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The Essential Medicinal Chemistry of Cannabidiol (CBD)

  • Kathryn M. Nelson
    Kathryn M. Nelson
    Department of Medicinal Chemistry, Institute for Therapeutics Discovery and Development, University of Minnesota, Minneapolis, Minnesota 55414, United States
  • Jonathan Bisson
    Jonathan Bisson
    Center for Natural Product Technologies, Program for Collaborative Research in the Pharmaceutical Sciences (PCRPS), and Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United States
    Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United States
  • Gurpreet Singh
    Gurpreet Singh
    Department of Medicinal Chemistry, Institute for Therapeutics Discovery and Development, University of Minnesota, Minneapolis, Minnesota 55414, United States
  • James G. Graham
    James G. Graham
    Center for Natural Product Technologies, Program for Collaborative Research in the Pharmaceutical Sciences (PCRPS), and Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United States
    Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United States
  • Shao-Nong Chen
    Shao-Nong Chen
    Center for Natural Product Technologies, Program for Collaborative Research in the Pharmaceutical Sciences (PCRPS), and Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United States
    Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United States
  • J. Brent Friesen
    J. Brent Friesen
    Center for Natural Product Technologies, Program for Collaborative Research in the Pharmaceutical Sciences (PCRPS), and Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United States
  • Jayme L. Dahlin
    Jayme L. Dahlin
    Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts 02115, United States
    Harvard Medical School, Boston, Massachusetts 02115, United States
  • Matthias Niemitz
    Matthias Niemitz
    NMR Solutions Ltd., Puijonkatu 24, 70110 Kuopio, Finland
  • Michael A. Walters
    Michael A. Walters
    Department of Medicinal Chemistry, Institute for Therapeutics Discovery and Development, University of Minnesota, Minneapolis, Minnesota 55414, United States
  • , and 
  • Guido F. Pauli*
    Guido F. Pauli
    Center for Natural Product Technologies, Program for Collaborative Research in the Pharmaceutical Sciences (PCRPS), and Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United States
    Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United States
    *Phone: (312) 355-1949. E-mail: [email protected]
Cite this: J. Med. Chem. 2020, 63, 21, 12137–12155
Publication Date (Web):August 17, 2020
https://doi.org/10.1021/acs.jmedchem.0c00724

Copyright © 2020 American Chemical Society. This publication is licensed under these Terms of Use.

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Abstract

This Perspective of the published essential medicinal chemistry of cannabidiol (CBD) provides evidence that the popularization of CBD-fortified or CBD-labeled health products and CBD-associated health claims lacks a rigorous scientific foundation. CBD’s reputation as a cure-all puts it in the same class as other “natural” panaceas, where valid ethnobotanicals are reduced to single, purportedly active ingredients. Such reductionist approaches oversimplify useful, chemically complex mixtures in an attempt to rationalize the commercial utility of natural compounds and exploit the “natural” label. Literature evidence associates CBD with certain semiubiquitous, broadly screened, primarily plant-based substances of undocumented purity that interfere with bioassays and have a low likelihood of becoming therapeutic agents. Widespread health challenges and pandemic crises such as SARS-CoV-2 create circumstances under which scientists must be particularly vigilant about healing claims that lack solid foundational data. Herein, we offer a critical review of the published medicinal chemistry properties of CBD, as well as precise definitions of CBD-containing substances and products, distilled to reveal the essential factors that impact its development as a therapeutic agent.

Introduction

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CBD is big business. The industry surrounding the use of cannabidiol (CBD) in products from cosmetics and clothing to food, beverages, and both over-the-counter supplements and prescription pharmaceuticals is staggering. With a global market estimated at $4.6 billion in 2018 (1) and projected CBD sales surpassing $20 billion in the U.S. alone by 2024, (2) the rate at which the public is consuming or coming into contact with this chemical has increased steadily. Similar to the expansive literature surrounding another widely used natural product we recently reviewed (curcumin and curcumin-containing products), (3) getting a handle on the published knowledge surrounding CBD and CBD-containing products is daunting. The sheer volume and breadth of information on CBD are a challenge for consumers and researchers alike as they seek to understand the true utility and value of both pharmaceutical-grade CBD and many CBD-labeled products from diverse sources. Hasty conclusions on the human-health impact of CBD, stemming from experiments that are often only remotely connected to biological relevance, add to the confusion. The health emergency presented by SARS-CoV-2 (and purported “cures” thereof), which emerged during the writing of this article, is a stark reminder to the scientific community that we have a serious responsibility to bring clear evidence about product composition and quality as well as the safety and efficacy to any claim for the improvement of human health.

What’s in the Name?

As with many natural products, much conflation and confusion exist between plants (here, cannabis and/or hemp), products derived from them, and a single chemical entity (here, CBD). This semantic reductionism distills one or a few species of plant (here, Cannabis sativa, C. indica, or C. ruderalis) down to two compounds, Δ9-tetrahydrocannabinol (THC) and CBD, creating a damaging assumption that single and/or major ingredients can explain the ethnobotanical use of an entire plant. Such reductionism ignores both the whole-plant aspect of ethno-based biological activity as well as the metabolomic chemistry of the plant, both of which are key tenets of contemporary pharmacognosy. Recent work highlights the importance of considering polypharmacology and/or synergistic mechanisms of dietary and medicinal plant bioactivity. (4−6) Even when only considering cannabinoids (vide infra), the chemodiversity of the CBD-producing plants is expansive, leaving no justification for semantic (or scientific) reductionism.
The widespread promotion of CBD as a quasi-synonym for any Cannabis or hemp product has an exemplary analogy in the global dietary supplement market, where the term “curcumin” is widely, and mostly erroneously, used to refer to crude preparations from the rhizome of Curcuma longa. (7) Confusion on this level has great potential to interfere with, or even void, the scientific validity of discussions surrounding CBD, as well as other erroneously promoted natural product isolates. Despite this concern, there are stark differences between the case of Cannabis/THC/CBD and that of Curcuma/curcumin. For example, little evidence exists that the curcumin molecule itself has an in vivo effect after it has been consumed by humans. In comparison, THC has a known, pronounced CNS effect, which is part of the rationale behind its special status and regulation in many countries. CBD, while structurally very similar to THC, does not seem to share THC’s psychoactive properties. (8)

Aims of This Perspective

The goal of this work is to summarize the scientific facts known about CBD and provide a useful reference for anyone wishing to understand the hype surrounding CBD. This Perspective covers the legal status of CBD in the U.S., fundamentals of CBD as a natural product and its potential status as an IMP (invalid metabolic panacea), natural sourcing of CBD and the challenges of quality control The synthetic sourcing of CBD is covered in a companion review (DOI 10.1021/acs.jmedchem.0c00095), the fundamental chemistry, pharmacology, pharmacokinetics, and pharmacodynamics (PK/PD) of CBD, and an indication-guided analysis of human clinical trials. Our work is current up to March 1, 2020, and generally relies on information published within the past 5 years. We have steered away from in vivo animal studies because they are too numerous, difficult to interpret, and subject to experimental artifacts, (9) choosing instead to focus on the evidence for therapeutic utility presented by well-designed human clinical trials.
While the verdict on CBD remains to be decided, our perspective is that it is certainly not the universal panacea that it is touted to be. Nor is it an innocuous natural substance that should be unregulated in the marketplace and/or used to fortify products for credulous human consumption. This Perspective hopes to clear up some of the smoke clouding the discussion of CBD by providing essential facts that help cut through the media chaos.

Ten Facts about CBD

The following summarizes ten key facts related to CBD.
(1)

CBD is a promoter of DDI (drug–drug interactions) and potentiates the action of many drugs (5–10 μM). (10)

(2)

CBD is a membrane interactor: it promiscuously affects ion channels by membrane pressure and direct binding (0.1–5 μM). (11,12)

(3)

CBD has a strong “meaning effect”: individuals expect it to work. (13)

(4)

CBD is 6% orally bioavailable by some reports. (14)

(5)

CBD’s typical dose in nonmedicinal products is much lower than that used in clinical trials and in prescriptions (25 mg in a typical nonmedicinal product versus 150–1500 mg/day clinical trials). (15)

(6)

“CBD has the potential to harm you” (similar to other drugs). (16)

(7)

CBD can be converted to THC by chemical means but appears not to convert to THC under physiological conditions (vide infra).

(8)

CBD is currently considered an illegal supplement (“It is currently illegal to market CBD by adding it to a food or labeling it as a dietary supplement”). (16)

(9)

“CBD” is a popular product label but often misleading: frequently “CBD” products contain many other chemically complex ingredients in addition to varying, sometimes small, amounts of CBD. Valid CBD label-claims require rigorous analytical characterization of its identity, purity, and stability (elements of residual complexity; vide infra) rather than blanket statements such as “pure” or “natural”.

(10)

CBD has not displayed meaningful activity on its own in a double-blinded, placebo-controlled clinical trial. Trials that underlie claims of a wide range of health have predominantly used CBD as minor ingredient or part of adjunctive therapy schemes that coadminister other substances/preparations, often seeking to leverage “botanical synergy” (also involving residual complexity; vide infra). This is also important considering that CBD displays strong DDIs (vide infra).

