of the more compelling arguments supporting the notion that “mystical” or “peak” experiences play a critical role in psychedelic-induced therapeutic responses is related to the fact that mystical-type effects better correlate with antidepressant, anxiolytic, and antiaddictive outcomes than do the intensities of general subjective drug effects. (11,12) However, mystical-type effects, such as spiritual experiences, feelings of unity, and disembodiment, might simply be better indicators of 5-HT2A receptor activation than are other subjective drug effects (e.g., perceptual changes, complex imagery, synesthesia, etc.). Analogously, psilocybin increases blood pressure (but not heart rate), (8) an effect likely mediated by 5-HT2A receptors expressed in vascular smooth muscle cells. While it is attractive to speculate that mystical experiences are directly linked to therapeutic effects, we must also consider that mystical experiences, like increases in blood pressure, could simply be a good biomarker for 5-HT2A receptor activation. As 5-HT2A receptors have been shown to mediate both the hallucinogenic (17) and psychoplastogenic (4) effects of psychedelics, positive correlations between clinical efficacy and subjective effects should be viewed as expected dose–response relationships. Further experimentation is needed to claim any causal relationship between mystical experiences or enhanced neural plasticity and therapeutic outcomes.
Despite defying conventional wisdom, increasing evidence suggests that the therapeutic properties of psychedelics and related psychoplastogens can be dissociated from their subjective effects. Thus, if enhanced neural plasticity in key circuits is driving psychedelic-induced changes in behavior, peak mystical experiences may not be necessary for these drugs to treat mental illness. It is interesting to note that while the subjective effects of ketamine treatment subside within a few hours, the antidepressant response continues to intensify for several days. (18) The time course of ketamine’s antidepressant effect is consistent with our understanding of how ketamine and serotonergic psychedelics alter neuronal structure over time. An exceedingly short stimulation period (<1 h) is sufficient for psychoplastogens to activate cortical neuron growth mechanisms that can last for several days. (19) Furthermore, the Liston group recently used a photoactivatable Rac1 to demonstrate the causal relationship between ketamine-induced spine growth in the PFC and the drug’s long-lasting antidepressant-like behavioral effects in rodents. (20)
As evidence continues to mount implicating structural plasticity in the therapeutic properties of ketamine and psychedelics, additional pieces of data indicate that the subjective effects of these drugs may not be necessary to produce long-lasting therapeutic effects. First, clinical evidence suggests that a racemic mixture of ketamine enantiomers may be more effective than the S-enantiomer, though head-to-head clinical trials are lacking. Moreover, the R-enantiomer of ketamine is a more potent psychoplastogen than the S-enantiomer, producing longer-lasting antidepressant-like effects in preclinical animal studies (21) despite having lower affinity for the NMDA receptor and reduced psychotomimetic effects. (22) Furthermore, (2R,6R)-hydroxynorketamine—a metabolite of R-ketamine lacking dissociative properties—has demonstrated robust antidepressant-like effects in rodents. (23) Future clinical trials using R-ketamine and (2R,6R)-hydroxynorketamine will help to shed light on the role of ketamine’s subjective effects in its antidepressant properties.
Like R-ketamine, other psychoplastogens that do not produce psilocybin-like mystical effects have also proven effective treatments for mental illness. Perhaps the most well-known is 3,4-methylenedioxymethamphetamine (MDMA)—an atypical psychedelic of the entactogen family. (24) Only 20% of recreational MDMA users report experiencing any visual hallucinations, and these are often extremely mild compared to the perceptual effects induced by compounds like psilocybin or lysergic acid diethylamide (LSD). (24) With the exception of its ability to induce a “blissful state,” MDMA does not produce subjective effects rivaling those of ketamine or classic serotonergic psychedelics (e.g., psilocybin and LSD) as measured using a variety of scales related to altered states of consciousness and mystical-type experiences. (25,26) Despite its relatively mild subjective effects compared to classic psychedelics, MDMA potently promotes neural plasticity (4) and has shown enormous potential in the clinic for treating stress-related neuropsychiatric diseases such as PTSD. (24)
Administration of low, subhallucinogenic doses of psychedelics also has the potential to shed light on the role of mystical-type experiences in therapeutic responses. Though anecdotal reports suggest that psychedelic microdosing—the chronic, intermittent use of subhallucinogenic doses—may produce beneficial effects and relieve symptoms of depression and anxiety, (27,28) these results should be interpreted with caution given that there are currently no double-blind, placebo-controlled clinical trials related to the therapeutic effects of psychedelic microdosing. (29) Our group recently demonstrated that psychedelic microdosing produced antidepressant-like and anxiolytic effects in rodents with minimal to no impact on other behavioral measures, (30) but these results will need to be confirmed in humans. Unlike with clinical trials using high doses of psychedelics, it should be possible to effectively blind microdosing studies. However, the low doses required to avoid significant subjective effects may simply be insufficient to activate 5-HT2A receptors to produce long-lasting changes in neural circuitry.
Even if psychedelic microdosing ultimately proves to be efficacious, significant regulatory hurdles and issues related to abuse potential will need to be overcome if patients are to benefit from this dosing regimen. The development of nonhallucinogenic compounds capable of producing psychedelic-like therapeutic effects would solve these issues and greatly improve patient access. Recently, our group has made significant progress in this area. For example, simple transposition of the N,N-dimethylaminoethyl group of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) from the C3 to the N1 position of the indole yields 6-MeO-isoDMT. This compound exhibits significantly reduced hallucinogenic potential, as measured by the mouse head-twitch response (HTR) assay, while retaining psychoplastogenic potency comparable to its hallucinogenic congener (Figure 1). (31) Because 6-MeO-isoDMT is at least equipotent to 5-MeO-DMT with respect to its ability to promote neural plasticity, it cannot simply be viewed as a less potent hallucinogen. In fact, many of the nonhallucinogenic analogues of psychedelics that our group has developed will not produce hallucinogenic behavioral responses in rodents even at extremely high doses.
Figure 1
Figure 1. Hallucinogenic and psychoplastogenic effects can be decoupled through careful chemical design. Approximate potencies and efficacies are shown for mouse head-twitch response behavioral tests (hallucinogenic effects) and cortical neuron dendritogenesis assays (psychoplastogenic effects).
Until recently, it was unknown if nonhallucinogenic psychoplastogens could produce beneficial behavioral effects comparable to psychedelics. Through careful chemical design, we were able to engineer tabernanthalog (TBG)—a nonhallucinogenic analogue of 5-MeO-DMT (Figure 1) that promotes cortical neuron structural plasticity through activation of 5-HT2A receptors. (32) Like psychedelic compounds, TBG has demonstrated preclinical therapeutic effects suggesting that it might be effective at treating a range of neuropsychiatric diseases including depression, alcohol use disorder, and heroin use disorder. (32) Future work needs to address why functionally selective 5-HT2A receptor ligands such as TBG can produce plasticity and therapeutic behavioral responses without inducing behavioral effects characteristic of classic psychedelics.
Ultimately, clinical trials will be necessary to determine if psychoplastogenic analogues of psychedelics can produce therapeutic effects in humans without inducing mystical-like experiences. Additionally, there are several other experiments that could potentially be performed to elucidate the roles of both subjective effects and enhanced neural plasticity in the therapeutic properties of psychedelics. One option is to employ a compound producing mystical-like effects without promoting neuronal growth in the PFC as a true active placebo. However, no such compound has been identified yet, and such a compound might not even exist if hallucinogenic effects inevitably lead to enhanced neural plasticity.
Alternatively, psychedelics could be administered to patients under anesthesia. This would solve the blinding issue by preventing patients from experiencing the altered state of consciousness. Such an experimental design could be a powerful way to dissociate the psychological from the neurobiological effects of these drugs. However, care must be taken in the design of such studies, as several common anesthetics are known to promote neural plasticity and produce antidepressant effects themselves.
To the best of my knowledge, no clinical trial has administered a classic serotonergic psychedelic after the induction of general anesthesia. However, several studies have demonstrated that intraoperative ketamine can improve postoperative mood despite the fact that patients were unconscious during ketamine administration. (33−35) While this suggests that ketamine-induced mystical experiences may not be necessary to produce therapeutic responses, the patients in these studies were not severely depressed. Thus, studies administering ketamine under general anesthesia to patients with major depressive disorder are warranted, and at least one such study is currently ongoing. (36)
While preliminary evidence suggests that the subjective effects of psychedelics are not necessary to produce therapeutic responses, they may be critical for achieving maximal efficacy. Though the strong positive correlation between mystical-type experiences and the strength of therapeutic responses does not imply causation, it does implicate either psychological mechanisms or perhaps an exceptionally strong placebo effect in the impressive effect sizes observed following psychedelic-assisted therapy. Thus, the combination of a pharmacologically induced state of heightened neural plasticity with a profound subjective experience could prove invaluable for treating those who are especially ill or who have attempted other treatments without success.
Despite the promising therapeutic responses produced by psychedelic-assisted therapy, the intense subjective effects of these drugs make it unlikely that they will ever become widespread treatments for disorders such as depression. In contrast, strategies for rewiring pathological neural circuitry without producing psychedelic-like mystical effects hold enormous promise as potential first-line treatments for a variety of neuropsychiatric diseases. Regardless, nonhallucinogenic analogues of psychedelics will provide a wealth of information about the fundamental neurobiology underlying both compound-induced neural plasticity and hallucinogenic effects. For an alternative perspective, please see a companion Viewpoint in this issue. (37)
Author Information
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- David E. Olson - Department of Chemistry, University of California, Davis, One Shields Avenue, Davis, California 95616, United States; Department of Biochemistry & Molecular Medicine, School of Medicine, University of California, Davis, 2700 Stockton Blvd, Suite 2102, Sacramento, California 95817, United States; Center for Neuroscience, University of California, Davis, 1544 Newton Court, Davis, California 95618, United States;
http://orcid.org/0000-0002-4517-0543;
D.E.O. wrote the manuscript.
Acknowledgments
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This work was supported by funds from the National Institutes of Health (NIH) (R01GM128997 to D.E.O.). The author would like to thank Boris Heifets as well as Max Vargas, Lindsay Cameron, and the rest of the Olson Lab for helpful discussions. Special thanks to Lindsay Cameron and Lee Dunlap for providing the image of DMT crystals used in the graphical abstract.
References
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This article references 37 other publications.
- 1Whiteford, H. A., Degenhardt, L., Rehm, J., Baxter, A. J., Ferrari, A. J., Erskine, H. E., Charlson, F. J., Norman, R. E., Flaxman, A. D., Johns, N. (2013) Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010. Lancet 382, 1575– 1586, DOI: 10.1016/S0140-6736(13)61611-6Google Scholar2Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010Whiteford Harvey A; Degenhardt Louisa; Rehm Jurgen; Baxter Amanda J; Ferrari Alize J; Erskine Holly E; Charlson Fiona J; Norman Rosana E; Flaxman Abraham D; Johns Nicole; Burstein Roy; Murray Christopher J L; Vos TheoLancet (London, England) (2013), 382 (9904), 1575-86 ISSN:.BACKGROUND: We used data from the Global Burden of Diseases, Injuries, and Risk Factors Study 2010 (GBD 2010) to estimate the burden of disease attributable to mental and substance use disorders in terms of disability-adjusted life years (DALYs), years of life lost to premature mortality (YLLs), and years lived with disability (YLDs). METHODS: For each of the 20 mental and substance use disorders included in GBD 2010, we systematically reviewed epidemiological data and used a Bayesian meta-regression tool, DisMod-MR, to model prevalence by age, sex, country, region, and year. We obtained disability weights from representative community surveys and an internet-based survey to calculate YLDs. We calculated premature mortality as YLLs from cause of death estimates for 1980-2010 for 20 age groups, both sexes, and 187 countries. We derived DALYs from the sum of YLDs and YLLs. We adjusted burden estimates for comorbidity and present them with 95% uncertainty intervals. FINDINGS: In 2010, mental and substance use disorders accounted for 183·9 million DALYs (95% UI 153·5 million-216·7 million), or 7·4% (6·2-8·6) of all DALYs worldwide. Such disorders accounted for 8·6 million YLLs (6·5 million-12·1 million; 0·5% [0·4-0·7] of all YLLs) and 175·3 million YLDs (144·5 million-207·8 million; 22·9% [18·6-27·2] of all YLDs). Mental and substance use disorders were the leading cause of YLDs worldwide. Depressive disorders accounted for 40·5% (31·7-49·2) of DALYs caused by mental and substance use disorders, with anxiety disorders accounting for 14·6% (11·2-18·4), illicit drug use disorders for 10·9% (8·9-13·2), alcohol use disorders for 9·6% (7·7-11·8), schizophrenia for 7·4% (5·0-9·8), bipolar disorder for 7·0% (4·4-10·3), pervasive developmental disorders for 4·2% (3·2-5·3), childhood behavioural disorders for 3·4% (2·2-4·7), and eating disorders for 1·2% (0·9-1·5). DALYs varied by age and sex, with the highest proportion of total DALYs occurring in people aged 10-29 years. The burden of mental and substance use disorders increased by 37·6% between 1990 and 2010, which for most disorders was driven by population growth and ageing. INTERPRETATION: Despite the apparently small contribution of YLLs--with deaths in people with mental disorders coded to the physical cause of death and suicide coded to the category of injuries under self-harm--our findings show the striking and growing challenge that these disorders pose for health systems in developed and developing regions. In view of the magnitude of their contribution, improvement in population health is only possible if countries make the prevention and treatment of mental and substance use disorders a public health priority. FUNDING: Queensland Department of Health, National Health and Medical Research Council of Australia, National Drug and Alcohol Research Centre-University of New South Wales, Bill & Melinda Gates Foundation, University of Toronto, Technische Universitat, Ontario Ministry of Health and Long Term Care, and the US National Institute of Alcohol Abuse and Alcoholism.
- 2Berton, O. and Nestler, E. J. (2006) New approaches to antidepressant drug discovery: beyond monoamines. Nat. Rev. Neurosci. 7, 137– 151, DOI: 10.1038/nrn1846Google Scholar3New approaches to antidepressant drug discovery: beyond monoaminesBerton, Olivier; Nestler, Eric J.Nature Reviews Neuroscience (2006), 7 (2), 137-151CODEN: NRNAAN; ISSN:1471-003X. (Nature Publishing Group)A review. All available antidepressant medications are based on serendipitous discoveries of the clin. efficacy of two classes of antidepressants more than 50 years ago. These tricyclic and monoamine oxidase inhibitor antidepressants were subsequently found to promote serotonin or noradrenaline function in the brain. Newer agents are more specific but have the same core mechanisms of action in promoting these monoamine neurotransmitters. This is unfortunate, because only ∼50% of individuals with depression show full remission in response to these mechanisms. This review summarizes the obstacles that have hindered the development of non-monoamine-based antidepressants, and provides a progress report on some of the most promising current strategies.