Natural Product (Bio-)Chemistry Overview

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CBD Is Just One Molecule in the Vast Chemical Space of Cannabinoids

Formally, CBD can be considered to have a tetrahydrobiphenyl skeleton: a bicyclic core that represents an adduct formed by the monoterpene, p-cymene, and the alkylresorcinol derivative, olivetol (Figure 1). CBD can be converted into the tricyclic dibenzopyran, Δ9-THC (THC), via an acid-catalyzed reaction. (17,18) While CBD and THC are prominent members of the cannabinoid family of compounds, they are just a part of the numerous representatives of the chemical subspace of the terpenylalkylresorcinol metabolome of plants of the Cannabis genus.
Irrespective of their close biogenetic relationships (vide infra, Biosynthetic Pathways), the cannabinoids represent a structurally diverse chemical space. While this diversity has been explored relatively extensively due to the strong general interest in Cannabis phytochemistry, it offers much untapped structural potential for reasons that become evident from the following chemical and biogenic rationales.

Figure 1

Figure 1. (A) Tetrahydrodiphenyl skeleton of CBD in the context of the base structures of three other main classes of cannabinoids (dibenzopyrans, benzopyrans, and acyclic prenyl-olivetols) and (B) five principal structural variations that occur in all cannabinoid classes. Different combinations of these four classes, with variations such as these presented as well as additional redox-driven metabolic modifications, explain why CBD and THC are just two molecules within the complex metabolome of cannabinoids.

The expression of naturally occurring cannabinoids (phytocannabinoids) undergoes dynamic changes during the course of plant growth (19) and consist of four major classes of molecules with distinct skeletons (Figure 1). All of these major classes contain an olivetol core (i.e., a resorcinol) in which one hydroxyl group is replaced by an alkyl chain (C5 in olivetol; with linear and branched C4 to C7 alkyl chains also known to occur). In addition to the bicyclic tetrahydrodiphenyl and tricyclic dibenzopyran classes, benzopyrans (synonym, chromenes; prototype, cannabichromene [CBC]) and acyclic prenyl-olivetols (prototype, cannabigerol [CBG]) (20) are the other key classes of cannabinoids. Within each, a variety of possible metabolomic processes in the plant can effect further structural modifications, expanding the Cannabis metabolome in five major dimensions: (1) the variation of terpenyl saturation and linkage; (2) the terpenyl stereochemistry; (3) the presence vs absence of C-2 carboxylation (“acids”); (4) the variation of length and branching of the olivetol alkyl chain (e.g., homologous cannabinoids); (20) (5) the presence and variation of the monoterpene vs sesquiterpene moieties. Collectively, this gives rise to a plethora of natural cannabinoid metabolites. The full breadth of the resulting cannabinoid chemodiversity likely remains to be explored. Moreover, cannabinoids are only one family among several phytoconstituent classes in Cannabis plants.

Biosynthetic Pathways

In the living plant and fresh plant material, many cannabinoids are present in the form of carboxylic acids. The underlying biogenic pathways are sufficiently well-characterized to allow for heterologous expression of the overall pathway. (21) In plant material, CBD acid and analogous cannabinoids are readily decarboxylated to their neutral forms in the presence of heat and during other mechanical manipulation and/or storage. For example, dried and aged plant material contains both neutral and acidic forms of CBD. The extent of decarboxylation also depends on the extraction method and processing that occurs before the CBD content is measured.
Cannabis sp. are prolific producers of terpenes and terpenoids, a phenomenon that can also be observed in other plants such as Eucalyptus sp. that are known to produce hundreds of these compounds. (21,22) It is likely that most of the cannabinoids are produced at the intersection of three major biosynthetic pathways: the DXP (deoxyxylulose phosphate, also called methylerythrol phosphate [MEP]) pathway, the MVA (mevalonic acid) pathway, and the fatty acid pathway that feeds a polyketide synthase (PKS), olivetolic acid synthase (Figure 2). (21,23) The diversity of cannabinoids produced by Cannabis sp. is mainly achieved through nonenzymatic modifications occurring after the production of a common precursor. (21,23) While predictive studies of the kinds of cannabinoids that could potentially be produced by these plants are unavailable, the diversity of metabolites arising from these pathways is congruent with the already hundreds of identified cannabinoids.

Figure 2

Figure 2. The biosynthetic pathway of cannabinoids is the result of the intersection of three metabolic pathways in Cannabis sp.

CBD Residual Complexity, Purity, Identity, and Quality Control

When choosing a method of chemical separation of the cannabinoid metabolome, the occurrence of homologous alkyl and prenyl side chains, single vs double cyclized monoterpene rings, and presence vs absence of pyran/chromene rings (Figure 1) present a chromatographic challenge. These three structural permutations alone produce a mixture of molecules with closely similar polarities and overall molecular shapes. These challenges for the resolution capabilities of current chromatographic systems apply equally to detection methods that depend on prior separation such as GC– and LC–MS, as well as to preparative methods including adsorbent-based column and countercurrent/centrifugal partition (CCC/CPC) chromatography that are employed for the targeted purification of cannabinoids, such as CBD. Accordingly, when working with Cannabis and related materials, it would be naive to assume that individual chromatographic peaks arise from single (“pure”) compounds. Even narrow elution time windows probably contain residual amounts of congeneric cannabinoids and, therefore, represent cases of residual complexity (https://go.uic.edu/residualcomplexity).
Accordingly, CBD, THC, and any other “purified” individual cannabinoids are subject to the principles of residual complexity and its analytical implications. This caveat applies even when high purity has been demonstrated by a rigorous method, such as a combination of LC–UV/MS and quantitative NMR (qNMR), (24) as the stability of high purity material and/or chemical changes during biological/clinical testing (i.e., dynamic residual complexity) needs to be demonstrated separately. While thermoanalytical (DSC, TGA) purity assays for CBD are unavailable in the literature, they have recently been introduced for cocrystal forms of CBD. (25) Extraction methods or synthetic methodologies used in the preparation of CBD products have a significant impact on what constitutes the final preparation labeled with/as “CBD”.
In addition, residual complexity can involve both phytochemicals or synthetic reagents present in the original preparation that can be carried through to the final step, as well as known (e.g., decarboxylation) or unanticipated chemical transformations that may occur under the conditions used for extraction or purification. Some concern exists that CBD may rearrange to THC, but this transformation, while chemically feasible (vide infra), is not likely to occur during extraction, separation, or purification. (26)
The unique fingerprints of such residually complex materials can be used to help identify the source and method of production of a CBD product. Chemical fingerprinting methodology, currently used to identify illegal/counterfeit drugs, could be adopted for cannabinoids to aid with the identification of the source (material, origin) of various CBD products. (27)
Considering the permutational variations and resulting close structural resemblance of natural cannabinoids, authentic CBD, including CBD reference materials, must undergo rigorous characterization involving at least HRMS supporting its molecular formula (C21H30O2), 1D/2D 1H and 13C NMR assignments, as well as physicochemical determination of its properties including UV, IR, melting point (66–67 °C, although this is dependent on polymorph) and boiling point (189 °C, experimental conditions incl. pressure not reported), and optical rotation (−125°) (from https://scifinder.cas.org and ref (28)). Ideally, the reference material is crystalline, and its quality is supported by X-ray diffraction analysis. Universal as well as simultaneous qualitative and quantitative capabilities (24,29) make NMR a highly versatile analytical method that is particularly suitable for CBD and cannabinoids in general. This potential was already recognized in 2004 by Hazekamp, Choi, and Verpoorte, (30) who utilized the relatively simple resonances of the uncoupled or meta-coupled aromatic hydrogens as well as that of the olefinic hydrogen in the monoterpene moiety to determine the purity of isolated cannabinoids, as well as their quantity, in extracts. A recently published quantitative NMR (qNMR) method permits the absolute quantitation of CBD using combined external (crystalline CBD) and internal (residual CHCl3 signal) calibration. (31)
One important feature of the 1D 1H NMR spectra of CBD that has been underutilized to date pertains to the information richness of the underlying 1H,1H spin coupling systems. Considering the cyclic, unsaturated partial structure of CBD, it can be anticipated that not only geminal and vicinal (2/3J) but also a wealth of long-range couplings (predominantly 4/5J) are present in the molecule. This gives rise to numerous fine splittings in the apparently simple “singlet” signals that reveal themselves as “multiplet” resonances upon closer inspection. Another complication of interpreting the 1D 1H NMR spectrum of CBD, which actually represents a highly characteristic feature for the identification of the compound, relates to the higher order coupling effects of closely resonating methylene and methine hydrogens. Recent advancement in the quantum mechanics-based computational analysis of 1H NMR spectra has enabled a full interpretation of such spectra, using an approach termed HiFSA (1H iterative full spin analysis), (32) leading to the extraction of full sets of chemical shifts (δ) and coupling constants (J).
One major advantage of HiFSA profiles is that they enable the calculation and comparison of 1H NMR spectra at any field strength, (32) thus covering all practically available NMR instruments from 40 to 900+ MHz. Another feature of HiFSA is that it can utilize digitally archived raw NMR data, as long as they are maintained and shared among scientists and practitioners using FAIR principles. (33,34) This enables the comparison of samples and verification of compound identity over a long period of time, across multiple laboratories, and without the need for authentic reference materials. In order to help leverage the capabilities of HiFSA profiles for future applications and demonstrate the power of raw data sharing, we have performed a retrospective HiFSA analysis of a 2004 CBD raw 1H NMR data (FID; Supporting Information section S1). Figure 3 shows how the highly characteristic single 1H NMR resonance of H-4″ax (axial) can serve as a fingerprint signal that represents the entire CBD molecule. This enables the use of routine 1H NMR spectroscopy for unambiguous identity assays via comparison of 1H NMR spectra at any field strength. (32) Moreover, due to the inherently quantitative nature of NMR, appropriately acquired qualitative data can be utilized for qNMR-based CBD purity analysis that is independent of identical reference standards.