- 3Olson, D. E. (2018) Psychoplastogens: A Promising Class of Plasticity-Promoting Neurotherapeutics. J. Exp. Neurosci. 12, 117906951880050 DOI: 10.1177/1179069518800508Google ScholarThere is no corresponding record for this reference.
- 4Ly, 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., and Olson, D. E. (2018) Psychedelics Promote Structural and Functional Neural Plasticity. Cell Rep. 23, 3170– 3182, DOI: 10.1016/j.celrep.2018.05.022Google Scholar5Psychedelics Promote Structural and Functional Neural PlasticityLy, 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.
- 5Nichols, D. E., Johnson, M. W., and Nichols, C. D. (2017) Psychedelics as Medicines: An Emerging New Paradigm. Clin. Pharmacol. Ther. 101, 209– 219, DOI: 10.1002/cpt.557Google Scholar6Psychedelics as Medicines: An Emerging New ParadigmNichols D E; Johnson M W; Nichols C DClinical pharmacology and therapeutics (2017), 101 (2), 209-219 ISSN:.Scientific interest in serotonergic psychedelics (e.g., psilocybin and LSD; 5-HT2A receptor agonists) has dramatically increased within the last decade. Clinical studies administering psychedelics with psychotherapy have shown preliminary evidence of robust efficacy in treating anxiety and depression, as well as addiction to tobacco and alcohol. Moreover, recent research has suggested that these compounds have potential efficacy against inflammatory diseases through novel mechanisms, with potential advantages over existing antiinflammatory agents. We propose that psychedelics exert therapeutic effects for psychiatric disorders by acutely destabilizing local brain network hubs and global network connectivity via amplification of neuronal avalanches, providing the occasion for brain network "resetting" after the acute effects have resolved. Antiinflammatory effects may hold promise for efficacy in treatment of inflammation-related nonpsychiatric as well as potentially for psychiatric disorders. Serotonergic psychedelics operate through unique mechanisms that show promising effects for a variety of intractable, debilitating, and lethal disorders, and should be rigorously researched.
- 6Nutt, D., Erritzoe, D., and Carhart-Harris, R. (2020) Psychedelic Psychiatry’s Brave New World. Cell 181, 24– 28, DOI: 10.1016/j.cell.2020.03.020Google Scholar7Psychedelic Psychiatry's Brave New WorldNutt, David; Erritzoe, David; Carhart-Harris, RobinCell (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.
- 7Griffiths, R. R., Johnson, M. W., Carducci, M. A., Umbricht, A., Richards, W. A., Richards, B. D., Cosimano, M. P., and Klinedinst, M. A. (2016) Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial. J. Psychopharmacol. 30, 1181– 1197, DOI: 10.1177/0269881116675513Google Scholar8Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: a randomized double-blind trialGriffiths, 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.
- 8Ross, 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., and Schmidt, B. L. (2016) Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial. J. Psychopharmacol. 30, 1165– 1180, DOI: 10.1177/0269881116675512Google Scholar9Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trialRoss, 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.
- 9Davis, A. K., Clifton, J. M., Weaver, E. G., Hurwitz, E. S., Johnson, M. W., and Griffiths, R. R. (2020) Survey of entity encounter experiences occasioned by inhaled N,N-dimethyltryptamine: Phenomenology, interpretation, and enduring effects. J. Psychopharmacol. 34, 1008– 1020, DOI: 10.1177/0269881120916143Google Scholar10Survey of entity encounter experiences occasioned by inhaled N,N-dimethyltryptamine: Phenomenology, interpretation, and enduring effectsDavis, Alan K.; Clifton, John M.; Weaver, Eric G.; Hurwitz, Ethan S.; Johnson, Matthew W.; Griffiths, Roland R.Journal of Psychopharmacology (London, United Kingdom) (2020), 34 (9), 1008-1020CODEN: JOPSEQ; ISSN:0269-8811. (Sage Publications Ltd.)The study characterized the subjective phenomena, interpretation, and persisting changes that people attribute to N,N-dimethyltryptamine-occasioned entity encounter experiences. 2561 Individuals completed an online survey about their single most memorable entity encounter after taking N,N-dimethyltryptamine. Respondents reported the primary senses involved in the encounter were visual and extrasensory. The most common descriptive labels for the entity were being, guide, spirit, alien, and helper. Although 41% of respondents reported fear during the encounter, the most prominent emotions both in the respondent and attributed to the entity were love, kindness, and joy. Most respondents endorsed that the entity had the attributes of being conscious, intelligent, and benevolent, existed in some real but different dimension of reality, and continued to exist after the encounter. Respondents endorsed receiving a message (69%) or a prediction about the future (19%) from the experience. More than half of those who identified as atheist before the experience no longer identified as atheist afterwards. N,N-dimethyltryptamine-occasioned entity encounter experiences have many similarities to non-drug entity encounter experiences such as those described in religious, alien abduction, and near-death contexts. Aspects of the experience and its interpretation produced profound and enduring ontol. changes in worldview.
- 10Bogenschutz, M. P., Forcehimes, A. A., Pommy, J. A., Wilcox, C. E., Barbosa, P. C., and Strassman, R. J. (2015) Psilocybin-assisted treatment for alcohol dependence: a proof-of-concept study. J. Psychopharmacol. 29, 289– 299, DOI: 10.1177/0269881114565144Google Scholar11Psilocybin-assisted treatment for alcohol dependence: a proof-of-concept studyBogenschutz, Michael P.; Forcehimes, Alyssa A.; Pommy, Jessica A.; Wilcox, Claire E.; Barbosa, P. C. R.; Strassman, Rick J.Journal of Psychopharmacology (London, United Kingdom) (2015), 29 (3), 289-299CODEN: JOPSEQ; ISSN:0269-8811. (Sage Publications Ltd.)Several lines of evidence suggest that classic (5HT2A agonist) hallucinogens have clin. relevant effects in alc. and drug addiction. Although recent studies have investigated the effects of psilocybin in various populations, there have been no studies on the efficacy of psilocybin for alc. dependence. We conducted a single-group proof-of-concept study to quantify acute effects of psilocybin in alc.-dependent participants and to provide preliminary outcome and safety data. Ten volunteers with DSM-IV alc. dependence received orally administered psilocybin in one or two supervised sessions in addn. to Motivational Enhancement Therapy and therapy sessions devoted to prepn. for and debriefing from the psilocybin sessions. Participants' responses to psilocybin were qual. similar to those described in other populations. Abstinence did not increase significantly in the first 4 wk of treatment (when participants had not yet received psilocybin), but increased significantly following psilocybin administration (p < 0.05). Gains were largely maintained at follow-up to 36 wk. The intensity of effects in the first psilocybin session (at week 4) strongly predicted change in drinking during weeks 5-8 (r = 0.76 to r = 0.89) and also predicted decreases in craving and increases in abstinence self-efficacy during week 5. There were no significant treatment-related adverse events. These preliminary findings provide a strong rationale for controlled trials with larger samples to investigate efficacy and mechanisms.
- 11Garcia-Romeu, A., Griffiths, R. R., and Johnson, M. W. (2015) Psilocybin-occasioned mystical experiences in the treatment of tobacco addiction. Curr. Drug Abuse Rev. 7, 157– 164, DOI: 10.2174/1874473708666150107121331Google ScholarThere is no corresponding record for this reference.
- 12Roseman, L., Nutt, D. J., and Carhart-Harris, R. L. (2018) Quality of Acute Psychedelic Experience Predicts Therapeutic Efficacy of Psilocybin for Treatment-Resistant Depression. Front. Pharmacol. 8, 974, DOI: 10.3389/fphar.2017.00974Google ScholarThere is no corresponding record for this reference.
- 13Sos, P., Klirova, M., Novak, T., Kohutova, B., Horacek, J., and Palenicek, T. (2013) Relationship of ketamine’s antidepressant and psychotomimetic effects in unipolar depression. Neuro. Endocrinol. Lett. 34, 287– 293Google Scholar14Relationship of ketamine's antidepressant and psychotomimetic effects in unipolar depressionSos Peter; Klirova Monika; Novak Tomas; Kohutova Barbora; Horacek Jiri; Palenicek TomasNeuro endocrinology letters (2013), 34 (4), 287-93 ISSN:0172-780X.OBJECTIVES: Ketamine and other NMDA (N-methyl-D-aspartate) antagonists produce fast-acting antidepressant-like effects, although the underlying mechanism is unclear. Furthermore, high affinity NMDA antagonists such as ketamine are associated with psychotomimetic effects. To date the link between the antidepressant and psychotomimetic effects of ketamine has not been explored. We examined the relationship between the antidepressant and psychotomimetic effects of a single ketamine infusion in subjects diagnosed with major depressive disorder. METHODS: In a double-blind, cross-over, placebo-controlled, two weeks clinical trial we studied the effects of ketamine (0.54 mg/kg within 30 min) in a group of 27 hospitalized depressive patients. RESULTS: Higher intensity of psychotomimetic symptoms, measured using BPRS, during ketamine administration correlated with alleviation in mood ratings during the following week with maximum on day seven. Ketamine was superior to placebo in all visits (day 1, 4, and 7) assessed by MADRS with effect size (Cohen's d) of 0.62, 0.57, and 0.44 respectively. There was no significant correlation between ketamine and nor-ketamine plasma levels and MADRS score change at any study time point. CONCLUSION: The substantial relationship between ketamine's antidepressant and psychotomimetic effects was found. This relationship could be mediated by the initial steps of ketamine's action, trough NMDA receptors, shared by both ketamine's clinical effects.
- 14Luckenbaugh, D. A., Niciu, M. J., Ionescu, D. F., Nolan, N. M., Richards, E. M., Brutsche, N. E., Guevara, S., and Zarate, C. A. (2014) Do the dissociative side effects of ketamine mediate its antidepressant effects?. J. Affective Disord. 159, 56– 61, DOI: 10.1016/j.jad.2014.02.017Google Scholar15Do the dissociative side effects of ketamine mediate its antidepressant effects?Luckenbaugh, David A.; Niciu, Mark J.; Ionescu, Dawn F.; Nolan, Neal M.; Richards, Erica M.; Brutsche, Nancy E.; Guevara, Sara; Zarate, Carlos A.Journal of Affective Disorders (2014), 159 (), 56-61CODEN: JADID7; ISSN:0165-0327. (Elsevier Inc.)Background: The N-methyl-D-aspartate receptor antagonist ketamine has rapid antidepressant effects in major depression. Psychotomimetic symptoms, dissocn. and hemodynamic changes are known side effects of ketamine, but it is unclear if these side effects relate to its antidepressant efficacy. Methods: Data from 108 treatment-resistant inpatients meeting criteria for major depressive disorder and bipolar disorder who received a single subanesthetic ketamine infusion were analyzed. Pearson correlations were performed to examine potential assocns. between rapid changes in dissocn. and psychotomimesis with the Clinician-Administered Dissociative States Scale (CADSS) and Brief Psychiatric Rating Scale (BPRS), resp., manic symptoms with Young Mania Rating Scale (YMRS), and vital sign changes, with percent change in the 17-item Hamilton Depression Rating scale (HDRS) at 40 and 230 min and Days 1 and 7. Results: Pearson correlations showed significant assocn. between increased CADSS score at 40 min and percent improvement with ketamine in HDRS at 230 min (r=-0.35, p=0.007) and Day 7 (r=-0.41, p=0.01). Changes in YMRS or BPRS Pos. Symptom score at 40 min were not significantly correlated with percent HDRS improvement at any time point with ketamine. Changes in systolic blood pressure, diastolic blood pressure, and pulse were also not significantly related to HDRS change. Limitations: Secondary data anal., combined diagnostic groups, potential unblinding. Conclusions: Among the examd. mediators of ketamine's antidepressant response, only dissociative side effects predicted a more robust and sustained antidepressant. Prospective, mechanistic investigations are critically needed to understand why intra-infusion dissocn. correlates with a more robust antidepressant efficacy of ketamine.
- 15Dakwar, E., Anerella, C., Hart, C. L., Levin, F. R., Mathew, S. J., and Nunes, E. V. (2014) Therapeutic infusions of ketamine: do the psychoactive effects matter?. Drug Alcohol Depend. 136, 153– 157, DOI: 10.1016/j.drugalcdep.2013.12.019Google Scholar16Therapeutic infusions of ketamine: Do the psychoactive effects matter?Dakwar, E.; Anerella, C.; Hart, C. L.; Levin, F. R.; Mathew, S. J.; Nunes, E. V.Drug and Alcohol Dependence (2014), 136 (), 153-157CODEN: DADEDV; ISSN:0376-8716. (Elsevier Ireland Ltd.)Sub-anesthetic ketamine infusions may benefit a variety of psychiatric disorders, including addiction. Though ketamine engenders transient alterations in consciousness, it is not known whether these alterations influence efficacy. This anal. evaluates the mystical-type effects of ketamine, which may have therapeutic potential according to prior research, and assesses whether these effects mediate improvements in dependence-related deficits, 24 h postinfusion. Eight cocaine dependent individuals completed this double-blind, randomized, inpatient study. Three counter-balanced infusions sepd. by 48 h were received: lorazepam (2 mg) and two doses of ketamine (0.41 mg/kg and 0.71 mg/kg, with the former dose always preceding the latter). Infusions were followed within 15 min by measures of dissocn. (Clinician Administered Dissociative Symptoms Scale: CADSS) and mystical-type effects (adapted from Hood's Mysticism Scale: HMS). At baseline and 24 h postinfusion, participants underwent assessments of motivation to stop cocaine (University of Rhode Island Change Assessment) and cue-induced craving (by visual analog scale for cocaine craving during cue exposure). Ketamine led to significantly greater acute mystical-type effects (by HMS) relative to the active control lorazepam; ketamine 0.71 mg/kg was assocd. with significantly higher HMS scores than was the 0.41 mg/kg dose. HMS score, but not CADSS score, was found to mediate the effect of ketamine on motivation to quit cocaine 24 h postinfusion. These findings suggest that psychol. mechanisms may be involved in some of the anti-addiction benefits resulting from ketamine. Future research can evaluate whether the psychoactive effects of ketamine influence improvements in larger samples.