Figure 3

Figure 3. Not only is the axial hydrogen, H-4″ax, involved in multiple J-couplings within the monoterpene moiety, but its 1H NMR resonance is also affected by the close resonance behavior of its coupling partners. The resulting pronounced higher order effects of the ddddddq-type multiplet encode the spin parameters of half of the molecule in such a way that the H-4″ax resonance alone becomes diagnostic for the entire CBD molecule. See section S1, Supporting Information, for the detailed results of the underlying 1H iterative full spin analysis (HiFSA).

General identity and purity assays for CBD involve liquid- and gas-chromatographic comparison with authentic reference material. However, product purity can deviate substantially from assumed grades or values, even when quantitatively measured against authentic standards, as the method is only as reliable as the characterization of the reference material. The vastly different abundance of the metabolites in crude cannabinoid mixtures explains why minor components can go undetected unless multiple preparative steps and/or orthogonal separation systems are employed. At the same time, minor components can be the principal or even sole factors for biological outcomes, as shown recently for a 0.24% impurity of an antimycobacterial agent. (35) Likewise, a major “pure” component can exhibit only minor or no real effects. As the biological potency of individual compounds spans many orders of magnitude, correlations between compound abundance and observed potency can be counterintuitive when considered from a chemical perspective alone. (36)
Applied to CBD and the other cannabinoids, the concept of residual complexity has to be considered carefully when using materials for preclinical biological studies and/or for clinical interventions, including as nutritional supplements, and is essential for the reproducibility of any studies with such materials. The recent work by Citti et al. on the production and purity of CBD as well as the identification of the 3-butyl homologue as a common impurity confirms the relevance of the residual complexity for CBD and other cannabinoids. (37) In their article, the authors also highlight the applicability of ICH guidelines (Q3A(R2)), calling for the impurity analysis of APIs to the level of 0.10% and 0.05% for daily doses of below and above 2 g of the API, respectively. (37)

Regulatory Overview

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As of March 2020, the U.S. Federal Drug Administration (FDA) had not approved the marketing of cannabis for the treatment of any disease or condition. The FDA has, however, approved one cannabis-derived product for medicinal use (Table 1), Epidiolex, which contains CBD as API and is only available from a licensed healthcare provider with a prescription. (14,40) The FDA has not approved any other CBD products currently on the market in the United States. Epidiolex is an oral solution that contains 100 mg/mL CBD, and the underlying patent refers to CBD from both Cannabis plant extracts and synthesis as potential sources. Inactive ingredients in this formulation include dehydrated alcohol [not less than 98% volume EtOH], sesame seed oil, strawberry flavor, and sucralose. (41) Epidiolex was approved for the treatment of seizures associated with Lennox–Gastaut or Dravet syndrome in patients 2 years of age or older. (39) Both syndromes are rare forms of treatment refractory epilepsy that represent <5% of all childhood epilepsies. Regarding the various products that contain (or claim to contain (42)) CBD and are marketed without a prescription, the FDA has published the following guidance, which we quote here for clarity.
Table 1. Key Terms and Definitions (38)
MaterialDefinition
CannabisPlant of the Cannabaceae family that produces biologically active cannabinoids, some of which are controlled under the Controlled Substances Act (CSA) since 1970 (39)
MarijuanaCannabis plant that produces THC at 20%+ levels
HempThe plant Cannabis sativa L. and any part of the plant and all derivatives thereof with a THC content of <0.3% (dry weight). (39) Hemp can contain as much as 20% or more CBD.
Hemp seeds/oilWhole seeds or oil, containing fatty acid esters, that is expressed or extracted from seeds. These products contain 0% THC and trace levels of CBD.
CannabinoidsFamily of chemicals that act on the endocannabinoid system. The Cannabis plant synthesizes many cannabinoids, such as THC and CBD.
THCΔ9-Tetrahydrocannabinol, a cannabinoid used for medicinal purposes and nonmedicinally for its (intoxicating) CNS effects. CAS no. 1972-08-3
CBDCannabidiol, a cannabinoid with an undefined mechanism of action. Biosynthetically related to THC. Not intoxicating even at high doses. CAS no. 13956-29-1
Cannabis-derived products for medicinal useMedicinal products containing cannabis or cannabinoids derived from the Cannabis plant (e.g., THC and/or CBD in well-defined proportions)
Synthetic cannabinoids for medicinal useMedicinal products containing synthetically produced cannabinoids that typically mimic the effects of THC
Nonmedicinal CBD productsProducts containing CBD that are widely sold as herbal remedies but are not regulated as medicinal products
Nonmedicinal cannabisMaterial from the Cannabis plant that is not regulated as a medicinal product, widely used for its (intoxicating) CNS effects
Nonmedicinal synthetic cannabinoidsSynthetic cannabinoids that are typically not structurally related to naturally occurring cannabinoids and are not currently recognized for medicinal use (e.g., synthetic cannabinoid receptor agonists, found in products such as “spice”)

“Under the FD&C Act [note: Food, Drug, and Cosmetic Act, 1938], any product intended to have a therapeutic or medical use, and any product (other than a food) that is intended to affect the structure or function of the body of humans or animals, is a drug. Drugs must generally either receive premarket approval by the FDA through the New Drug Application (NDA) process or conform to a “monograph” for a particular drug category, as established by FDA’s Over-the-Counter (OTC) Drug Review. CBD was not an ingredient considered under the OTC drug review. An unapproved new drug cannot be distributed or sold in interstate commerce. FDA continues to be concerned at the proliferation of products asserting to contain CBD that are marketed for therapeutic or medical uses although they have not been approved by FDA. Often such products are sold online and are therefore available throughout the country. Selling unapproved products with unsubstantiated therapeutic claims is not only a violation of the law, but also can put patients at risk, as these products have not been proven to be safe or effective. This deceptive marketing of unproven treatments also raises significant public health concerns, because patients and other consumers may be influenced not to use approved therapies to treat serious and even fatal diseases. Unlike drugs approved by FDA, products that have not been subject to FDA review as part of the drug approval process have not been evaluated as to whether they work, what the proper dosage may be if they do work, how they could interact with other drugs, or whether they have dangerous side effects or other safety concerns.” (39)

In addition to one CBD product, the FDA has approved three non-CBD cannabis-related drug products (Figure 4). Marinol and Syndros have both been approved for therapeutic uses in the United States, including for the treatment of anorexia associated with weight loss in AIDS patients. Both therapies include dronabinol as the active ingredient, a synthetic form of THC, which is considered the psychoactive component of cannabis. Cesamet is an FDA-approved product that contains nabilone as the active ingredient, which is synthetically derived and has a chemical structure similar to THC.

Figure 4

Figure 4. Structures of the active ingredients of FDA-approved drugs containing CBD or related compounds.

With these four exceptions, no product containing cannabis or cannabis-derived compounds (either plant-based or synthetic) have been approved as safe and effective for use in any patient population, whether pediatric or adult. Going even farther, CBD containing products are explicitly excluded from being sold as “dietary supplements”. Following section 201(ff)(3)(B) of the FD&C Act [21 U.S.C. § 321(ff)(3)(B)], if a substance (here, CBD) is approved as an active ingredient in a drug product, then products containing that substance are excluded from the definition of a dietary supplement.

Conversion of CBD to THC

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(−)-CBD was the major phytocannabinoid in extracts of Cannabis sativa L. plants from which it was first isolated and structurally characterized in 1940. (43,44) Jones subsequently confirmed the chemical structure by X-ray crystallography in 1977. (45) CBD is chemically unstable at room temperature, undergoes air oxidation to form cannabidiol hydroxyquinone, (46,47) and can isomerize to other cannabinoids in acidic environments. Gaoni and Mechoulam reported the isomerization of CBD to THC and other cannabinoids under aqueous acidic conditions; however this conversion results in a mixture of isomeric THCs in low yields. More recently, in a patented method, CBD was converted to Δ9-THC in quantitative yield using boron trifluoride etherate as a Lewis acid in anhydrous CH2Cl2. (48) The sensitivity of CBD to acidic conditions has led to the hypothesis that conversion of CBD to THC under the gastric acidic environment in vivo can cause adverse pharmacological effects from CBD-based marketed products. (49) This conversion has been debated in the literature, however, and there is no direct evidence of the conversion of CBD to THC in the human gut. (50) Two in vitro studies have used simulated gastric fluid to test the plausibility of this conversion. The first study reported the formation of THC in 2.9% yield along with other cannabinoid products in artificial gastric fluid without pepsin. (51) In 2016, Zynerba Pharmaceuticals reported the formation of psychoactive cannabinoids (Δ9-THC and Δ8-THC) by exposing CBD to simulated gastric fluid (SGF), (49) showing 98% conversion of CBD to these THC products (∼49% yield) within 2 h by UPLC–MS analysis (Figure 5).

Figure 5

Figure 5. Acid instability of cannabidiol as reported by Zynerba Pharmaceuticals. (47)

However, Grotenhermen (52) and Nahler (50) later refuted the in vivo relevance of this report by pointing out that the SGF protocol differs significantly from the physiological conditions present in the stomach. Furthermore, these follow-up studies reviewed data from previously conducted clinical trials of CBD and found no reports of THC or related metabolites. A recent study by the Lachenmeier group further ruled out the feasibility of CBD to THC transformation. (53) They conducted stability studies of pure CBD solutions stored in SGF or subjected to a range of storage conditions, such as heat and light. Mass spectrometric (LC/MS/MS) and ultrahigh-pressure liquid chromatographic/quadrupole time-of-flight mass spectrometric (UHPLC-QTOF) analyses could not confirm the formation of THC under any of these conditions.
None of the in vitro experiments reviewed herein represent a sufficiently robust model to predict the in vivo gastric stability of CBD, and the findings in each case may be a product of the various experimental conditions employed. The currently available and always accumulating in vivo data should be used to rule out the possibility of THC formation, especially studies where CBD is dosed at high levels. In the simplest in vivo experiment, if CBD to THC conversion takes place in the stomach, one would expect to see THC in feces upon high oral dosing of the CBD. However, this has not yet been reported as both CBD and THC are excreted unchanged in the feces (vide infra).

Bioactivity of Simple CBD Analogs

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Inspired by the ethnopharmacology of Cannabis extracts and potentially driven by reductionist research approaches (vide supra), natural (−)-CBD has attracted attention as a drug candidate and as a lead compound for medicinal chemistry campaigns. However, efforts so far have resulted in few new compounds as clinical or preclinical candidates. The large number of such studies make it impossible to review all of the results herein, but an examination of close CBD analogs will put this body of work into context. Extensive first-pass metabolism and the observed polypharmacology of CBD make it challenging to relate its therapeutic effects to a precise molecular target (vide infra). This complicates the optimization of compounds because no one target can effectively drive structure–activity relationship studies. Synthetic analogues of CBD have been targeted based on modification of the C3-alkyl chain, the phenol ring, and the limonene moiety. Biological studies of these compounds led to identification of compounds with interesting pharmacological properties (Figure 6).

Figure 6

Figure 6. Selected bioactive synthetic analogs of cannabidiol.

Hydrogenation of the double bonds in CBD resulted in H2-CBD and H4-CBD, with reported anti-inflammatory properties, anticonvulsant properties, (54) and moderate affinity for the CB1 receptor. (55) Unlike the naturally occurring (−)-CBD, the enantiomeric (+)-CBD is not found in nature. (+)-CBD and its analogs have been synthesized and evaluated for CB1/CB2 receptor affinity, showing strong activity below 1 μM. (56,57) More interestingly, evaluation of these compounds in the tetrad group of assays, (58) commonly used for assessing effects on cannabinoid system, suggests that they do not activate CB1 receptors in the brain but may have potential to selectively target the peripheral CB1 receptors for the management of peripheral pain and inflammation. (57) Neuroprotective studies of C-3 alkyl chain analogs of CBD resulted in the identification of KLS-13019 that was 50-fold more potent (40 nM vs 2 μM for CBD) and >400-fold less toxic (therapeutic index of 7500 vs 16) than CBD in preventing ammonium acetate and ethanol-induced damage to hippocampal neurons. (59) A recently completed preclinical study concluded that KLS-13019 regulates the mitochondrial sodium–calcium exchanger-1 (mNCX-1), which is an important therapeutic target for the treatment of chemotherapy-induced peripheral neuropathy (CIPN). (60) Abn-CBD, a synthetic regioisomer of CBD, and O-1602 have been reported to engage orphan receptors GPR-18 (no EC50 reported) and GPR-55 (EC50 2 nM), respectively, that are involved in diverse physiological processes. (61−64)

Pharmacology

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CBD Receptor Activity

The broad-ranging therapeutic utility claimed of CBD has been attributed to its reported pharmacological activity at a number of receptors. Some of the most frequently highlighted targets of CBD include the following: ligand-gated ion channels (GlyR, NaV, nAch, GABAA), TRP channels (TRPV1, TRPV2, TRPA1, TRPM8), GPCRs (5-HT1A, α1A, μ-OPR, δ-OPR, CB1, CB2, GPR18, GPR55), enzymes (FAAH, CYP450), and nuclear receptors (PPARg). (65−67) From a careful inspection of the original publications where these bioactivities are reported, the outcomes are almost certainly irrelevant to most nonprescription products given the relatively small dose of CBD that such products contain and the low bioavailability of CBD (vide infra, Absorption).
Even in the case of high-dose pharmaceutical products, some in vivo activities of CBD are only supported by brain concentrations that are achieved if CBD is dosed at 120 mg/kg in mice. (68) For example, the allosteric effects reported for μ- and δ-opioid receptors were stated by the study authors not to be of significance because the EC50 values of those interactions are approximately 100-fold higher than those of the plasma concentration of 36 ng/mL (approximately 100 nM) in humans when given a single dose of an oral preparation containing 100 mg of CBD. (69) Likewise, CBD only displaced the agonist [3H]-8-OH-DPAT from the 5-HT1A receptor at EC50 = 8–16 μM and [3H]-ketaserin from 5-HT2A at EC50 ∼ 32 μM. (70) In the case of ion channels, it has been noted that the channel modulating effects of CBD are rather promiscuous and may be explained by a combination of direct interaction of CBD with the channel and the impact of CBD on membrane bilayer flexibility. (11,12) This is similar to the membrane disrupting effects seen with many (overstudied) natural products. (71,72)
Importantly, it is generally accepted that CBD is 50-fold less active at the endocannabinoid receptors (Ki of 4350 nM at CB1 and 2860 nM at CB2) than THC (Ki of 40.7 nM at CB1 and 36.4 nM at CB2). (73) This has been used to explain the lack of psychoactive effects of CBD even at high dosing. Ironically, the observed therapeutic utility of CBD may be due to the “meaning effect” activating this placebo pathway (vide infra). (74)
In an attempt to better understand some of the reported receptor activities of CBD, we profiled a broad panel of neurological receptors offered by the Psychoactive Drug Screening Program at UNC (Supporting Information section S2). CBD did not show appreciable activity (<50% inhibition at 10 μM) at 37 of the 45 targets assayed. It displayed measurable, but not significant, inhibition (>50% inhibition at 10 μM) at the following receptors: 5-HT2C, MOR, KOR, D1, H3, α2b, σ2, α2C, and DOR (Figure 7A). CBD failed to achieve full inhibition at any of these receptors, as evidenced by dose–response curves that do not reach 0% activity at the highest concentrations tested (see Supporting Information section S2). The reported Ki values for these nine receptors were all >1 μM. Considering that pharmacological activity can only be achieved by free or unbound compound in circulation (the free drug principle (75)), the plasma protein binding of CBD becomes important in relation to these Ki values. CBD is reported as ∼90% plasma protein bound, (76) meaning that in the presence of serum proteins the Ki may be significantly higher. However, plasma protein binding alone cannot predict the relevant in vivo concentration of a compound. (77) Therefore, whether or not these activities are relevant to the in vivo activity of CBD in humans remains to be further investigated.

Figure 7

Figure 7. Interference profiling of CBD. (A) CBD shows moderate activity at several receptors. Ki values were reported from testing by PDSP. Full data are in Supporting Information. (B) CBD shows concentration-dependent, detergent-sensitive inhibition of AmpC in a colloidal aggregation counterscreen. TIPT, positive aggregation control; 2-BTBA, positive nonaggregator control. Data are the mean ± SD of four intrarun technical replicates. (C) CBD shows detergent-sensitive inhibition of MDH in an orthogonal aggregation counterscreen. Compounds were tested at 33 or 100 μM final concentrations in either the presence (blue) or absence (magenta) of buffer containing freshly added 0.01% Triton X-100 (v/v). Data are the mean ± SD of at least three intrarun technical replicates. (D) CBD forms detectible colloidal aggregates at approximately 12.5 μM by DLS. (E) CBD does not produce detectable H2O2 in a HRP-PR redox-cycling counterscreen. Compounds were assayed at 250 μM final concentrations, 1 mM DTT, enzyme. H2O2, positive control; NSC-663284 and 4-amino-1-naphthol, positive control compounds. Data are mean ± SD of at least three intrarun technical replicates.