- 16Nielson, E. M., May, D. G., Forcehimes, A. A., and Bogenschutz, M. P. (2018) The Psychedelic Debriefing in Alcohol Dependence Treatment: Illustrating Key Change Phenomena through Qualitative Content Analysis of Clinical Sessions. Front. Pharmacol. 9, 132, DOI: 10.3389/fphar.2018.00132Google Scholar17The psychedelic debriefing in alcohol dependence treatment: illustrating key change phenomena through qualitative content analysis of clinical sessionsNielson, Elizabeth M.; May, Darrick G.; Forcehimes, Alyssa A.; Bogenschutz, Michael P.Frontiers in Pharmacology (2018), 9 (), 132/1-132/13CODEN: FPRHAU; ISSN:1663-9812. (Frontiers Media S.A.)Research on the clin. applications of psychedelic-assisted psychotherapy has demonstrated promising early results for treatment of alc. dependence. Detailed description of the content and methods of psychedelic-assisted psychotherapy, as it is conducted in clin. settings, is scarce. An open-label pilot (proof-of-concept) study of psilocybin-assisted treatment of alc. dependence (NCT01534494) was conducted to generate data for a phase 2 RCT (NCT02061293) of a similar treatment in a larger population. The present paper presents a qual. content anal. of the 17 debriefing sessions conducted in the pilot study, which occurred the day after corresponding psilocybin medication sessions. Participants articulated a series of key phenomena related to change in drinking outcomes and acute subjective effects of psilocybin. The data illuminate change processes in patients' own words during clin. sessions, shedding light on potential therapeutic mechanisms of change and how participants express effects of psilocybin. This study is unique in analyzing actual clin. sessions, as opposed to interviews of patients conducted sep. from treatment.
- 17Vollenweider, F. X., Vollenweider-Scherpenhuyzen, M. F., Babler, A., Vogel, H., and Hell, D. (1998) Psilocybin induces schizophrenia- like psychosis in humans via a serotonin-2 agonist action. NeuroReport 9, 3897– 3902, DOI: 10.1097/00001756-199812010-00024Google Scholar18Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2A agonist actionVollenweider, Franz X.; Vollenweider-Scherpenhuyzen, Margreet F. I.; Babler, Andreas; Vogel, Helen; Hell, DanielNeuroReport (1998), 9 (17), 3897-3902CODEN: NERPEZ; ISSN:0959-4965. (Lippincott Williams & Wilkins)Psilocybin, an indoleamine hallucinogen, produces a psychosis-like syndrome in humans that resembles first episodes of schizophrenia. In healthy human volunteers, the psychotomimetic effects of psilocybin were blocked dose-dependently by the serotonin-2A antagonist ketanserin or the atypical antipsychotic risperidone but were increased by the dopamine antagonist and typical antipsychotic haloperidol. These data are consistent with animal studies and provide the first evidence in humans that psilocybin-induced psychosis is due to serotonin-2A receptor activation, independently of dopamine stimulation. Thus, serotonin-2A overactivity may be involved in the pathophysiol. of schizophrenia and serotonin-2A antagonism may contribute to therapeutic effects of antipsychotics.
- 18Berman, R. M., Cappiello, A., Anand, A., Oren, D. A., Heninger, G. R., Charney, D. S., and Krystal, J. H. (2000) Antidepressant effects of ketamine in depressed patients. Biol. Psychiatry 47, 351– 354, DOI: 10.1016/S0006-3223(99)00230-9Google Scholar19Antidepressant effects of ketamine in depressed patientsBerman, R. M.; Cappiello, A.; Anand, A.; Oren, D. A.; Heninger, G. R.; Charney, D. S.; Krystal, J. H.Biological Psychiatry (2000), 47 (4), 351-354CODEN: BIPCBF; ISSN:0006-3223. (Elsevier Science Inc.)Subjects with major depression completed 2 test days that involved i.v. treatment with ketamine-HCl [an N-methyl-D-aspartate (NMDA) receptor antagonist] (0.5 mg/kg) or saline solns. under randomized, double-blind conditions. The subjects evidenced significant improvement in depressive symptoms within 72 h after ketamine but not placebo infusion. These results suggest a potential role for NMDA receptor-modulating drugs in the treatment of depression.
- 19Ly, C., Greb, C. A., Vargas, M. V., Duim, W. C., Grodzki, A. C. G., Lein, P. J., and Olson, D. E. (2020) Transient Stimulation with Psychoplastogens is Sufficient to Initiate Neuronal Growth. ACS Pharmacol. Transl. Sci., DOI: 10.1021/acsptsci.0c00065 .Google ScholarThere is no corresponding record for this reference.
- 20Moda-Sava, R. N., Murdock, M. H., Parekh, P. K., Fetcho, R. N., Huang, B. S., Huynh, T. N., Witztum, J., Shaver, D. C., Rosenthal, D. L., Always, E. J., Lopez, K., Meng, Y., Nellissen, L., Grosenick, L., Milner, T. A., Deisseroth, K., Bito, H., Kasai, H., and Liston, C. (2019) Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation. Science 364, eaat8078 DOI: 10.1126/science.aat8078Google ScholarThere is no corresponding record for this reference.
- 21Yang, C, Shirayama, Y, Zhang, J-c, Ren, Q, Yao, W, Ma, M, Dong, C, and Hashimoto, K (2015) a rapid-onset and sustained antidepressant without psychotomimetic side effects. Transl. Psychiatry 5, e632 DOI: 10.1038/tp.2015.136Google Scholar22R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effectsYang, C.; Shirayama, Y.; Zhang, J.-C.; Ren, Q.; Yao, W.; Ma, M.; Dong, C.; Hashimoto, K.Translational Psychiatry (2015), 5 (9), e632CODEN: TPRSCF; ISSN:2158-3188. (Nature Publishing Group)Although the efficacy of racemate ketamine, a rapid onset and sustained antidepressant, for patients with treatment-resistant depression was a serendipitous finding, clin. use of ketamine is limited, due to psychotomimetic side effects and abuse liability. Behavioral and side-effect evaluation tests were applied to compare the two stereoisomers of ketamine. To elucidate their potential therapeutic mechanisms, we examd. the effects of these stereoisomers on brain-derived neurotrophic factor (BDNF)-TrkB signaling, and synaptogenesis in selected brain regions. In the social defeat stress and learned helplessness models of depression, R-ketamine showed a greater potency and longer-lasting antidepressant effect than S-ketamine (esketamine). Furthermore, R-ketamine induced a more potent beneficial effect on decreased dendritic spine d., BDNF-TrkB signaling and synaptogenesis in the prefrontal cortex (PFC), CA3 and dentate gyrus (DG) of the hippocampus from depressed mice compared with S-ketamine. However, neither stereoisomer affected these alterations in the nucleus accumbens of depressed mice. In behavioral tests for side effects, S-ketamine, but not R-ketamine, pptd. behavioral abnormalities, such as hyperlocomotion, prepulse inhibition deficits and rewarding effects. In addn., a single dose of S-ketamine, but not R-ketamine, caused a loss of parvalbumin (PV)-pos. cells in the prelimbic region of the medial PFC and DG. These findings suggest that, unlike S-ketamine, R-ketamine can elicit a sustained antidepressant effect, mediated by increased BDNF-TrkB signaling and synaptogenesis in the PFC, DG and CA3. R-ketamine appears to be a potent, long-lasting and safe antidepressant, relative to S-ketamine, as R-ketamine appears to be free of psychotomimetic side effects and abuse liability.
- 22Vollenweider, F. X., Leenders, K. L., Oye, I., Hell, D., and Angst, J. (1997) Differential psychopathology and patterns of cerebral glucose utilisation produced by (S)- and (R)-ketamine in healthy volunteers using positron emission tomography (PET). Eur. Neuropsychopharmacol. 7, 25– 38, DOI: 10.1016/S0924-977X(96)00042-9Google Scholar23Differential psychopathology and patterns of cerebral glucose utilization produced by (S)- and (R)-ketamine in healthy volunteers using positron emission tomography (PET)Vollenweider, F. X.; Leenders, K. L.; Oye, I.; Hell, D.; Angst, J.European Neuropsychopharmacology (1997), 7 (1), 25-38CODEN: EURNE8; ISSN:0924-977X. (Elsevier)Until recently, racemic ketamine (S-ketamine/R-ketamine = 50:50) has been used to study NMDA receptor hypofunction in relation to pathophysiol. models of schizophrenia. Ketamine given to normal humans in subanesthetic doses produces a model psychosis including both pos. and neg. symptoms of schizophrenia. More recently it has been shown that at subanesthetic doses the pure (S)- and (R)-ketamine enantiomeres interact differently with the NMDA and sigma receptor sites in human brain. It was found that (S)-ketamine binds with a 3-4 time higher affinity to the PCP binding site of the NMDA receptor than (R)-ketamine, and that at these concns. (R)-ketamine interacts also weakly with the sigma receptor sites, where (S)-ketamine binds only negligibly. To further investigate the role of NMDA-receptor mediated neurotransmission in schizophrenic psychosis, the effects of pure (S)- and (R)-ketamine enantiomeres on brain energy metab. in normal humans using positron emission tomog. and [18F]fluorodeoxyglucose (FDG) are reported here. Psychotomimetic doses of (S)-ketamine increased cerebral metabolic rates of glucose (CMRglu) markedly in the frontal cortex including the anterior cingulate, parietal and left sensorimotor cortex, and in the thalamus. The metabolic changes in the frontal and left temporal cortex correlated with ego-disintegration and hallucinatory phenomena. Equimolar doses of (R)-ketamine tended to decrease CMRglu across brain regions and significantly suppressed CMRglu in the temporomedial cortex and left insula. (R)-ketamine did not produce psychotic symptoms, but a state of relaxation. The (S)-ketamine-induced metabolic hyperfrontality appears to parallel similar metabolic findings in acute psychotic schizophrenic patients and encourages further investigations of glutamatergic disturbances in schizophrenia.
- 23Zanos, P., Moaddel, R., Morris, P. J., Georgiou, P., Fischell, J., Elmer, G. E., Alkondon, M., Yuan, P., Pribut, H. J., Singh, N. S., Dossou, K. S. S., Fang, Y., Huang, X.-P., Mayo, C. L., Wainer, I. W., Albuquerque, E. X., Thompson, S. M., Thomas, C. J., Zarate, C. A., Jr, and Gould, T. D. (2016) NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature 533, 481– 486, DOI: 10.1038/nature17998Google Scholar24NMDAR inhibition-independent antidepressant actions of ketamine metabolitesZanos, Panos; Moaddel, Ruin; Morris, Patrick J.; Georgiou, Polymnia; Fischell, Jonathan; Elmer, Greg I.; Alkondon, Manickavasagom; Yuan, Peixiong; Pribut, Heather J.; Singh, Nagendra S.; Dossou, Katina S. S.; Fang, Yuhong; Huang, Xi-Ping; Mayo, Cheryl L.; Wainer, Irving W.; Albuquerque, Edson X.; Thompson, Scott M.; Thomas, Craig J.; Zarate, Carlos A., Jr; Gould, Todd D.Nature (London, United Kingdom) (2016), 533 (7604), 481-486CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)Major depressive disorder affects around 16% of the world population at some point in their lives. Despite the availability of numerous monoaminergic-based antidepressants, most patients require several weeks, if not months, to respond to these treatments, and many patients never attain sustained remission of their symptoms. The noncompetitive, glutamatergic NMDAR (N-methyl-D-aspartate receptor) antagonist (R,S)-ketamine exerts rapid and sustained antidepressant effects after a single dose in patients with depression, but its use is assocd. with undesirable side effects. Here the authors show that the metab. of (R,S)-ketamine to (2S,6S;2R,6R)-hydroxynorketamine (HNK) is essential for its antidepressant effects, and that the (2R,6R)-HNK enantiomer exerts behavioral, electroencephalog., electrophysiol. and cellular antidepressant-related actions in mice. These antidepressant actions are independent of NMDAR inhibition but involve early and sustained activation of AMPARs (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors). The authors also establish that (2R,6R)-HNK lacks ketamine-related side effects. The data implicate a novel mechanism underlying the antidepressant properties of (R,S)-ketamine and have relevance for the development of next-generation, rapid-acting antidepressants.
- 24Dunlap, L. E., Andrews, A. A., and Olson, D. E. (2018) Dark Classics in Chemical Neuroscience: 3,4-Methylenedioxymethamphetamine. ACS Chem. Neurosci. 9, 2408– 2427, DOI: 10.1021/acschemneuro.8b00155Google Scholar25Dark Classics in Chemical Neuroscience: 3,4-MethylenedioxymethamphetamineDunlap, Lee E.; Andrews, Anne M.; Olson, David E.ACS Chemical Neuroscience (2018), 9 (10), 2408-2427CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)Better known as "ecstasy", 3,4-methylenedioxymethamphetamine (MDMA) is a small mol. that has played a prominent role in defining the ethos of today's teenagers and young adults, much like lysergic acid diethylamide (LSD) did in the 1960s. Though MDMA possesses structural similarities to compds. like amphetamine and mescaline, it produces subjective effects that are unlike any of the classical psychostimulants or hallucinogens and is one of the few compds. capable of reliably producing prosocial behavioral states. As a result, MDMA has captured the attention of recreational users, the media, artists, psychiatrists, and neuropharmacologists alike. Here, we detail the synthesis of MDMA as well as its pharmacol., metab., adverse effects, and potential use in medicine. Finally, we discuss its history and why it is perhaps the most important compd. for the future of psychedelic science-having the potential to either facilitate new psychedelic research initiatives, or to usher in a second Dark Age for the field.
- 25Studerus, E., Gamma, A., and Vollenweider, F. X. (2010) Psychometric evaluation of the altered states of consciousness rating scale (OAV). PLoS One 5, e12412 DOI: 10.1371/journal.pone.0012412Google Scholar26Psychometric evaluation of the altered states of consciousness rating scale (OAV)Studerus Erich; Gamma Alex; Vollenweider Franz XPloS one (2010), 5 (8), e12412 ISSN:.BACKGROUND: The OAV questionnaire has been developed to integrate research on altered states of consciousness (ASC). It measures three primary and one secondary dimensions of ASC that are hypothesized to be invariant across ASC induction methods. The OAV rating scale has been in use for more than 20 years and applied internationally in a broad range of research fields, yet its factorial structure has never been tested by structural equation modeling techniques and its psychometric properties have never been examined in large samples of experimentally induced ASC. METHODOLOGY/PRINCIPAL FINDINGS: The present study conducted a psychometric evaluation of the OAV in a sample of psilocybin (n = 327), ketamine (n = 162), and MDMA (n = 102) induced ASC that was obtained by pooling data from 43 experimental studies. The factorial structure was examined by confirmatory factor analysis, exploratory structural equation modeling, hierarchical item clustering (ICLUST), and multiple indicators multiple causes (MIMIC) modeling. The originally proposed model did not fit the data well even if zero-constraints on non-target factor loadings and residual correlations were relaxed. Furthermore, ICLUST suggested that the "oceanic boundlessness" and "visionary restructuralization" factors could be combined on a high level of the construct hierarchy. However, because these factors were multidimensional, we extracted and examined 11 new lower order factors. MIMIC modeling indicated that these factors were highly measurement invariant across drugs, settings, questionnaire versions, and sexes. The new factors were also demonstrated to have improved homogeneities, satisfactory reliabilities, discriminant and convergent validities, and to differentiate well among the three drug groups. CONCLUSIONS/SIGNIFICANCE: The original scales of the OAV were shown to be multidimensional constructs. Eleven new lower order scales were constructed and demonstrated to have desirable psychometric properties. The new lower order scales are most likely better suited to assess drug induced ASC.
- 26Holze, F., Vizeli, P., Müller, F., Ley, L., Duerig, R., Varghese, N., Eckert, A., Borgwardt, S., and Liechti, M. E. (2020) Distinct acute effects of LSD, MDMA, and D-amphetamine in healthy subjects. Neuropsychopharmacology 45, 462– 471, DOI: 10.1038/s41386-019-0569-3Google Scholar27Distinct acute effects of LSD, MDMA, and D-amphetamine in healthy subjectsHolze, Friederike; Vizeli, Patrick; Muller, Felix; Ley, Laura; Duerig, Raoul; Varghese, Nimmy; Eckert, Anne; Borgwardt, Stefan; Liechti, Matthias E.Neuropsychopharmacology (2020), 45 (3), 462-471CODEN: NEROEW; ISSN:0893-133X. (Nature Research)Lysergic acid diethylamide (LSD) is a classic psychedelic, 3,4-methylenedioxymethamphetamine (MDMA) is an empathogen, and D-amphetamine is a classic stimulant. All three substances are used recreationally. LSD and MDMA are being investigated as medications to assist psychotherapy, and D-amphetamine is used for the treatment of attention-deficit/hyperactivity disorder. All three substances induce distinct acute subjective effects. However, differences in acute responses to these prototypical psychoactive substances have not been characterized in a controlled study. We investigated the acute autonomic, subjective, and endocrine effects of single doses of LSD (0.1 mg), MDMA (125 mg), D-amphetamine (40 mg), and placebo in a randomized, double-blind, cross-over study in 28 healthy subjects. All of the substances produced comparable increases in hemodynamic effects, body temp., and pupil size, indicating equiv. autonomic responses at the doses used. LSD and MDMA increased heart rate more than D-amphetamine, and D-amphetamine increased blood pressure more than LSD and MDMA. LSD induced significantly higher ratings on the 5 Dimensions of Altered States of Consciousness scale and Mystical Experience Questionnaire than MDMA and D-amphetamine. LSD also produced greater subjective drug effects, ego dissoln., introversion, emotional excitation, anxiety, and inactivity than MDMA and D-amphetamine. LSD also induced greater impairments in subjective ratings of concn., sense of time, and speed of thinking compared with MDMA and D-amphetamine. MDMA produced greater ratings of good drug effects, liking, high, and ego dissoln. compared with D-amphetamine. D-Amphetamine increased ratings of activity and concn. compared with LSD. MDMA but not LSD or D-amphetamine increased plasma concns. of oxytocin. None of the substances altered plasma concns. of brain-derived neurotrophic factor. These results indicate clearly distinct acute effects of LSD, MDMA, and D-amphetamine and may assist the dose-finding in substance-assisted psychotherapy research.
- 27Anderson, T., Petranker, R., Rosenbaum, D., Weissman, C. R., Dinh-Williams, L.-A., Hui, K., Hapke, E., and Farb, N. A. S. (2019) Microdosing psychedelics: personality, mental health, and creativity differences in microdosers. Psychopharmacology (Berl) 236, 731– 740, DOI: 10.1007/s00213-018-5106-2Google Scholar28Microdosing psychedelics: personality, mental health, and creativity differences in microdosersAnderson Thomas; Farb Norman A S; Petranker Rotem; Rosenbaum Daniel; Weissman Cory R; Hui Katrina; Hapke Emma; Weissman Cory R; Hapke Emma; Dinh-Williams Le-AnhPsychopharmacology (2019), 236 (2), 731-740 ISSN:.RATIONALE: Microdosing psychedelics-the regular consumption of small amounts of psychedelic substances such as LSD or psilocybin-is a growing trend in popular culture. Recent studies on full-dose psychedelic psychotherapy reveal promising benefits for mental well-being, especially for depression and end-of-life anxiety. While full-dose therapies include perception-distorting properties, microdosing mayprovide complementary clinical benefits using lower-risk, non-hallucinogenic doses. OBJECTIVES: This pre-registered study aimed to investigate whether microdosing psychedelics is related to differences in personality, mental health, and creativity. METHODS: In this observational study, respondents recruited from online forums self-reported their microdosing behaviors and completed questionnaires concerning dysfunctional attitudes, wisdom, negative emotionality, open-mindedness, and mood. Respondents also performed the Unusual Uses Task to assess their creativity. RESULTS: Current and former microdosers scored lower on measures of dysfunctional attitudes (p < 0.001, r = - 0.92) and negative emotionality (p = 0.009, r = - 0.85) and higher on wisdom (p < 0.001, r = 0.88), openmindedness(p = 0.027, r = 0.67), and creativity (p < 0.001, r = 0.15) when compared to non-microdosing controls. CONCLUSIONS: These findings provide promising initial evidence that warrants controlled experimental research to directly test safety and clinical efficacy. As microdoses are easier to administer than full-doses, this new paradigm has the exciting potential to shape future psychedelic research.
- 28Cameron, L. P., Nazarian, A., and Olson, D. E. (2020) Psychedelic Microdosing: Prevalence and Subjective Effects. J. Psychoact. Drugs 52, 113– 122, DOI: 10.1080/02791072.2020.1718250Google Scholar29Psychedelic Microdosing: Prevalence and Subjective EffectsCameron Lindsay P; Nazarian Angela; Olson David E; Olson David E; Olson David EJournal of psychoactive drugs (2020), 52 (2), 113-122 ISSN:.Anecdotal reports suggest that the administration of sub-hallucinogenic doses of psychedelic compounds on a chronic, intermittent schedule - a practice known as psychedelic microdosing - is becoming increasingly popular among young adults due to its purported ability to reduce symptoms of depression and anxiety while improving cognitive function and promoting social interaction. Using an anonymous online survey, we collected data from 2347 people to 1) assess the prevalence of psychedelic microdosing and characterize the demographics of microdosers, 2) determine whether microdosers associate the practice with changes in mood, cognitive function, social interaction, or physiology, and 3) investigate frequent motives for discontinuing the practice. Fifty-nine percent of respondents (NT = 2183) reported familiarity with the concept of psychedelic microdosing, with 17% (383 respondents, NT = 2200) having engaged in this practice. Microdosers attributed psychedelic microdosing with improving their mood, decreasing their anxiety, and enhancing their memory, attention, and sociability. The most frequently cited reasons for quitting microdosing (NT = 243) were the risks associated with taking an illegal substance (24.28%) and the difficulty of obtaining psychedelic compounds (22.63%). Overall, our findings suggest that psychedelic microdosing is relatively common and is subjectively associated with a broad spectrum of socio-affective, cognitive, and physical outcomes.
- 29Kuypers, K. P., Ng, L., Erritzoe, D., Knudsen, G. M., Nichols, C. D., Nichols, D. E., Pani, L., Soula, A., and Nutt, D. (2019) Microdosing psychedelics: More questions than answers? An overview and suggestions for future research. J. Psychopharmacol. 33, 1039– 1057, DOI: 10.1177/0269881119857204Google Scholar30Microdosing psychedelics: More questions than answers? An overview and suggestions for future researchKuypers, Kim P. C.; Ng, Livia; Erritzoe, David; Knudsen, Gitte M.; Nichols, Charles D.; Nichols, David E.; Pani, Luca; Soula, Anais; Nutt, DavidJournal of Psychopharmacology (London, United Kingdom) (2019), 33 (9), 1039-1057CODEN: JOPSEQ; ISSN:0269-8811. (Sage Publications Ltd.)A review. Background:: In the past few years, the issue of 'microdosing' psychedelics has been openly discussed in the public arena where claims have been made about their pos. effect on mood state and cognitive processes such as concn. However, there are very few scientific studies that have specifically addressed this issue, and there is no agreed scientific consensus on what microdosing is. Aim:: This critique paper is designed to address questions that need to be answered by future scientific studies and to offer guidelines for these studies. Approach:: Owing to its proximity for a possible approval in clin. use and short-lasting pharmacokinetics, our focus is predominantly on psilocybin. Psilocybin is allegedly, next to lysergic acid diethylamide (LSD), one of the two most frequently used psychedelics to microdose. Where relevant and available, data for other psychedelic drugs are also mentioned. Conclusion:: It is concluded that while most anecdotal reports focus on the pos. experiences with microdosing, future research should also focus on potential risks of (multiple) administrations of a psychedelic in low doses. To that end, (pre)clin. studies including biol. (e.g. heart rate, receptor turnover and occupancy) as well as cognitive (e.g. memory, attention) parameters have to be conducted and will shed light on the potential neg. consequences microdosing could have.
- 30Cameron, L. P., Benson, C. J., DeFelice, B. C., Fiehn, O., and Olson, D. E. (2019) Chronic, Intermittent Microdoses of the Psychedelic N,N-Dimethyltryptamine (DMT) Produce Positive Effects on Mood and Anxiety in Rodents. ACS Chem. Neurosci. 10, 3261– 3270, DOI: 10.1021/acschemneuro.8b00692Google Scholar31Chronic, Intermittent Microdoses of the Psychedelic N,N-Dimethyltryptamine (DMT) Produce Positive Effects on Mood and Anxiety in RodentsCameron, Lindsay P.; Benson, Charlie J.; DeFelice, Brian C.; Fiehn, Oliver; Olson, David E.ACS Chemical Neuroscience (2019), 10 (7), 3261-3270CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)Drugs capable of ameliorating symptoms of depression and anxiety while also improving cognitive function and sociability are highly desirable. Anecdotal reports have suggested that serotonergic psychedelics administered in low doses on a chronic, intermittent schedule, so-called "microdosing", might produce beneficial effects on mood, anxiety, cognition, and social interaction. Here, we test this hypothesis by subjecting male and female Sprague Dawley rats to behavioral testing following the chronic, intermittent administration of low doses of the psychedelic N,N-dimethyltryptamine (DMT). The behavioral and cellular effects of this dosing regimen were distinct from those induced following a single high dose of the drug. We found that chronic, intermittent, low doses of DMT produced an antidepressant-like phenotype and enhanced fear extinction learning without impacting working memory or social interaction. Addnl., male rats treated with DMT on this schedule gained a significant amt. of body wt. during the course of the study. Taken together, our results suggest that psychedelic microdosing may alleviate symptoms of mood and anxiety disorders, though the potential hazards of this practice warrant further investigation.
- 31Dunlap, L. E., Azinfar, A., Ly, C., Cameron, L. P., Viswanathan, J., Tombari, R. J., Myers-Turnbull, D., Taylor, J. C., Grodzki, A. C., Lein, P. J., Kokel, D., and Olson, D. E. (2020) Identification of Psychoplastogenic N,N-Dimethylaminoisotryptamine (isoDMT) Analogs Through Structure-Activity Relationship Studies. J. Med. Chem. 63, 1142– 1155, DOI: 10.1021/acs.jmedchem.9b01404Google Scholar32Identification of Psychoplastogenic N,N-Dimethylaminoisotryptamine (isoDMT) Analogues through Structure-Activity Relationship StudiesDunlap, Lee E.; Azinfar, Arya; Ly, Calvin; Cameron, Lindsay P.; Viswanathan, Jayashri; Tombari, Robert J.; Myers-Turnbull, Douglas; Taylor, Jack C.; Grodzki, Ana Cristina; Lein, Pamela J.; Kokel, David; Olson, David E.Journal of Medicinal Chemistry (2020), 63 (3), 1142-1155CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Ketamine, N,N-dimethyltryptamine (DMT), and other psychoplastogens possess enormous potential as neurotherapeutics due to their ability to potently promote neuronal growth. Here, we report the first-ever structure-activity relationship study with the explicit goal of identifying novel psychoplastogens. We have discovered several key features of the psychoplastogenic pharmacophore and used this information to develop N,N-dimethylaminoisotryptamine (isoDMT) psychoplastogens that are easier to synthesize, have improved physicochem. properties, and possess reduced hallucinogenic potential as compared to their DMT counterparts.
- 32Cameron, L. P., Tombari, R. J., Lu, J., Pell, A. J., Hurley, Z. Q., Ehinger, Y., Vargas, M. V., McCarroll, M. N., Taylor, J. C., Myers-Turnbull, D., Liu, T., Yaghoobi, B., Laskowski, L. J., Anderson, E. I., Zhang, G., Viswanathan, J., Brown, B. M., Tjia, M., Dunlap, L. E., Rabow, Z. T., Fiehn, O., Wulff, H., McCorvy, J. D., Lein, P. J., Kokel, D., Ron, D., Peters, J., Zuo, Y., and Olson, D. E. (2020) A Non-Hallucinogenic Psychedelic Analog with Therapeutic Potential. Nature DOI: 10.1038/s41586-020-3008-zGoogle ScholarThere is no corresponding record for this reference.