Interaction of CBD with CYPs

The most relevant observed bioactivity of CBD as it relates to current therapeutic utility appears to be its ability to interact with CYPs. This binding has been demonstrated in numerous settings and leads to the best-documented activities of CBD, which are drug–drug interactions (DDIs) or, in the case of herbal products, drug–herb interactions (DHIs). These DDIs/DHIs cause an increase of plasma concentration of drugs that are metabolized by the CYPs, in turn generating a measurable increase in the effect of said drugs. For example, a bidirectional drug interaction occurs with the combination epilepsy medication clobazam and CBD. This results in a 1.7- to 2.2-fold increase in the mean plasma clobazam concentration in patients receiving clobazam concomitantly with 40 mg kg–1 day–1 of CBD oral solution compared with 10 mg kg–1 day–1 and 20 mg kg–1 day–1. (78)
In a phase I, open-label pharmacokinetic trial, dosing CBD concomitantly with clobazam led to an 3.4-fold increase in Cmax and AUC of N-desmethylclobazam, the major active metabolite of clobazam. (10) CBD treatment of pediatric patients taking clobazam resulted in higher reporting of side effects that could be ameliorated by clobazam dose reduction. (79) Finally, clinical trial simulations of the effect of 20 mg kg–1 day–1 CBD on drop-seizure frequency in patients (some of whom were also taking clobazam) with Lennox–Gastaut syndrome showed that the claimed efficacy of CBD may be largely explained by its drug–drug interaction with clobazam. (80) Clobazam is primarily metabolized in the liver by CYP3A4, with minor involvement from CYP2C19 and CYP2B6. (81) CBD is active at these CYPs at or below 1 μM (vide infra, Toxicology). Therefore, while CBD is an effective part of the therapy, the mechanism of action of CBD may be simply to increase the tissue concentration of another disease-modifying therapeutic. While possessing therapeutically useful properties as an adjuvant, CBD alone has not, to our knowledge, been shown to have disease-modifying effects on epilepsy or any other disease.

Bioassay Interferences of CBD

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CBD exhibits bioassay promiscuity. This unwanted effect is likely due to CBD’s ability to disrupt membranes and its high lipophilicity, especially when paired with high compound test concentrations in vitro (i.e., micromolar). Table 2 details several relevant physicochemical properties calculated for CBD using ChemDraw Professional 16 (PerkinElmer) and Molinspiration Property Calculation Service (version 2018.10). (82) Compounds can interfere with assay technologies to produce false-positive readouts or nonspecifically perturb biological systems by poorly optimizable mechanisms of action such as redox cycling, colloidal aggregation, membrane perturbation, and general cytotoxicity, to name a few. (83) This motivated the profiling of CBD for several common sources of biological assay interference as part of this study.
Table 2. Physicochemical Properties of CBD
PropertyValue
MW314.47 g/mol
log P5.91
ClogP6.64
tPSA40.46 Å2s
H-bond donors2
H-bond acceptors2
rotatable bonds6
In our experiments (see experimental details in Supporting Information), CBD showed detergent-sensitive inhibition of two unrelated enzymes, AmpC β-lactamase and malate dehydrogenase (MDH), at low micromolar concentrations, which is consistent with nonspecific inhibition by colloidal aggregation (Figure 7B,C). CBD formed detectable colloidal aggregates by dynamic light scattering (DLS) at approximately 12.5 μM [Figure 7D; n.b. the critical aggregation concentration (CAC) can vary several-fold depending on experimental conditions]. By contrast, CBD did not produce detectable levels of H2O2 in a counterscreen for redox activity (Figure 7E). These data suggest that CBD likely forms colloidal aggregates at low micromolar concentrations, which is significant as aggregators can nonspecifically perturb proteins in both cell-free and cellular assays. Along with the noted effects of CBD on in vitro cellular health (e.g., cytotoxicity, proapoptotic), this calls into question how to interpret and practically apply studies that attribute specific bioactivities to CBD when testing concentrations were near the approximate CAC (or within ranges that may adversely perturb cellular health). (11,84,85)
In our experience with chemical probe validation, tantalizing readouts and pharmacological models produced under these conditions can be reproduced by a variety of bad-acting compounds, pointing to a nonspecific mechanism of action. In addition, these experiments can lack relevance as the in vitro conditions would never be achieved in vivo. Cell-based activity should always be accompanied by biomarker evidence of target engagement. Given its ability to injure cells, we would recommend that future in vitro studies characterize the effects of CBD on cellular health in parallel to activity studies.

ADMET: Absorption, Distribution, Metabolism, Excretion, Toxicology

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Due to the diverse nature of the routes of administration by which CBD has been studied, its pharmacokinetic (PK) analysis is more complex than for other therapeutics. In addition to the traditional oral (i.e., capsule) and parenteral (i.e., intravenous) routes, CBD has also been studied as oral sublingual drops, oromucosal spray, or a component of a food product and as an inhalation agent through an aerosol, nebulizer, vapor, or cigarettes. All of these varied formulations and routes of administration carry different propensities for adsorption and distribution, which then affects the rest of the measured PK characteristics of the compound.

Absorption

CBD has been studied in a wide variety of formulations but has generally been administered orally either as a capsule, dissolved in an oil or other organic solvent, or as an oromucosal spray. (15) Study doses are commonly a single dose in the 2–20 mg range, with some studies testing doses upward of 800 mg (Table 3). The plasma Cmax generally increases with increased dose and is slightly increased in the fed vs fasted state; the Tmax is not significantly impacted by dose. Absorption appears highest upon inhalation, whether by smoking or other forms of vaporization. At the time of this article, the only rigorous bioavailability (F) reported was in a smoking study of five male participants that reported an average bioavailability of 31%. (86) When considering the differences seen in plasma concentration from oral dosing, it is expected that oral bioavailability is significantly lower. In an animal study of CBD oral bioavailability, three dogs led to an F range of 13–19%. (87)
Table 3. Average CBD Dose, Tmax, and Cmax for Human Studies of CBD Administrationa
 avg dose (mg)avg Tmax (h)avg Cmax (ng/mL)avg Cmax (nM)F (%) (if reported)
low oral doseb14 ± 151.9 ± 1.22.8 ± 2.20.9 
high oral dosec525 ± 3403.1 ± 0.3131.9 ± 82.541.5 
inhalation dosed3.5 ± 5.50.3 ± 0.335.3 ± 41.311.131
a

Analysis of 50 reported studies of CBD dosing that included reported plasma levels.

b

Dose range: 1.5–20 mg.

c

Dose range: 100–800 mg.

d

Dose range: 1.5–20 mg.

Distribution

Complete details of bodily distribution of CBD are not readily available. In the same study as cited above on oral bioavailability, the volume of distribution of CBD upon iv dosing was 2520 L. (86) Several studies of volume of distribution for oromucosal spray formulations report extremely high volumes of distribution between 26 000 and 31 000 L. (88) These data suggest that any CBD that enters systemic circulation is widely distributed throughout the tissues of the body. In a study of CBD oral dosing in mice, 120 mg/kg resulted in a range of maximum brain tissue concentrations of 4–21 μM. (89) Another study looked at the concentration of CBD in the brain of mice after subcutaneous administration at 10 mg/kg and reported a Cmax of 1–2 μM. (68) Not surprisingly, the concentration of CBD in brain tissue is always measured as being lower than the correlating plasma concentration. Therefore, CBD levels in human brain tissue are likely to be lower than the reported plasma concentrations in humans (see Table 3, <50 nM); however there appears to be no significant barrier to brain penetration of CBD.

Metabolism

In general, CBD shows similar metabolism to that of THC, which aligns with their structural similarity (Figure 1A). CBD is subject to a high first-pass effect, similar to THC. (90) CBD is affected by extensive oxidative metabolism, with the most prominent metabolites being allylic hydroxylation products at the 6- and 7-positions, followed by alkyl hydroxylation products at all positions along the alkyl chain (Figure 8). (91,92) Several of these metabolites have been identified in human plasma, (93) and at least one report of the analysis of human urine identifies these and the glucuronides of the phenolic oxygen species. (94) Several in vitro studies have investigated which cytochrome P450 enzymes are primarily responsible for these transformations. The allylic hydroxylations are primarily performed by CYP2C19 and CYP3A4, while the alkyl hydroxylations can be produced by a wider variety of enzymes: CYP3A4, CYP3A5, CYP1A1, CYP1A2, CYP2C9, and CYP2D6. Recent in vitro evidence showed the formation of decarbonylated metabolites via CYP3A4 activity in human liver microsomes. (95) To date, no literature suggests significant receptor activity for any of these identified CBD metabolites.

Figure 8

Figure 8. Major metabolites of cannabidiol.