- 33Kudoh, A., Takahira, Y., Katagai, H., and Takazawa, T. (2002) Small-dose ketamine improves the postoperative state of depressed patients. Anesth. Analg. 95, 114– 118, DOI: 10.1097/00000539-200207000-00020Google Scholar34Small-dose ketamine improves the postoperative state of depressed patientsKudoh, Akira; Takahira, Yoko; Katagai, Hiroshi; Takazawa, TomokoAnesthesia & Analgesia (Baltimore, MD, United States) (2002), 95 (1), 114-118CODEN: AACRAT; ISSN:0003-2999. (Lippincott Williams & Wilkins)We investigated whether ketamine is suitable for depressed patients who had undergone orthopedic surgery. We studied 70 patients with major depression and 25 patients as the control (Group C). The depressed patients were divided randomly into two groups; patients in Group A (n = 35) were induced with propofol, fentanyl, and ketamine and patients in Group B (n = 35) were induced with propofol and fentanyl, and all patients were maintained with 1.5%-2.0% isoflurane plus nitrous oxide. The mean Hamilton Depression Rating (HDR) score was 12.7 ± 5.4 for Group A and 12.3 ± 6.0 for Group B 2 days before surgery and 9.9 ± 4.1 for Group A and 14.4 ± 3.8 for Group B 1 day after surgery. The HDR score in Group A 1 day after surgery was significantly (P < 0.05) lower than that in Group B. The HDR score in Group C was 4.2 ± 1.7 2 days before surgery and 4.8 ± 1.6 1 day after surgery. Depressed mood, suicidal tendencies, somatic anxiety, and hypochondriasis significantly decreased in Group A as compared with Group B. Postoperative pain scores in Group A at 8 and 16 h after the end of anesthesia were 26.6 ± 8.7 and 24.9 ± 8.2, resp., which were significantly (P < 0.05) lower than 34.3 ± 12.0 and 31.1 ± 8.8 in Group B. In conclusion, small-dose ketamine improved the postoperative depressive state and relieved postoperative pain in depressed patients.
- 34Jiang, M., Wang, M.-H., Wang, X.-B., Liu, L., Wu, J.-L., Yang, X.-L., Liu, X.-R., and Zhang, C.-X. (2016) Effect of intraoperative application of ketamine on postoperative depressed mood in patients undergoing elective orthopedic surgery. J. Anesth. 30, 232– 237, DOI: 10.1007/s00540-015-2096-7Google Scholar35Effect of intraoperative application of ketamine on postoperative depressed mood in patients undergoing elective orthopedic surgeryJiang Min; Wang Mao-Hua; Wang Xiao-Bin; Liu Li; Wu Jia-Li; Yang Xiao-Lin; Liu Xue-Ru; Zhang Chun-XiangJournal of anesthesia (2016), 30 (2), 232-7 ISSN:.PURPOSE: A depressed mood frequently occurs in perioperative patients, negatively impacting patient recovery. Recent studies suggested that ketamine has a rapid, obvious, and persistent antidepressant effect. The purpose of this study was to investigate the impact of intraoperative application of ketamine on postoperative depressive mood in patients undergoing elective orthopedic surgery. METHODS: This was a randomized, double-blind, controlled study. A total of 120 patients (ASA grade I-II) undergoing elective orthopedic surgery were divided randomly into a ketamine group (group K) and a control group (group C). In the K group, 0.5 mg/kg (0.05 ml/kg) ketamine was given at induction of anesthesia, followed by 0.25 mg/kg/h (0.025 ml/kg/h) continuous infusion for 30 min. In the C group, 0.05 ml/kg 0.9 % saline was used at induction of anesthesia, followed by 0.025 ml/kg/h continuous infusion of saline for 30 min. PHQ-9 score was recorded preoperatively (1 day before surgery) and postoperatively (on day 1 and day 5 following surgery). Blood at these time points was drawn for serum brain-derived neurotrophic factor (BDNF) level analysis. Intraoperative blood loss, surgery time, postoperative visual analog scale pain scores and perioperative complications were also recorded. RESULTS: There were no differences in age, sex, surgery time, blood loss, and preoperative PHQ-9 scores between the two groups (P > 0.05). There were no differences in PHQ-9 scores preoperatively and postoperatively for the C group (P > 0.05); however, the PHQ-9 postoperative scores were lower than the preoperative PHQ-9 scores in the K group (P < 0.01). Postoperative PHQ-9 scores of K group were lower than those of C group (P < 0.05). There were no differences in serum BDNF levels in C group pre- to postoperatively (P > 0.05). Compared with the preoperative BDNF levels of K group, postoperative BDNF levels in K group increased significantly (P < 0.01). An inverse correlation between PHQ-9 score and serum BDNF level was shown. CONCLUSION: Intraoperative application of ketamine was associated with improved scores for depressed mood and increased serum BDNF levels in patients undergoing elective orthopedic surgery.
- 35Xu, R., Zhan, Y., and Chen, S. (2017) Effect of intraoperative single administration of sub-anesthesia ketamine on breast cancer patients with depression. Biomedical Res. S552– S556Google ScholarThere is no corresponding record for this reference.
- 36Intraoperative Ketamine Versus Saline in Depressed Patients Undergoing Anesthesia for Non-cardiac Surgery. September 25, 2019; https://clinicaltrials.gov/ct2/show/NCT03861988 (accessed 2020).Google ScholarThere is no corresponding record for this reference.
- 37Yaden, D. B., and Griffiths, R. R. (2020) The Subjective Effects of Psychedelics Are Necessary for Their Enduring Therapeutic Effects. ACS Pharmacol. Transl. Sci.. DOI: 10.1021/acsptsci.0c00194Google ScholarThere is no corresponding record for this reference.
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Abstract
Figure 1
Figure 1. Hallucinogenic and psychoplastogenic effects can be decoupled through careful chemical design. Approximate potencies and efficacies are shown for mouse head-twitch response behavioral tests (hallucinogenic effects) and cortical neuron dendritogenesis assays (psychoplastogenic effects).
References
This article references 37 other publications.
- 1Whiteford, H. A., Degenhardt, L., Rehm, J., Baxter, A. J., Ferrari, A. J., Erskine, H. E., Charlson, F. J., Norman, R. E., Flaxman, A. D., Johns, N. (2013) Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010. Lancet 382, 1575– 1586, DOI: 10.1016/S0140-6736(13)61611-62Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010Whiteford Harvey A; Degenhardt Louisa; Rehm Jurgen; Baxter Amanda J; Ferrari Alize J; Erskine Holly E; Charlson Fiona J; Norman Rosana E; Flaxman Abraham D; Johns Nicole; Burstein Roy; Murray Christopher J L; Vos TheoLancet (London, England) (2013), 382 (9904), 1575-86 ISSN:.BACKGROUND: We used data from the Global Burden of Diseases, Injuries, and Risk Factors Study 2010 (GBD 2010) to estimate the burden of disease attributable to mental and substance use disorders in terms of disability-adjusted life years (DALYs), years of life lost to premature mortality (YLLs), and years lived with disability (YLDs). METHODS: For each of the 20 mental and substance use disorders included in GBD 2010, we systematically reviewed epidemiological data and used a Bayesian meta-regression tool, DisMod-MR, to model prevalence by age, sex, country, region, and year. We obtained disability weights from representative community surveys and an internet-based survey to calculate YLDs. We calculated premature mortality as YLLs from cause of death estimates for 1980-2010 for 20 age groups, both sexes, and 187 countries. We derived DALYs from the sum of YLDs and YLLs. We adjusted burden estimates for comorbidity and present them with 95% uncertainty intervals. FINDINGS: In 2010, mental and substance use disorders accounted for 183·9 million DALYs (95% UI 153·5 million-216·7 million), or 7·4% (6·2-8·6) of all DALYs worldwide. Such disorders accounted for 8·6 million YLLs (6·5 million-12·1 million; 0·5% [0·4-0·7] of all YLLs) and 175·3 million YLDs (144·5 million-207·8 million; 22·9% [18·6-27·2] of all YLDs). Mental and substance use disorders were the leading cause of YLDs worldwide. Depressive disorders accounted for 40·5% (31·7-49·2) of DALYs caused by mental and substance use disorders, with anxiety disorders accounting for 14·6% (11·2-18·4), illicit drug use disorders for 10·9% (8·9-13·2), alcohol use disorders for 9·6% (7·7-11·8), schizophrenia for 7·4% (5·0-9·8), bipolar disorder for 7·0% (4·4-10·3), pervasive developmental disorders for 4·2% (3·2-5·3), childhood behavioural disorders for 3·4% (2·2-4·7), and eating disorders for 1·2% (0·9-1·5). DALYs varied by age and sex, with the highest proportion of total DALYs occurring in people aged 10-29 years. The burden of mental and substance use disorders increased by 37·6% between 1990 and 2010, which for most disorders was driven by population growth and ageing. INTERPRETATION: Despite the apparently small contribution of YLLs--with deaths in people with mental disorders coded to the physical cause of death and suicide coded to the category of injuries under self-harm--our findings show the striking and growing challenge that these disorders pose for health systems in developed and developing regions. In view of the magnitude of their contribution, improvement in population health is only possible if countries make the prevention and treatment of mental and substance use disorders a public health priority. FUNDING: Queensland Department of Health, National Health and Medical Research Council of Australia, National Drug and Alcohol Research Centre-University of New South Wales, Bill & Melinda Gates Foundation, University of Toronto, Technische Universitat, Ontario Ministry of Health and Long Term Care, and the US National Institute of Alcohol Abuse and Alcoholism.
- 2Berton, O. and Nestler, E. J. (2006) New approaches to antidepressant drug discovery: beyond monoamines. Nat. Rev. Neurosci. 7, 137– 151, DOI: 10.1038/nrn18463New approaches to antidepressant drug discovery: beyond monoaminesBerton, Olivier; Nestler, Eric J.Nature Reviews Neuroscience (2006), 7 (2), 137-151CODEN: NRNAAN; ISSN:1471-003X. (Nature Publishing Group)A review. All available antidepressant medications are based on serendipitous discoveries of the clin. efficacy of two classes of antidepressants more than 50 years ago. These tricyclic and monoamine oxidase inhibitor antidepressants were subsequently found to promote serotonin or noradrenaline function in the brain. Newer agents are more specific but have the same core mechanisms of action in promoting these monoamine neurotransmitters. This is unfortunate, because only ∼50% of individuals with depression show full remission in response to these mechanisms. This review summarizes the obstacles that have hindered the development of non-monoamine-based antidepressants, and provides a progress report on some of the most promising current strategies.
- 3Olson, D. E. (2018) Psychoplastogens: A Promising Class of Plasticity-Promoting Neurotherapeutics. J. Exp. Neurosci. 12, 117906951880050 DOI: 10.1177/1179069518800508There is no corresponding record for this reference.
- 4Ly, 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., and Olson, D. E. (2018) Psychedelics Promote Structural and Functional Neural Plasticity. Cell Rep. 23, 3170– 3182, DOI: 10.1016/j.celrep.2018.05.0225Psychedelics Promote Structural and Functional Neural PlasticityLy, 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.
- 5Nichols, D. E., Johnson, M. W., and Nichols, C. D. (2017) Psychedelics as Medicines: An Emerging New Paradigm. Clin. Pharmacol. Ther. 101, 209– 219, DOI: 10.1002/cpt.5576Psychedelics as Medicines: An Emerging New ParadigmNichols D E; Johnson M W; Nichols C DClinical pharmacology and therapeutics (2017), 101 (2), 209-219 ISSN:.Scientific interest in serotonergic psychedelics (e.g., psilocybin and LSD; 5-HT2A receptor agonists) has dramatically increased within the last decade. Clinical studies administering psychedelics with psychotherapy have shown preliminary evidence of robust efficacy in treating anxiety and depression, as well as addiction to tobacco and alcohol. Moreover, recent research has suggested that these compounds have potential efficacy against inflammatory diseases through novel mechanisms, with potential advantages over existing antiinflammatory agents. We propose that psychedelics exert therapeutic effects for psychiatric disorders by acutely destabilizing local brain network hubs and global network connectivity via amplification of neuronal avalanches, providing the occasion for brain network "resetting" after the acute effects have resolved. Antiinflammatory effects may hold promise for efficacy in treatment of inflammation-related nonpsychiatric as well as potentially for psychiatric disorders. Serotonergic psychedelics operate through unique mechanisms that show promising effects for a variety of intractable, debilitating, and lethal disorders, and should be rigorously researched.
- 6Nutt, D., Erritzoe, D., and Carhart-Harris, R. (2020) Psychedelic Psychiatry’s Brave New World. Cell 181, 24– 28, DOI: 10.1016/j.cell.2020.03.0207Psychedelic Psychiatry's Brave New WorldNutt, David; Erritzoe, David; Carhart-Harris, RobinCell (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.
- 7Griffiths, R. R., Johnson, M. W., Carducci, M. A., Umbricht, A., Richards, W. A., Richards, B. D., Cosimano, M. P., and Klinedinst, M. A. (2016) Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial. J. Psychopharmacol. 30, 1181– 1197, DOI: 10.1177/02698811166755138Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: a randomized double-blind trialGriffiths, 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.
- 8Ross, 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., and Schmidt, B. L. (2016) Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial. J. Psychopharmacol. 30, 1165– 1180, DOI: 10.1177/02698811166755129Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trialRoss, 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.
- 9Davis, A. K., Clifton, J. M., Weaver, E. G., Hurwitz, E. S., Johnson, M. W., and Griffiths, R. R. (2020) Survey of entity encounter experiences occasioned by inhaled N,N-dimethyltryptamine: Phenomenology, interpretation, and enduring effects. J. Psychopharmacol. 34, 1008– 1020, DOI: 10.1177/026988112091614310Survey of entity encounter experiences occasioned by inhaled N,N-dimethyltryptamine: Phenomenology, interpretation, and enduring effectsDavis, Alan K.; Clifton, John M.; Weaver, Eric G.; Hurwitz, Ethan S.; Johnson, Matthew W.; Griffiths, Roland R.Journal of Psychopharmacology (London, United Kingdom) (2020), 34 (9), 1008-1020CODEN: JOPSEQ; ISSN:0269-8811. (Sage Publications Ltd.)The study characterized the subjective phenomena, interpretation, and persisting changes that people attribute to N,N-dimethyltryptamine-occasioned entity encounter experiences. 2561 Individuals completed an online survey about their single most memorable entity encounter after taking N,N-dimethyltryptamine. Respondents reported the primary senses involved in the encounter were visual and extrasensory. The most common descriptive labels for the entity were being, guide, spirit, alien, and helper. Although 41% of respondents reported fear during the encounter, the most prominent emotions both in the respondent and attributed to the entity were love, kindness, and joy. Most respondents endorsed that the entity had the attributes of being conscious, intelligent, and benevolent, existed in some real but different dimension of reality, and continued to exist after the encounter. Respondents endorsed receiving a message (69%) or a prediction about the future (19%) from the experience. More than half of those who identified as atheist before the experience no longer identified as atheist afterwards. N,N-dimethyltryptamine-occasioned entity encounter experiences have many similarities to non-drug entity encounter experiences such as those described in religious, alien abduction, and near-death contexts. Aspects of the experience and its interpretation produced profound and enduring ontol. changes in worldview.
- 10Bogenschutz, M. P., Forcehimes, A. A., Pommy, J. A., Wilcox, C. E., Barbosa, P. C., and Strassman, R. J. (2015) Psilocybin-assisted treatment for alcohol dependence: a proof-of-concept study. J. Psychopharmacol. 29, 289– 299, DOI: 10.1177/026988111456514411Psilocybin-assisted treatment for alcohol dependence: a proof-of-concept studyBogenschutz, Michael P.; Forcehimes, Alyssa A.; Pommy, Jessica A.; Wilcox, Claire E.; Barbosa, P. C. R.; Strassman, Rick J.Journal of Psychopharmacology (London, United Kingdom) (2015), 29 (3), 289-299CODEN: JOPSEQ; ISSN:0269-8811. (Sage Publications Ltd.)Several lines of evidence suggest that classic (5HT2A agonist) hallucinogens have clin. relevant effects in alc. and drug addiction. Although recent studies have investigated the effects of psilocybin in various populations, there have been no studies on the efficacy of psilocybin for alc. dependence. We conducted a single-group proof-of-concept study to quantify acute effects of psilocybin in alc.-dependent participants and to provide preliminary outcome and safety data. Ten volunteers with DSM-IV alc. dependence received orally administered psilocybin in one or two supervised sessions in addn. to Motivational Enhancement Therapy and therapy sessions devoted to prepn. for and debriefing from the psilocybin sessions. Participants' responses to psilocybin were qual. similar to those described in other populations. Abstinence did not increase significantly in the first 4 wk of treatment (when participants had not yet received psilocybin), but increased significantly following psilocybin administration (p < 0.05). Gains were largely maintained at follow-up to 36 wk. The intensity of effects in the first psilocybin session (at week 4) strongly predicted change in drinking during weeks 5-8 (r = 0.76 to r = 0.89) and also predicted decreases in craving and increases in abstinence self-efficacy during week 5. There were no significant treatment-related adverse events. These preliminary findings provide a strong rationale for controlled trials with larger samples to investigate efficacy and mechanisms.
- 11Garcia-Romeu, A., Griffiths, R. R., and Johnson, M. W. (2015) Psilocybin-occasioned mystical experiences in the treatment of tobacco addiction. Curr. Drug Abuse Rev. 7, 157– 164, DOI: 10.2174/1874473708666150107121331There is no corresponding record for this reference.
- 12Roseman, L., Nutt, D. J., and Carhart-Harris, R. L. (2018) Quality of Acute Psychedelic Experience Predicts Therapeutic Efficacy of Psilocybin for Treatment-Resistant Depression. Front. Pharmacol. 8, 974, DOI: 10.3389/fphar.2017.00974There is no corresponding record for this reference.
- 13Sos, P., Klirova, M., Novak, T., Kohutova, B., Horacek, J., and Palenicek, T. (2013) Relationship of ketamine’s antidepressant and psychotomimetic effects in unipolar depression. Neuro. Endocrinol. Lett. 34, 287– 29314Relationship of ketamine's antidepressant and psychotomimetic effects in unipolar depressionSos Peter; Klirova Monika; Novak Tomas; Kohutova Barbora; Horacek Jiri; Palenicek TomasNeuro endocrinology letters (2013), 34 (4), 287-93 ISSN:0172-780X.OBJECTIVES: Ketamine and other NMDA (N-methyl-D-aspartate) antagonists produce fast-acting antidepressant-like effects, although the underlying mechanism is unclear. Furthermore, high affinity NMDA antagonists such as ketamine are associated with psychotomimetic effects. To date the link between the antidepressant and psychotomimetic effects of ketamine has not been explored. We examined the relationship between the antidepressant and psychotomimetic effects of a single ketamine infusion in subjects diagnosed with major depressive disorder. METHODS: In a double-blind, cross-over, placebo-controlled, two weeks clinical trial we studied the effects of ketamine (0.54 mg/kg within 30 min) in a group of 27 hospitalized depressive patients. RESULTS: Higher intensity of psychotomimetic symptoms, measured using BPRS, during ketamine administration correlated with alleviation in mood ratings during the following week with maximum on day seven. Ketamine was superior to placebo in all visits (day 1, 4, and 7) assessed by MADRS with effect size (Cohen's d) of 0.62, 0.57, and 0.44 respectively. There was no significant correlation between ketamine and nor-ketamine plasma levels and MADRS score change at any study time point. CONCLUSION: The substantial relationship between ketamine's antidepressant and psychotomimetic effects was found. This relationship could be mediated by the initial steps of ketamine's action, trough NMDA receptors, shared by both ketamine's clinical effects.
- 14Luckenbaugh, D. A., Niciu, M. J., Ionescu, D. F., Nolan, N. M., Richards, E. M., Brutsche, N. E., Guevara, S., and Zarate, C. A. (2014) Do the dissociative side effects of ketamine mediate its antidepressant effects?. J. Affective Disord. 159, 56– 61, DOI: 10.1016/j.jad.2014.02.01715Do the dissociative side effects of ketamine mediate its antidepressant effects?Luckenbaugh, David A.; Niciu, Mark J.; Ionescu, Dawn F.; Nolan, Neal M.; Richards, Erica M.; Brutsche, Nancy E.; Guevara, Sara; Zarate, Carlos A.Journal of Affective Disorders (2014), 159 (), 56-61CODEN: JADID7; ISSN:0165-0327. (Elsevier Inc.)Background: The N-methyl-D-aspartate receptor antagonist ketamine has rapid antidepressant effects in major depression. Psychotomimetic symptoms, dissocn. and hemodynamic changes are known side effects of ketamine, but it is unclear if these side effects relate to its antidepressant efficacy. Methods: Data from 108 treatment-resistant inpatients meeting criteria for major depressive disorder and bipolar disorder who received a single subanesthetic ketamine infusion were analyzed. Pearson correlations were performed to examine potential assocns. between rapid changes in dissocn. and psychotomimesis with the Clinician-Administered Dissociative States Scale (CADSS) and Brief Psychiatric Rating Scale (BPRS), resp., manic symptoms with Young Mania Rating Scale (YMRS), and vital sign changes, with percent change in the 17-item Hamilton Depression Rating scale (HDRS) at 40 and 230 min and Days 1 and 7. Results: Pearson correlations showed significant assocn. between increased CADSS score at 40 min and percent improvement with ketamine in HDRS at 230 min (r=-0.35, p=0.007) and Day 7 (r=-0.41, p=0.01). Changes in YMRS or BPRS Pos. Symptom score at 40 min were not significantly correlated with percent HDRS improvement at any time point with ketamine. Changes in systolic blood pressure, diastolic blood pressure, and pulse were also not significantly related to HDRS change. Limitations: Secondary data anal., combined diagnostic groups, potential unblinding. Conclusions: Among the examd. mediators of ketamine's antidepressant response, only dissociative side effects predicted a more robust and sustained antidepressant. Prospective, mechanistic investigations are critically needed to understand why intra-infusion dissocn. correlates with a more robust antidepressant efficacy of ketamine.
- 15Dakwar, E., Anerella, C., Hart, C. L., Levin, F. R., Mathew, S. J., and Nunes, E. V. (2014) Therapeutic infusions of ketamine: do the psychoactive effects matter?. Drug Alcohol Depend. 136, 153– 157, DOI: 10.1016/j.drugalcdep.2013.12.01916Therapeutic infusions of ketamine: Do the psychoactive effects matter?Dakwar, E.; Anerella, C.; Hart, C. L.; Levin, F. R.; Mathew, S. J.; Nunes, E. V.Drug and Alcohol Dependence (2014), 136 (), 153-157CODEN: DADEDV; ISSN:0376-8716. (Elsevier Ireland Ltd.)Sub-anesthetic ketamine infusions may benefit a variety of psychiatric disorders, including addiction. Though ketamine engenders transient alterations in consciousness, it is not known whether these alterations influence efficacy. This anal. evaluates the mystical-type effects of ketamine, which may have therapeutic potential according to prior research, and assesses whether these effects mediate improvements in dependence-related deficits, 24 h postinfusion. Eight cocaine dependent individuals completed this double-blind, randomized, inpatient study. Three counter-balanced infusions sepd. by 48 h were received: lorazepam (2 mg) and two doses of ketamine (0.41 mg/kg and 0.71 mg/kg, with the former dose always preceding the latter). Infusions were followed within 15 min by measures of dissocn. (Clinician Administered Dissociative Symptoms Scale: CADSS) and mystical-type effects (adapted from Hood's Mysticism Scale: HMS). At baseline and 24 h postinfusion, participants underwent assessments of motivation to stop cocaine (University of Rhode Island Change Assessment) and cue-induced craving (by visual analog scale for cocaine craving during cue exposure). Ketamine led to significantly greater acute mystical-type effects (by HMS) relative to the active control lorazepam; ketamine 0.71 mg/kg was assocd. with significantly higher HMS scores than was the 0.41 mg/kg dose. HMS score, but not CADSS score, was found to mediate the effect of ketamine on motivation to quit cocaine 24 h postinfusion. These findings suggest that psychol. mechanisms may be involved in some of the anti-addiction benefits resulting from ketamine. Future research can evaluate whether the psychoactive effects of ketamine influence improvements in larger samples.
- 16Nielson, E. M., May, D. G., Forcehimes, A. A., and Bogenschutz, M. P. (2018) The Psychedelic Debriefing in Alcohol Dependence Treatment: Illustrating Key Change Phenomena through Qualitative Content Analysis of Clinical Sessions. Front. Pharmacol. 9, 132, DOI: 10.3389/fphar.2018.0013217The psychedelic debriefing in alcohol dependence treatment: illustrating key change phenomena through qualitative content analysis of clinical sessionsNielson, Elizabeth M.; May, Darrick G.; Forcehimes, Alyssa A.; Bogenschutz, Michael P.Frontiers in Pharmacology (2018), 9 (), 132/1-132/13CODEN: FPRHAU; ISSN:1663-9812. (Frontiers Media S.A.)Research on the clin. applications of psychedelic-assisted psychotherapy has demonstrated promising early results for treatment of alc. dependence. Detailed description of the content and methods of psychedelic-assisted psychotherapy, as it is conducted in clin. settings, is scarce. An open-label pilot (proof-of-concept) study of psilocybin-assisted treatment of alc. dependence (NCT01534494) was conducted to generate data for a phase 2 RCT (NCT02061293) of a similar treatment in a larger population. The present paper presents a qual. content anal. of the 17 debriefing sessions conducted in the pilot study, which occurred the day after corresponding psilocybin medication sessions. Participants articulated a series of key phenomena related to change in drinking outcomes and acute subjective effects of psilocybin. The data illuminate change processes in patients' own words during clin. sessions, shedding light on potential therapeutic mechanisms of change and how participants express effects of psilocybin. This study is unique in analyzing actual clin. sessions, as opposed to interviews of patients conducted sep. from treatment.
- 17Vollenweider, F. X., Vollenweider-Scherpenhuyzen, M. F., Babler, A., Vogel, H., and Hell, D. (1998) Psilocybin induces schizophrenia- like psychosis in humans via a serotonin-2 agonist action. NeuroReport 9, 3897– 3902, DOI: 10.1097/00001756-199812010-0002418Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2A agonist actionVollenweider, Franz X.; Vollenweider-Scherpenhuyzen, Margreet F. I.; Babler, Andreas; Vogel, Helen; Hell, DanielNeuroReport (1998), 9 (17), 3897-3902CODEN: NERPEZ; ISSN:0959-4965. (Lippincott Williams & Wilkins)Psilocybin, an indoleamine hallucinogen, produces a psychosis-like syndrome in humans that resembles first episodes of schizophrenia. In healthy human volunteers, the psychotomimetic effects of psilocybin were blocked dose-dependently by the serotonin-2A antagonist ketanserin or the atypical antipsychotic risperidone but were increased by the dopamine antagonist and typical antipsychotic haloperidol. These data are consistent with animal studies and provide the first evidence in humans that psilocybin-induced psychosis is due to serotonin-2A receptor activation, independently of dopamine stimulation. Thus, serotonin-2A overactivity may be involved in the pathophysiol. of schizophrenia and serotonin-2A antagonism may contribute to therapeutic effects of antipsychotics.
- 18Berman, R. M., Cappiello, A., Anand, A., Oren, D. A., Heninger, G. R., Charney, D. S., and Krystal, J. H. (2000) Antidepressant effects of ketamine in depressed patients. Biol. Psychiatry 47, 351– 354, DOI: 10.1016/S0006-3223(99)00230-919Antidepressant effects of ketamine in depressed patientsBerman, R. M.; Cappiello, A.; Anand, A.; Oren, D. A.; Heninger, G. R.; Charney, D. S.; Krystal, J. H.Biological Psychiatry (2000), 47 (4), 351-354CODEN: BIPCBF; ISSN:0006-3223. (Elsevier Science Inc.)Subjects with major depression completed 2 test days that involved i.v. treatment with ketamine-HCl [an N-methyl-D-aspartate (NMDA) receptor antagonist] (0.5 mg/kg) or saline solns. under randomized, double-blind conditions. The subjects evidenced significant improvement in depressive symptoms within 72 h after ketamine but not placebo infusion. These results suggest a potential role for NMDA receptor-modulating drugs in the treatment of depression.
- 19Ly, C., Greb, C. A., Vargas, M. V., Duim, W. C., Grodzki, A. C. G., Lein, P. J., and Olson, D. E. (2020) Transient Stimulation with Psychoplastogens is Sufficient to Initiate Neuronal Growth. ACS Pharmacol. Transl. Sci., DOI: 10.1021/acsptsci.0c00065 .There is no corresponding record for this reference.
- 20Moda-Sava, R. N., Murdock, M. H., Parekh, P. K., Fetcho, R. N., Huang, B. S., Huynh, T. N., Witztum, J., Shaver, D. C., Rosenthal, D. L., Always, E. J., Lopez, K., Meng, Y., Nellissen, L., Grosenick, L., Milner, T. A., Deisseroth, K., Bito, H., Kasai, H., and Liston, C. (2019) Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation. Science 364, eaat8078 DOI: 10.1126/science.aat8078There is no corresponding record for this reference.