Of great interest is the question of whether CBD can be converted to THC after dosing. While there is some contested evidence that highly acidic environments can facilitate this transformation (vide supra), no evidence in the current literature suggests that CBD is metabolized into THC in vivo. (96−98)

Excretion

The half-life of elimination (t1/2) of CBD is variable and depends especially on its route of administration. Generally, oral administration via oil, oromucosal spray, or nebulizer/aerosol leads to a t1/2 of about 2 h. (99,100) Administration via iv, smoking, or chronic oral administration leads to a significantly longer t1/2 of 24 h, 31 h, (86) or 2–5 days, (101) respectively.
While CBD and THC are both subject to a strong first-pass effect, a significant portion of both cannabinoids are excreted unchanged in the feces. (102) This suggests that a large portion of a CBD dose is not absorbed, which matches the reports of low bioavailability. (14) The families of oxidized and glucuronidated metabolites are largely excreted by the kidneys and can be identified in the urine.
The overall plasma clearance of CBD varies depending on the fed vs fasted state. Oromucosal spray administration of doses ranging from 5 to 20 mg yields apparent plasma clearance (CL′) ranging from 2500 to 4700 L/h. (88,103,104) This decreases to 533 L/h for the same concentration range in a fed state. (103) In contrast, the mean elimination rate (Kel) does not change significantly between the fed and fasted states. There is some variation in elimination rate depending on the route of administration. Oromucosal spray administration results in Kel (1/h) values ranging from 0.12 to 0.17. Nebulizer or aerosol administration, however, results in Kel values of of 0.98 and 0.43, respectively. (99)

Toxicology

CBD appears to generally be safe upon administration via several routes at low doses (<100 mg). However, studies of CBD use in combination with other drugs, and animal toxicological studies, raise concerns of DDIs and other potential adverse effects.
As the metabolism of CBD has been well-studied (vide supra), the administration of CBD when taking drugs that are known to inhibit or activate relevant cytochrome P450s will alter the overall plasma concentration and/or half-life of CBD in the plasma. In addition, CBD has been shown to inhibit some cytochrome P450 enzymes at physiologically achievable levels (Table 4). (105) Importantly, CBD interferes with the metabolism of both hexobarbital (106) and, as presented earlier, clobazam (79) if given concomitantly, raising concerns for drug–drug interactions (DDIs).
Table 4. In Vitro Inhibition of CYP Activity by CBD (105)
 CBD Ki (μM)
CYP1A10.16
CYP1A22.69
CYP1B13.63
CYP2A655.0
CYP2B60.69
CYP2C95.60
CYP2C1120.7
CYP2C190.79
CYP2D62.42
CYP3A41.00
CYP3A50.19
CYP3A712.3
CYP17124
More recently, several studies have been published warning about potential adverse effects of CBD administration, as determined through cellular or animal studies. In 2017, the hypothesis that CBD can be neuroprotective in neonatal hypoxic–ischemia was tested in pigs. High-dose (25 or 50 mg/kg) CBD resulted in significant hypotension (mean arterial blood pressure drop below 70% of baseline), including death by fatal cardiac arrest in at least one animal. In addition, no neuroprotective effect was observed in this model as measured by neuropathology, astrocytic markers, and other plasma markers. (107) In 2018, the pattern of DNA methylation in the sperm of cannabis users was found to be significantly altered, and overall sperm concentration was significantly lower as compared to nonusers. (108) These changes were similar to the shift in epigenetic patterns seen in THC-exposed rats, which raises the concern for possible inheritable epigenetic changes related to cannabis use. (109) It is not known whether chronic use of CBD alone can lead to epigenetic changes.
Research into the reproductive toxicity of chronic CBD exposure in male mice corroborates the potential reproductive toxicity. (110) The authors report that 34 days of 15 or 30 mg/kg daily dosing resulted in significant changes in several measures of reproductive health, including testosterone levels, spermatogenesis, daily sperm production, and increased abnormal sperm morphology. A 2019 study aimed at determining the potential hepatotoxicity of CBD evaluated gene expression arrays in mice after oral dosing of a single high dose (246–2460 mg/kg) or a chronic lower dose (61.5–615 mg/kg for 10 days) of CBD. (111) In this study, gene expression arrays showed alteration of >50 genes following CBD dosing, relating to oxidative stress responses, lipid metabolism pathways, and drug metabolizing enzymes. Finally, a study of CBD exposure in two human-derived cell lines showed nuclear aberrations and DNA damage consistent with single and double strand breaks and apurinic sites. (112) This cellular damage was observed at CBD concentrations (0.22 μM) that are relevant to reported CBD exposure in humans.

Clinical Trials

From a thorough analysis of the literature, it appears that CBD has not shown efficacy as a single substance in any phase II or III clinical trials. In phase I trials, CBD has been shown to be generally well-tolerated at single doses up to 6000 mg and multiple doses up to 1500 mg twice daily. (93) The most common side-effects were gastrointestinal disorders, headaches, and somnolence. CBD has advanced to phase III clinical trials in certain rare forms of epilepsy. In the pivotal phase III clinical trials (multicenter, randomized, double-blind, placebo-controlled) that led to the approval of Epidiolex, all patients were typically taking at least three other seizure medicines along with CBD: clobazam (47–51%), valproate (all forms, 37–39%), levetiracetam (30–32%), lamotrigine (26–33%), or rufinamide (26–34%) (name of the medication, percent of patients taking the drug across all arms of the trial). (113) In this trial, the median percent reduction from baseline in drop-seizure frequency was 42% in the 20 mg kg–1 day–1 group (the average age of study participant was 15 years, ∼1000 mg/day) and 17% in the placebo group.
Although this result was in part responsible for the approval of Epidiolex in these hard-to-manage forms of epilepsy, the significance of this result with respect to the pharmacological action of CBD has been called into question. This is because of known DDIs between CBD and other antiepileptic drugs, (114) which is especially relevant in the case of clobazam and its active metabolite, N-desmethylclobazam. CBD doses of 20 mg kg–1 day–1 (as were used in the Epidiolex trial) are known to increase the exposure of N-desmethylclobazam 2- to 6-fold in children with refractory epilepsy despite clobazam dose reductions. (79) This, and other evidence, led Groeneveld to propose that the effect of CBD on drop-seizure frequency may be explained solely on this DDI, without the need to invoke any special epilepsy-treating pharmacology to CBD. (80,115) The American Epilepsy Society had the following to say about these clinical trials (quoted here for clarity):

“Recently, there have been several scientifically rigorous, double-blind, placebo-controlled randomized clinical trials of one specific pharmaceutical-grade, purified, highly concentrated CBD for patients with refractory epilepsy that have been published. Studies evaluating the pharmacokinetics and potential drug–drug interactions with this formulation have also been published or presented at epilepsy congresses. These trials demonstrated that this one pharmaceutical-grade CBD is moderately effective in the treatment of patients with seizures in both Lennox–Gastaut syndrome (LGS) and Dravet syndrome. However, these studies also showed that CBD has more side effects than placebo and revealed previously unrecognized drug–drug interactions.” (116)

We found several examples of CBD being touted as a remedy for addiction, (117) aging, (118) anxiety, arthritis, (119) concussion, (120) depression, nausea, obesity, (121) pain, Parkinson’s disease, (122) post-traumatic stress disorder, and psychiatric disorders (among others). (117) However, no evidence of double-blinded, placebo-controlled clinical trials that supported these claims could be located. One double-blinded trial, albeit not placebo-controlled, in patients with schizophrenia reported a clinically significant reduction in PANSS scores (positive and negative symptoms scale) of patients treated with 800 mg/day. In this case, the quality of the CBD used in the trial was not reported. (123)
Anecdotal claims of CBD therapeutic utility often arise from what are actually inconclusive studies. For example, some claims of the therapeutic utility of CBD are based on studies where the substance being tested was actually cannabis (extract) rather than CBD; in other studies the size of the trial was too small to make any conclusive judgements; and in still others the patients were taking other medications that may be subject to CBD DDIs. Therefore, it remains blurred whether any clinical trials have shown CBD alone to be effective for therapeutic use. Claims to the contrary must ensure the relevance of the referenced clinical trial by qualifying the following points:
(1)

What was the exact identity and purity of the CBD used? Note that APIs are distinct from crude preparations (such as plant extracts) and that residual complexity (including significant content in, for example, THC; vide supra) is relevant and will confound the study results.

(2)

Was the trial placebo-controlled?

(3)

Was the trial double-blinded?

(4)

Was the statistical analysis plan published before the trial? (124)

(5)

Did the authors claim significance of the results?

(6)

If CBD was used in combination, was the possibility of DDIs considered? Is the coadministered agent metabolized by CYPs?

It is also important to note that the effective CBD doses used in most reported clinical trials are typically 800–1000 mg/day. Putting this into the perspective, commercial “tinctures” or “oils” commonly found in the marketplace consist of less than 20 mg of CBD per serving. A typical consumer-sized bottle of CBD oil (30 mL) might contain 1000 mg total CBD and cost on the order of $50–60. (125)
With respect to anecdotal reports of efficacies of CBD oils and tinctures, such CBD “personal trials” may be subject to a “placebo” response based on the cachet of CBD as a well-known component of (medical) cannabis. The intricate influence of the placebo effect on the testing of cannabis and cannabinoids has been discussed; e.g., Gertsch wrote recently, (13)Unlike with other medicinal plants that have rather questionable efficacies and unknown mechanisms of action, nobody seems to doubt a priori the therapeutic effectiveness of cannabis. Accordingly, patients who use medical cannabis products have high expectations of beneficial effects (i.e., the plant is meaningful to them).” and “Rather than being either a placebo or drug, cannabis might be a drug both conveying and inducing a meaning response.” The anthropologist, David Moerman, referred to this effect of the conveyed meaning embodied in the placebo as the “meaning response”. (126) Therefore, because CBD has been so conflated with cannabis, even if CBD has no direct pharmacological effect, its associated “meaning effect” may activate a secondary pharmacological effect. Ironically, this meaning effect in CBD trials may occur via the endocannabinoid CB1 and CB2 pathways, receptors for which CBD has no intrinsic activity, though they are the primary mediators of THC’s effects. (13,127) Clinical trials of botanical preparations fail to reject the placebo-based null hypothesis (128) and report unexpectedly pronounced placebo effects (129,130) more commonly than API-based trials, which further supports the relevance of “meaning responses” and “meaning effects”.

Summary

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Cannabis is a useful therapeutic and source of lead compounds. At the same time, the reductionist tendencies of Western medicine have seen certain Cannabis preparations reduced to the pure compound, CBD. While this study could not find evidence supporting the numerous and broad health claims associated with CBD, evidence suggests that CBD can affect biological systems in the following ways: (a) through a strong, physiologically relevant interaction with metabolizing enzymes, thereby modulating the activity of other substances; (b) via a strong “meaning effect”; (c) by means of a weak, promiscuous, and low-level modulation of membrane-bound proteins.
The recent FDA approval of CBD as a drug excludes it from being used as a dietary supplement in the U.S. If used at low doses, e.g., as one (minor) constituent of supplements, which often carry the potentially misleading “CBD” label, CBD most likely cannot produce any therapeutic effect. When used at high doses, any therapeutic effect is likely due to either the strong interaction of CBD with metabolic enzymes, its likely “meaning effect”, or a result of other components contained in products labeled as “CBD”. Additionally, at the highest doses, negative side-effects are likely to become more pronounced, thereby limiting the utility of this substance.
Unless the purity of CBD is assessed rigorously, or whenever a chemically complex (crude) material is the component of a product bearing the “CBD” label, residual complexity can become a major disruptor in the logical chain that connects CBD as an API and pharmacological agent with its role as the key active component of the preparation: residually complex materials have a much increased chance of containing other, especially minor and/or more potent, bioactives.
While many claims have been made about a large variety of potential health benefits of CBD, the present work uncovers a lack of scientific foundation to most of these claims. While CBD can enter systemic circulation at potentially physiologically relevant levels, there is no clear understanding of the receptor activity of CBD and an even greater deficiency in terms of potentially harmful adverse effects. Whereas an FDA-approved therapeutic regimen containing CBD does exist, the efficacy of the treatment appears to be related to its DDI mechanisms. Importantly, unless new biological targets for antiviral and/or health resilience can be discovered and validated, product claims that CBD has health effects for treatment or alleviation of SARS-CoV-2 and analogous viral pathogens should be considered unsubstantiated and misguided. (131)
Widely available products with chemically complex ingredients containing various amounts of CBD are a major confounding factor in distinguishing sound experimental evidence, including clinical trials and other in vivo outcomes, from unsubstantiated or anecdotal health claims. This observation reflects a concerning global trend of obscuring the lack of quality control parameters and objective health outcomes of freely available products by associating them with the word “natural” and similarly implicative terms. More rigorous work needs to be done to determine what, if any, specific efficacy CBD may have as a therapeutic agent.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jmedchem.0c00724.

  • Quantum-mechanical 1H NMR characterization of CBD using HiFSA, psychoactive drug screening program activity of CBD, and pharmacological methods for evaluation of CBD (PDF)

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Author Information

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  • Corresponding Author
    • Guido F. Pauli - Center for Natural Product Technologies, Program for Collaborative Research in the Pharmaceutical Sciences (PCRPS), and Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United StatesInstitute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United StatesOrcidhttp://orcid.org/0000-0003-1022-4326 Email: [email protected]
  • Authors
    • Kathryn M. Nelson - Department of Medicinal Chemistry, Institute for Therapeutics Discovery and Development, University of Minnesota, Minneapolis, Minnesota 55414, United StatesOrcidhttp://orcid.org/0000-0001-8274-2064
    • Jonathan Bisson - Center for Natural Product Technologies, Program for Collaborative Research in the Pharmaceutical Sciences (PCRPS), and Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United StatesInstitute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United StatesOrcidhttp://orcid.org/0000-0003-1640-9989
    • Gurpreet Singh - Department of Medicinal Chemistry, Institute for Therapeutics Discovery and Development, University of Minnesota, Minneapolis, Minnesota 55414, United StatesOrcidhttp://orcid.org/0000-0002-5878-3154
    • James G. Graham - Center for Natural Product Technologies, Program for Collaborative Research in the Pharmaceutical Sciences (PCRPS), and Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United StatesInstitute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United StatesOrcidhttp://orcid.org/0000-0002-7114-8921
    • Shao-Nong Chen - Center for Natural Product Technologies, Program for Collaborative Research in the Pharmaceutical Sciences (PCRPS), and Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United StatesInstitute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United StatesOrcidhttp://orcid.org/0000-0003-0748-0863
    • J. Brent Friesen - Center for Natural Product Technologies, Program for Collaborative Research in the Pharmaceutical Sciences (PCRPS), and Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United StatesOrcidhttp://orcid.org/0000-0002-0739-9224
    • Jayme L. Dahlin - Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts 02115, United StatesHarvard Medical School, Boston, Massachusetts 02115, United StatesOrcidhttp://orcid.org/0000-0003-4151-9944
    • Matthias Niemitz - NMR Solutions Ltd., Puijonkatu 24, 70110 Kuopio, FinlandOrcidhttp://orcid.org/0000-0002-5452-5203
    • Michael A. Walters - Department of Medicinal Chemistry, Institute for Therapeutics Discovery and Development, University of Minnesota, Minneapolis, Minnesota 55414, United StatesOrcidhttp://orcid.org/0000-0001-5650-9277
  • Notes
    The authors declare no competing financial interest.

Biographies

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Kathryn M. Nelson

Kathryn M. Nelson is a Research Assistant Professor in the Department of Medicinal Chemistry and Institute for Therapeutics Discovery & Development (ITDD) at the University of Minnesota, Minneapolis, MN. After obtaining a Ph.D. in Medicinal Chemistry from the University of Minnesota, she was a postdoctoral associate before becoming a Research Assistant Professor in Medicinal Chemistry at the ITDD. Her work has focused on target discovery, validation, and lead molecule development for new targets in neurodegenerative diseases. She has also expanded her expertise to the development of biomarker assays for new targets in anticipation of preclinical evaluation.

Jonathan Bisson

Jonathan Bisson obtained an M.S. degree in Structural Biochemistry and started his phytochemistry journey under the mentorship of Dr. Vincent Dumontet at the Institut de Chimie des Substances Naturelles, Gif-sur-Yvette, France. He then obtained a Ph.D. in Science, Technology and Health from the University of Bordeaux, France, under the mentorship of Dr. Pierre Waffo-Téguo, specializing in methodology at the chemistry–biology interface and practicing liquid–liquid chromatography, NMR spectroscopy, and hyphenated techniques. In 2013, he joined the University of Illinois at Chicago, where he is currently a Visiting Research Assistant Professor, developing software tools, ontologies, and preparative and analytical methods for natural products research in interdisciplinary programs.

Gurpreet Singh

Gurpreet Singh is a Senior Scientist at the Institute for Therapeutics Discovery and Development (ITDD) at the University of Minnesota (UMN), U.S. He received his Master’s degree in Chemistry from Guru Nanak Dev University (GNDU) at Amritsar (India) and joined Dr. Reddy’s Laboratories Limited at Hyderabad (India) as a medicinal chemist where he contributed to the anti-infective program. In 2015, he obtained his Ph.D. in Medicinal Chemistry from the University of Kansas (KU) at Lawrence, Kansas (U.S.). During his doctoral research, he developed alkaloid natural-product-inspired libraries for the discovery of biological probes, and synthetic routes for the synthesis of enantioenriched cyclic-1,3-diols. Currently his research is focused on the discovery of new chemical probes and drugs for neurodegenerative diseases.

James G. Graham

James G. Graham is a Research Assistant Professor in the Department Pharmaceutical Sciences at the University of Illinois at Chicago College of Pharmacy. After obtaining a Ph.D. in Pharmacognosy in Chicago, he received an NIH postdoctoral fellowship in Miami and worked as Technical Officer at the World Health Organization in Geneva. In 2007 he returned to Chicago to work as a protege of Norman R. Farnsworth on his NAPRALERT (NAtural PRroduct ALERT) database, of which he is currently editor, as well as serving as Assistant Program Director, Program for Collaborative Research in the Pharmaceutical Sciences.