- 21Yang, C, Shirayama, Y, Zhang, J-c, Ren, Q, Yao, W, Ma, M, Dong, C, and Hashimoto, K (2015) a rapid-onset and sustained antidepressant without psychotomimetic side effects. Transl. Psychiatry 5, e632 DOI: 10.1038/tp.2015.13622R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effectsYang, C.; Shirayama, Y.; Zhang, J.-C.; Ren, Q.; Yao, W.; Ma, M.; Dong, C.; Hashimoto, K.Translational Psychiatry (2015), 5 (9), e632CODEN: TPRSCF; ISSN:2158-3188. (Nature Publishing Group)Although the efficacy of racemate ketamine, a rapid onset and sustained antidepressant, for patients with treatment-resistant depression was a serendipitous finding, clin. use of ketamine is limited, due to psychotomimetic side effects and abuse liability. Behavioral and side-effect evaluation tests were applied to compare the two stereoisomers of ketamine. To elucidate their potential therapeutic mechanisms, we examd. the effects of these stereoisomers on brain-derived neurotrophic factor (BDNF)-TrkB signaling, and synaptogenesis in selected brain regions. In the social defeat stress and learned helplessness models of depression, R-ketamine showed a greater potency and longer-lasting antidepressant effect than S-ketamine (esketamine). Furthermore, R-ketamine induced a more potent beneficial effect on decreased dendritic spine d., BDNF-TrkB signaling and synaptogenesis in the prefrontal cortex (PFC), CA3 and dentate gyrus (DG) of the hippocampus from depressed mice compared with S-ketamine. However, neither stereoisomer affected these alterations in the nucleus accumbens of depressed mice. In behavioral tests for side effects, S-ketamine, but not R-ketamine, pptd. behavioral abnormalities, such as hyperlocomotion, prepulse inhibition deficits and rewarding effects. In addn., a single dose of S-ketamine, but not R-ketamine, caused a loss of parvalbumin (PV)-pos. cells in the prelimbic region of the medial PFC and DG. These findings suggest that, unlike S-ketamine, R-ketamine can elicit a sustained antidepressant effect, mediated by increased BDNF-TrkB signaling and synaptogenesis in the PFC, DG and CA3. R-ketamine appears to be a potent, long-lasting and safe antidepressant, relative to S-ketamine, as R-ketamine appears to be free of psychotomimetic side effects and abuse liability.
- 22Vollenweider, F. X., Leenders, K. L., Oye, I., Hell, D., and Angst, J. (1997) Differential psychopathology and patterns of cerebral glucose utilisation produced by (S)- and (R)-ketamine in healthy volunteers using positron emission tomography (PET). Eur. Neuropsychopharmacol. 7, 25– 38, DOI: 10.1016/S0924-977X(96)00042-923Differential psychopathology and patterns of cerebral glucose utilization produced by (S)- and (R)-ketamine in healthy volunteers using positron emission tomography (PET)Vollenweider, F. X.; Leenders, K. L.; Oye, I.; Hell, D.; Angst, J.European Neuropsychopharmacology (1997), 7 (1), 25-38CODEN: EURNE8; ISSN:0924-977X. (Elsevier)Until recently, racemic ketamine (S-ketamine/R-ketamine = 50:50) has been used to study NMDA receptor hypofunction in relation to pathophysiol. models of schizophrenia. Ketamine given to normal humans in subanesthetic doses produces a model psychosis including both pos. and neg. symptoms of schizophrenia. More recently it has been shown that at subanesthetic doses the pure (S)- and (R)-ketamine enantiomeres interact differently with the NMDA and sigma receptor sites in human brain. It was found that (S)-ketamine binds with a 3-4 time higher affinity to the PCP binding site of the NMDA receptor than (R)-ketamine, and that at these concns. (R)-ketamine interacts also weakly with the sigma receptor sites, where (S)-ketamine binds only negligibly. To further investigate the role of NMDA-receptor mediated neurotransmission in schizophrenic psychosis, the effects of pure (S)- and (R)-ketamine enantiomeres on brain energy metab. in normal humans using positron emission tomog. and [18F]fluorodeoxyglucose (FDG) are reported here. Psychotomimetic doses of (S)-ketamine increased cerebral metabolic rates of glucose (CMRglu) markedly in the frontal cortex including the anterior cingulate, parietal and left sensorimotor cortex, and in the thalamus. The metabolic changes in the frontal and left temporal cortex correlated with ego-disintegration and hallucinatory phenomena. Equimolar doses of (R)-ketamine tended to decrease CMRglu across brain regions and significantly suppressed CMRglu in the temporomedial cortex and left insula. (R)-ketamine did not produce psychotic symptoms, but a state of relaxation. The (S)-ketamine-induced metabolic hyperfrontality appears to parallel similar metabolic findings in acute psychotic schizophrenic patients and encourages further investigations of glutamatergic disturbances in schizophrenia.
- 23Zanos, P., Moaddel, R., Morris, P. J., Georgiou, P., Fischell, J., Elmer, G. E., Alkondon, M., Yuan, P., Pribut, H. J., Singh, N. S., Dossou, K. S. S., Fang, Y., Huang, X.-P., Mayo, C. L., Wainer, I. W., Albuquerque, E. X., Thompson, S. M., Thomas, C. J., Zarate, C. A., Jr, and Gould, T. D. (2016) NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature 533, 481– 486, DOI: 10.1038/nature1799824NMDAR inhibition-independent antidepressant actions of ketamine metabolitesZanos, Panos; Moaddel, Ruin; Morris, Patrick J.; Georgiou, Polymnia; Fischell, Jonathan; Elmer, Greg I.; Alkondon, Manickavasagom; Yuan, Peixiong; Pribut, Heather J.; Singh, Nagendra S.; Dossou, Katina S. S.; Fang, Yuhong; Huang, Xi-Ping; Mayo, Cheryl L.; Wainer, Irving W.; Albuquerque, Edson X.; Thompson, Scott M.; Thomas, Craig J.; Zarate, Carlos A., Jr; Gould, Todd D.Nature (London, United Kingdom) (2016), 533 (7604), 481-486CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)Major depressive disorder affects around 16% of the world population at some point in their lives. Despite the availability of numerous monoaminergic-based antidepressants, most patients require several weeks, if not months, to respond to these treatments, and many patients never attain sustained remission of their symptoms. The noncompetitive, glutamatergic NMDAR (N-methyl-D-aspartate receptor) antagonist (R,S)-ketamine exerts rapid and sustained antidepressant effects after a single dose in patients with depression, but its use is assocd. with undesirable side effects. Here the authors show that the metab. of (R,S)-ketamine to (2S,6S;2R,6R)-hydroxynorketamine (HNK) is essential for its antidepressant effects, and that the (2R,6R)-HNK enantiomer exerts behavioral, electroencephalog., electrophysiol. and cellular antidepressant-related actions in mice. These antidepressant actions are independent of NMDAR inhibition but involve early and sustained activation of AMPARs (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors). The authors also establish that (2R,6R)-HNK lacks ketamine-related side effects. The data implicate a novel mechanism underlying the antidepressant properties of (R,S)-ketamine and have relevance for the development of next-generation, rapid-acting antidepressants.
- 24Dunlap, L. E., Andrews, A. A., and Olson, D. E. (2018) Dark Classics in Chemical Neuroscience: 3,4-Methylenedioxymethamphetamine. ACS Chem. Neurosci. 9, 2408– 2427, DOI: 10.1021/acschemneuro.8b0015525Dark Classics in Chemical Neuroscience: 3,4-MethylenedioxymethamphetamineDunlap, Lee E.; Andrews, Anne M.; Olson, David E.ACS Chemical Neuroscience (2018), 9 (10), 2408-2427CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)Better known as "ecstasy", 3,4-methylenedioxymethamphetamine (MDMA) is a small mol. that has played a prominent role in defining the ethos of today's teenagers and young adults, much like lysergic acid diethylamide (LSD) did in the 1960s. Though MDMA possesses structural similarities to compds. like amphetamine and mescaline, it produces subjective effects that are unlike any of the classical psychostimulants or hallucinogens and is one of the few compds. capable of reliably producing prosocial behavioral states. As a result, MDMA has captured the attention of recreational users, the media, artists, psychiatrists, and neuropharmacologists alike. Here, we detail the synthesis of MDMA as well as its pharmacol., metab., adverse effects, and potential use in medicine. Finally, we discuss its history and why it is perhaps the most important compd. for the future of psychedelic science-having the potential to either facilitate new psychedelic research initiatives, or to usher in a second Dark Age for the field.
- 25Studerus, E., Gamma, A., and Vollenweider, F. X. (2010) Psychometric evaluation of the altered states of consciousness rating scale (OAV). PLoS One 5, e12412 DOI: 10.1371/journal.pone.001241226Psychometric evaluation of the altered states of consciousness rating scale (OAV)Studerus Erich; Gamma Alex; Vollenweider Franz XPloS one (2010), 5 (8), e12412 ISSN:.BACKGROUND: The OAV questionnaire has been developed to integrate research on altered states of consciousness (ASC). It measures three primary and one secondary dimensions of ASC that are hypothesized to be invariant across ASC induction methods. The OAV rating scale has been in use for more than 20 years and applied internationally in a broad range of research fields, yet its factorial structure has never been tested by structural equation modeling techniques and its psychometric properties have never been examined in large samples of experimentally induced ASC. METHODOLOGY/PRINCIPAL FINDINGS: The present study conducted a psychometric evaluation of the OAV in a sample of psilocybin (n = 327), ketamine (n = 162), and MDMA (n = 102) induced ASC that was obtained by pooling data from 43 experimental studies. The factorial structure was examined by confirmatory factor analysis, exploratory structural equation modeling, hierarchical item clustering (ICLUST), and multiple indicators multiple causes (MIMIC) modeling. The originally proposed model did not fit the data well even if zero-constraints on non-target factor loadings and residual correlations were relaxed. Furthermore, ICLUST suggested that the "oceanic boundlessness" and "visionary restructuralization" factors could be combined on a high level of the construct hierarchy. However, because these factors were multidimensional, we extracted and examined 11 new lower order factors. MIMIC modeling indicated that these factors were highly measurement invariant across drugs, settings, questionnaire versions, and sexes. The new factors were also demonstrated to have improved homogeneities, satisfactory reliabilities, discriminant and convergent validities, and to differentiate well among the three drug groups. CONCLUSIONS/SIGNIFICANCE: The original scales of the OAV were shown to be multidimensional constructs. Eleven new lower order scales were constructed and demonstrated to have desirable psychometric properties. The new lower order scales are most likely better suited to assess drug induced ASC.
- 26Holze, F., Vizeli, P., Müller, F., Ley, L., Duerig, R., Varghese, N., Eckert, A., Borgwardt, S., and Liechti, M. E. (2020) Distinct acute effects of LSD, MDMA, and D-amphetamine in healthy subjects. Neuropsychopharmacology 45, 462– 471, DOI: 10.1038/s41386-019-0569-327Distinct acute effects of LSD, MDMA, and D-amphetamine in healthy subjectsHolze, Friederike; Vizeli, Patrick; Muller, Felix; Ley, Laura; Duerig, Raoul; Varghese, Nimmy; Eckert, Anne; Borgwardt, Stefan; Liechti, Matthias E.Neuropsychopharmacology (2020), 45 (3), 462-471CODEN: NEROEW; ISSN:0893-133X. (Nature Research)Lysergic acid diethylamide (LSD) is a classic psychedelic, 3,4-methylenedioxymethamphetamine (MDMA) is an empathogen, and D-amphetamine is a classic stimulant. All three substances are used recreationally. LSD and MDMA are being investigated as medications to assist psychotherapy, and D-amphetamine is used for the treatment of attention-deficit/hyperactivity disorder. All three substances induce distinct acute subjective effects. However, differences in acute responses to these prototypical psychoactive substances have not been characterized in a controlled study. We investigated the acute autonomic, subjective, and endocrine effects of single doses of LSD (0.1 mg), MDMA (125 mg), D-amphetamine (40 mg), and placebo in a randomized, double-blind, cross-over study in 28 healthy subjects. All of the substances produced comparable increases in hemodynamic effects, body temp., and pupil size, indicating equiv. autonomic responses at the doses used. LSD and MDMA increased heart rate more than D-amphetamine, and D-amphetamine increased blood pressure more than LSD and MDMA. LSD induced significantly higher ratings on the 5 Dimensions of Altered States of Consciousness scale and Mystical Experience Questionnaire than MDMA and D-amphetamine. LSD also produced greater subjective drug effects, ego dissoln., introversion, emotional excitation, anxiety, and inactivity than MDMA and D-amphetamine. LSD also induced greater impairments in subjective ratings of concn., sense of time, and speed of thinking compared with MDMA and D-amphetamine. MDMA produced greater ratings of good drug effects, liking, high, and ego dissoln. compared with D-amphetamine. D-Amphetamine increased ratings of activity and concn. compared with LSD. MDMA but not LSD or D-amphetamine increased plasma concns. of oxytocin. None of the substances altered plasma concns. of brain-derived neurotrophic factor. These results indicate clearly distinct acute effects of LSD, MDMA, and D-amphetamine and may assist the dose-finding in substance-assisted psychotherapy research.
- 27Anderson, T., Petranker, R., Rosenbaum, D., Weissman, C. R., Dinh-Williams, L.-A., Hui, K., Hapke, E., and Farb, N. A. S. (2019) Microdosing psychedelics: personality, mental health, and creativity differences in microdosers. Psychopharmacology (Berl) 236, 731– 740, DOI: 10.1007/s00213-018-5106-228Microdosing psychedelics: personality, mental health, and creativity differences in microdosersAnderson Thomas; Farb Norman A S; Petranker Rotem; Rosenbaum Daniel; Weissman Cory R; Hui Katrina; Hapke Emma; Weissman Cory R; Hapke Emma; Dinh-Williams Le-AnhPsychopharmacology (2019), 236 (2), 731-740 ISSN:.RATIONALE: Microdosing psychedelics-the regular consumption of small amounts of psychedelic substances such as LSD or psilocybin-is a growing trend in popular culture. Recent studies on full-dose psychedelic psychotherapy reveal promising benefits for mental well-being, especially for depression and end-of-life anxiety. While full-dose therapies include perception-distorting properties, microdosing mayprovide complementary clinical benefits using lower-risk, non-hallucinogenic doses. OBJECTIVES: This pre-registered study aimed to investigate whether microdosing psychedelics is related to differences in personality, mental health, and creativity. METHODS: In this observational study, respondents recruited from online forums self-reported their microdosing behaviors and completed questionnaires concerning dysfunctional attitudes, wisdom, negative emotionality, open-mindedness, and mood. Respondents also performed the Unusual Uses Task to assess their creativity. RESULTS: Current and former microdosers scored lower on measures of dysfunctional attitudes (p < 0.001, r = - 0.92) and negative emotionality (p = 0.009, r = - 0.85) and higher on wisdom (p < 0.001, r = 0.88), openmindedness(p = 0.027, r = 0.67), and creativity (p < 0.001, r = 0.15) when compared to non-microdosing controls. CONCLUSIONS: These findings provide promising initial evidence that warrants controlled experimental research to directly test safety and clinical efficacy. As microdoses are easier to administer than full-doses, this new paradigm has the exciting potential to shape future psychedelic research.
- 28Cameron, L. P., Nazarian, A., and Olson, D. E. (2020) Psychedelic Microdosing: Prevalence and Subjective Effects. J. Psychoact. Drugs 52, 113– 122, DOI: 10.1080/02791072.2020.171825029Psychedelic Microdosing: Prevalence and Subjective EffectsCameron Lindsay P; Nazarian Angela; Olson David E; Olson David E; Olson David EJournal of psychoactive drugs (2020), 52 (2), 113-122 ISSN:.Anecdotal reports suggest that the administration of sub-hallucinogenic doses of psychedelic compounds on a chronic, intermittent schedule - a practice known as psychedelic microdosing - is becoming increasingly popular among young adults due to its purported ability to reduce symptoms of depression and anxiety while improving cognitive function and promoting social interaction. Using an anonymous online survey, we collected data from 2347 people to 1) assess the prevalence of psychedelic microdosing and characterize the demographics of microdosers, 2) determine whether microdosers associate the practice with changes in mood, cognitive function, social interaction, or physiology, and 3) investigate frequent motives for discontinuing the practice. Fifty-nine percent of respondents (NT = 2183) reported familiarity with the concept of psychedelic microdosing, with 17% (383 respondents, NT = 2200) having engaged in this practice. Microdosers attributed psychedelic microdosing with improving their mood, decreasing their anxiety, and enhancing their memory, attention, and sociability. The most frequently cited reasons for quitting microdosing (NT = 243) were the risks associated with taking an illegal substance (24.28%) and the difficulty of obtaining psychedelic compounds (22.63%). Overall, our findings suggest that psychedelic microdosing is relatively common and is subjectively associated with a broad spectrum of socio-affective, cognitive, and physical outcomes.
- 29Kuypers, K. P., Ng, L., Erritzoe, D., Knudsen, G. M., Nichols, C. D., Nichols, D. E., Pani, L., Soula, A., and Nutt, D. (2019) Microdosing psychedelics: More questions than answers? An overview and suggestions for future research. J. Psychopharmacol. 33, 1039– 1057, DOI: 10.1177/026988111985720430Microdosing psychedelics: More questions than answers? An overview and suggestions for future researchKuypers, Kim P. C.; Ng, Livia; Erritzoe, David; Knudsen, Gitte M.; Nichols, Charles D.; Nichols, David E.; Pani, Luca; Soula, Anais; Nutt, DavidJournal of Psychopharmacology (London, United Kingdom) (2019), 33 (9), 1039-1057CODEN: JOPSEQ; ISSN:0269-8811. (Sage Publications Ltd.)A review. Background:: In the past few years, the issue of 'microdosing' psychedelics has been openly discussed in the public arena where claims have been made about their pos. effect on mood state and cognitive processes such as concn. However, there are very few scientific studies that have specifically addressed this issue, and there is no agreed scientific consensus on what microdosing is. Aim:: This critique paper is designed to address questions that need to be answered by future scientific studies and to offer guidelines for these studies. Approach:: Owing to its proximity for a possible approval in clin. use and short-lasting pharmacokinetics, our focus is predominantly on psilocybin. Psilocybin is allegedly, next to lysergic acid diethylamide (LSD), one of the two most frequently used psychedelics to microdose. Where relevant and available, data for other psychedelic drugs are also mentioned. Conclusion:: It is concluded that while most anecdotal reports focus on the pos. experiences with microdosing, future research should also focus on potential risks of (multiple) administrations of a psychedelic in low doses. To that end, (pre)clin. studies including biol. (e.g. heart rate, receptor turnover and occupancy) as well as cognitive (e.g. memory, attention) parameters have to be conducted and will shed light on the potential neg. consequences microdosing could have.
- 30Cameron, L. P., Benson, C. J., DeFelice, B. C., Fiehn, O., and Olson, D. E. (2019) Chronic, Intermittent Microdoses of the Psychedelic N,N-Dimethyltryptamine (DMT) Produce Positive Effects on Mood and Anxiety in Rodents. ACS Chem. Neurosci. 10, 3261– 3270, DOI: 10.1021/acschemneuro.8b0069231Chronic, Intermittent Microdoses of the Psychedelic N,N-Dimethyltryptamine (DMT) Produce Positive Effects on Mood and Anxiety in RodentsCameron, Lindsay P.; Benson, Charlie J.; DeFelice, Brian C.; Fiehn, Oliver; Olson, David E.ACS Chemical Neuroscience (2019), 10 (7), 3261-3270CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)Drugs capable of ameliorating symptoms of depression and anxiety while also improving cognitive function and sociability are highly desirable. Anecdotal reports have suggested that serotonergic psychedelics administered in low doses on a chronic, intermittent schedule, so-called "microdosing", might produce beneficial effects on mood, anxiety, cognition, and social interaction. Here, we test this hypothesis by subjecting male and female Sprague Dawley rats to behavioral testing following the chronic, intermittent administration of low doses of the psychedelic N,N-dimethyltryptamine (DMT). The behavioral and cellular effects of this dosing regimen were distinct from those induced following a single high dose of the drug. We found that chronic, intermittent, low doses of DMT produced an antidepressant-like phenotype and enhanced fear extinction learning without impacting working memory or social interaction. Addnl., male rats treated with DMT on this schedule gained a significant amt. of body wt. during the course of the study. Taken together, our results suggest that psychedelic microdosing may alleviate symptoms of mood and anxiety disorders, though the potential hazards of this practice warrant further investigation.
- 31Dunlap, L. E., Azinfar, A., Ly, C., Cameron, L. P., Viswanathan, J., Tombari, R. J., Myers-Turnbull, D., Taylor, J. C., Grodzki, A. C., Lein, P. J., Kokel, D., and Olson, D. E. (2020) Identification of Psychoplastogenic N,N-Dimethylaminoisotryptamine (isoDMT) Analogs Through Structure-Activity Relationship Studies. J. Med. Chem. 63, 1142– 1155, DOI: 10.1021/acs.jmedchem.9b0140432Identification of Psychoplastogenic N,N-Dimethylaminoisotryptamine (isoDMT) Analogues through Structure-Activity Relationship StudiesDunlap, Lee E.; Azinfar, Arya; Ly, Calvin; Cameron, Lindsay P.; Viswanathan, Jayashri; Tombari, Robert J.; Myers-Turnbull, Douglas; Taylor, Jack C.; Grodzki, Ana Cristina; Lein, Pamela J.; Kokel, David; Olson, David E.Journal of Medicinal Chemistry (2020), 63 (3), 1142-1155CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Ketamine, N,N-dimethyltryptamine (DMT), and other psychoplastogens possess enormous potential as neurotherapeutics due to their ability to potently promote neuronal growth. Here, we report the first-ever structure-activity relationship study with the explicit goal of identifying novel psychoplastogens. We have discovered several key features of the psychoplastogenic pharmacophore and used this information to develop N,N-dimethylaminoisotryptamine (isoDMT) psychoplastogens that are easier to synthesize, have improved physicochem. properties, and possess reduced hallucinogenic potential as compared to their DMT counterparts.
- 32Cameron, L. P., Tombari, R. J., Lu, J., Pell, A. J., Hurley, Z. Q., Ehinger, Y., Vargas, M. V., McCarroll, M. N., Taylor, J. C., Myers-Turnbull, D., Liu, T., Yaghoobi, B., Laskowski, L. J., Anderson, E. I., Zhang, G., Viswanathan, J., Brown, B. M., Tjia, M., Dunlap, L. E., Rabow, Z. T., Fiehn, O., Wulff, H., McCorvy, J. D., Lein, P. J., Kokel, D., Ron, D., Peters, J., Zuo, Y., and Olson, D. E. (2020) A Non-Hallucinogenic Psychedelic Analog with Therapeutic Potential. Nature DOI: 10.1038/s41586-020-3008-zThere is no corresponding record for this reference.
- 33Kudoh, A., Takahira, Y., Katagai, H., and Takazawa, T. (2002) Small-dose ketamine improves the postoperative state of depressed patients. Anesth. Analg. 95, 114– 118, DOI: 10.1097/00000539-200207000-0002034Small-dose ketamine improves the postoperative state of depressed patientsKudoh, Akira; Takahira, Yoko; Katagai, Hiroshi; Takazawa, TomokoAnesthesia & Analgesia (Baltimore, MD, United States) (2002), 95 (1), 114-118CODEN: AACRAT; ISSN:0003-2999. (Lippincott Williams & Wilkins)We investigated whether ketamine is suitable for depressed patients who had undergone orthopedic surgery. We studied 70 patients with major depression and 25 patients as the control (Group C). The depressed patients were divided randomly into two groups; patients in Group A (n = 35) were induced with propofol, fentanyl, and ketamine and patients in Group B (n = 35) were induced with propofol and fentanyl, and all patients were maintained with 1.5%-2.0% isoflurane plus nitrous oxide. The mean Hamilton Depression Rating (HDR) score was 12.7 ± 5.4 for Group A and 12.3 ± 6.0 for Group B 2 days before surgery and 9.9 ± 4.1 for Group A and 14.4 ± 3.8 for Group B 1 day after surgery. The HDR score in Group A 1 day after surgery was significantly (P < 0.05) lower than that in Group B. The HDR score in Group C was 4.2 ± 1.7 2 days before surgery and 4.8 ± 1.6 1 day after surgery. Depressed mood, suicidal tendencies, somatic anxiety, and hypochondriasis significantly decreased in Group A as compared with Group B. Postoperative pain scores in Group A at 8 and 16 h after the end of anesthesia were 26.6 ± 8.7 and 24.9 ± 8.2, resp., which were significantly (P < 0.05) lower than 34.3 ± 12.0 and 31.1 ± 8.8 in Group B. In conclusion, small-dose ketamine improved the postoperative depressive state and relieved postoperative pain in depressed patients.
- 34Jiang, M., Wang, M.-H., Wang, X.-B., Liu, L., Wu, J.-L., Yang, X.-L., Liu, X.-R., and Zhang, C.-X. (2016) Effect of intraoperative application of ketamine on postoperative depressed mood in patients undergoing elective orthopedic surgery. J. Anesth. 30, 232– 237, DOI: 10.1007/s00540-015-2096-735Effect of intraoperative application of ketamine on postoperative depressed mood in patients undergoing elective orthopedic surgeryJiang Min; Wang Mao-Hua; Wang Xiao-Bin; Liu Li; Wu Jia-Li; Yang Xiao-Lin; Liu Xue-Ru; Zhang Chun-XiangJournal of anesthesia (2016), 30 (2), 232-7 ISSN:.PURPOSE: A depressed mood frequently occurs in perioperative patients, negatively impacting patient recovery. Recent studies suggested that ketamine has a rapid, obvious, and persistent antidepressant effect. The purpose of this study was to investigate the impact of intraoperative application of ketamine on postoperative depressive mood in patients undergoing elective orthopedic surgery. METHODS: This was a randomized, double-blind, controlled study. A total of 120 patients (ASA grade I-II) undergoing elective orthopedic surgery were divided randomly into a ketamine group (group K) and a control group (group C). In the K group, 0.5 mg/kg (0.05 ml/kg) ketamine was given at induction of anesthesia, followed by 0.25 mg/kg/h (0.025 ml/kg/h) continuous infusion for 30 min. In the C group, 0.05 ml/kg 0.9 % saline was used at induction of anesthesia, followed by 0.025 ml/kg/h continuous infusion of saline for 30 min. PHQ-9 score was recorded preoperatively (1 day before surgery) and postoperatively (on day 1 and day 5 following surgery). Blood at these time points was drawn for serum brain-derived neurotrophic factor (BDNF) level analysis. Intraoperative blood loss, surgery time, postoperative visual analog scale pain scores and perioperative complications were also recorded. RESULTS: There were no differences in age, sex, surgery time, blood loss, and preoperative PHQ-9 scores between the two groups (P > 0.05). There were no differences in PHQ-9 scores preoperatively and postoperatively for the C group (P > 0.05); however, the PHQ-9 postoperative scores were lower than the preoperative PHQ-9 scores in the K group (P < 0.01). Postoperative PHQ-9 scores of K group were lower than those of C group (P < 0.05). There were no differences in serum BDNF levels in C group pre- to postoperatively (P > 0.05). Compared with the preoperative BDNF levels of K group, postoperative BDNF levels in K group increased significantly (P < 0.01). An inverse correlation between PHQ-9 score and serum BDNF level was shown. CONCLUSION: Intraoperative application of ketamine was associated with improved scores for depressed mood and increased serum BDNF levels in patients undergoing elective orthopedic surgery.
- 35Xu, R., Zhan, Y., and Chen, S. (2017) Effect of intraoperative single administration of sub-anesthesia ketamine on breast cancer patients with depression. Biomedical Res. S552– S556There is no corresponding record for this reference.
- 36Intraoperative Ketamine Versus Saline in Depressed Patients Undergoing Anesthesia for Non-cardiac Surgery. September 25, 2019; https://clinicaltrials.gov/ct2/show/NCT03861988 (accessed 2020).There is no corresponding record for this reference.
- 37Yaden, D. B., and Griffiths, R. R. (2020) The Subjective Effects of Psychedelics Are Necessary for Their Enduring Therapeutic Effects. ACS Pharmacol. Transl. Sci.. DOI: 10.1021/acsptsci.0c00194There is no corresponding record for this reference.