Shao-Nong Chen

Shao-Nong Chen obtained his Ph.D. in Organic Chemistry from Lanzhou University, then undertook two years of post-Ph.D. training at the Shanghai Institute of Materia Medica (SIMM) before joining Dr. Sydney Hecht’s group at the University of Virginia in 1999 as a research fellow. He moved to UIC in 2000, where he currently is an Associate Research Professor, working on botanical standardization and integrity in the UIC/NIH Botanical Center, as well as on method development for the analysis of bioactive natural products in interdisciplinary programs. He developed “chemical subtraction”, NMR-based natural product mining methods, and “dynamic residual complexity” concepts. He coauthored 140+ peer-reviewed articles and two book chapters.

J. Brent Friesen

J. Brent Friesen is a professor of chemistry in the Rosary College of Arts and Sciences at Dominican University. He earned his Ph.D. in Natural Products Chemistry at the University of Minnesota with Eddie Leete. He is the author or coauthor of nearly 50 scientific publications. His role in the development of countercurrent separation methodologies and technologies has helped to revolutionize the practice of countercurrent separation. These methodologies include pioneering work in elution–extrusion countercurrent chromatography, reciprocal symmetry plots, the Generally Useful Estimation of Solvent Systems (GUESS), optimization of countercurrent separation parameters, and the development of the phase metering apparatus. Currently, he is involved with biomedical research that will advance the application of countercurrent separation technologies to improve the isolation and characterization of bioactive compounds.

Jayme L. Dahlin

Jayme L. Dahlin is currently a Clinical Fellow at Brigham and Women’s Hospital and Harvard Medical School. He earned his B.A. (chemistry) from Carleton College (MN), his Ph.D. in Molecular Pharmacology and Experimental Therapeutics from Mayo Graduate School, and his M.D. from Mayo Medical School. He recently completed a clinical residency in clinical pathology at Brigham and Women’s Hospital, where he also served as Chief Resident. He is now board-certified in clinical pathology and is currently performing chemical biology research in the laboratories of Stuart L. Schreiber and Bridget K. Wagner at the Broad Institute. His current research interests include high-throughput screening and assay development.

Matthias Niemitz

Matthias Niemitz is a serial entrepreneur with more than 25 years of experience in quantum mechanical NMR spectral analysis and received his chemistry degree at the Free University Berlin. He joined the NMR group at the University of Kuopio, Finland, and established the PERCH NMR Software project. In 2001 he incorporated PERCH Solutions, a company that was bought by Bruker BioSpin in 2009. After Bruker closed PERCH Solutions, the former management and employees of PERCH incorporated a new company, NMR Solutions.

Michael A. Walters

Michael A. Walters is a Research Associate Professor of Medicinal Chemistry at the University of Minnesota (UMN). He began his academic career in the Department of Chemistry at Dartmouth College and then worked at Parke-Davis and Pfizer. He is currently the Director of the Lead and Probe Discovery Group in the Institute for Therapeutics Discovery and Development at the UMN. This institute serves as a minibiotech for the development of the ideas of biomedical researchers at the UMN and Mayo Clinic. His research interests currently focus on the investigation of compound reactivity as it applies to assay interference mechanisms, the development of Alzheimer’s disease therapeutics, and cheminformatics and computer assisted drug design.

Guido F. Pauli

Guido F. Pauli is a pharmacist with a doctoral degree in natural products chemistry and pharmacognosy. As Norman R. Farnsworth Professor of Pharmacognosy and Distinguished Professor at UIC, Chicago (IL), he directs and collaborates in various interdisciplinary natural-product-driven research projects. He develops bioanalytical methodology for active principles from complex natural products from plant and microbial metabolomes, with applications in anti-TB drug discovery, dental health, dietary supplements, and pharmaceutical quality control. Scholarly activities involve the education of the next generation of pharma(cogno)sists; service on pharmacopoeial expert, federal agency, and NGO panels; journal board functions; international collaborations and exchange; and active dissemination with currently 230+ peer-reviewed journal articles.

Acknowledgments

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The Ki determinations, receptor binding profiles, agonist and/or antagonist functional data, HERG data, MDR1 data, etc. as appropriate were generously provided by the National Institute of Mental Health’s Psychoactive Drug Screening Program, Contract HHSN-271-2018-00023-C (NIMH PDSP), directed by Dr. Bryan L. Roth at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscoll at NIMH, Bethesda, MD, U.S. The authors acknowledge the following financial support: J.L.D. through Grant T32 HL007627 from NHLBI/NIH; J.B., J.G.G., S.-N.C., and G.F.P. through Grants U41 AT008706 and P50 AT000155 jointly from ODS/NIH and NCCIH/NIH. Furthermore, the authors acknowledge the collegial spirit of Drs. Young-Hae Choi and Rob Verpoorte, University of Leiden, for kindly sharing their historic raw NMR data. J.L.D. gratefully acknowledges Drs. Parnian Lak and Brian Shoichet for performing DLS experiments. We kindly acknowledge the Research Open Access Publishing (ROAAP) Fund of the University of Illinois at Chicago for financial support towards the open access publishing fee for this article. Finally, the authors thank M. Backmann for help in creating the figure for the graphical abstract. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The opinions or assertions contained herein belong to the authors and are not necessarily the official views of the funders.

Abbreviations Used

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CBD

cannabidiol

DDI

drug–drug interaction

DHI

drug–herbal interaction

FDA

Food and Drug Administration

HiFSA

1H iterative full spin analysis

IMP

invalid metabolic panacea

OTC

over-the-counter

THC

Δ9-tetrahydrocannabinol

References

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This article references 131 other publications.

  1. 1
    Cannabidiol Market Size Analysis. CBD Industry Growth Report, 2025. https://www.grandviewresearch.com/industry-analysis/cannabidiol-cbd-market (accessed Apr 22, 2020).
  2. 2
    Dorbian, I. CBD Market Could Reach $20 Billion By 2024, Says New Study. Forbes May 20, 2019.
  3. 3
    Nelson, K. M.; Dahlin, J. L.; Bisson, J.; Graham, J.; Pauli, G. F.; Walters, M. A. The Essential Medicinal Chemistry of Curcumin. J. Med. Chem. 2017, 60 (5), 16201637,  DOI: 10.1021/acs.jmedchem.6b00975
  4. 4
    Dietz, B. M.; Chen, S.-N.; Alvarenga, R. F. R.; Dong, H.; Nikolić, D.; Biendl, M.; van Breemen, R. B.; Bolton, J. L.; Pauli, G. F. DESIGNER Extracts as Tools to Balance Estrogenic and Chemopreventive Activities of Botanicals for Women’s Health. J. Nat. Prod. 2017, 80, 22842294,  DOI: 10.1021/acs.jnatprod.7b00284
  5. 5
    Yang, Y.; Zhang, Z.; Li, S.; Ye, X.; Li, X.; He, K. Synergy Effects of Herb Extracts: Pharmacokinetics and Pharmacodynamic Basis. Fitoterapia 2014, 92, 133147,  DOI: 10.1016/j.fitote.2013.10.010
  6. 6
    Caesar, L. K.; Cech, N. B. Synergy and Antagonism in Natural Product Extracts: When 1 + 1 Does Not Equal 2. Nat. Prod. Rep. 2019, 36, 869888,  DOI: 10.1039/C9NP00011A
  7. 7
    Friesen, J. B.; Liu, Y.; Chen, S.-N.; McAlpine, J. B.; Pauli, G. F. Selective Depletion and Enrichment of Constituents in “Curcumin” and Other Curcuma longa Preparations. J. Nat. Prod. 2019, 82, 621630,  DOI: 10.1021/acs.jnatprod.9b00020
  8. 8
    Zuardi, A. W.; Crippa, J. A. S.; Hallak, J. E. C.; Moreira, F. A.; Guimarães, F. S. Cannabidiol, a Cannabis sativa Constituent, as an Antipsychotic Drug. Braz. J. Med. Biol. Res. 2006, 39, 421429,  DOI: 10.1590/S0100-879X2006000400001
  9. 9
    Mogil, J. S. Laboratory Environmental Factors and Pain Behavior: The Relevance of Unknown Unknowns to Reproducibility and Translation. Lab Anim. 2017, 46, 136141,  DOI: 10.1038/laban.1223
  10. 10
    Morrison, G.; Crockett, J.; Blakey, G.; Sommerville, K. A Phase 1, Open-Label, Pharmacokinetic Trial to Investigate Possible Drug-Drug Interactions Between Clobazam, Stiripentol, or Valproate and Cannabidiol in Healthy Subjects. Clin. Pharmacol. Drug Dev. 2019, 8, 10091031,  DOI: 10.1002/cpdd.665
  11. 11
    Ghovanloo, M.-R.; Shuart, N. G.; Mezeyova, J.; Dean, R. A.; Ruben, P. C.; Goodchild, S. J. Inhibitory Effects of Cannabidiol on Voltage-Dependent Sodium Currents. J. Biol. Chem. 2018, 293, 1654616558,  DOI: 10.1074/jbc.RA118.004929
  12. 12
    Watkins, A. R. Cannabinoid Interactions with Ion Channels and Receptors. Channels 2019, 13, 162167,  DOI: 10.1080/19336950.2019.1615824
  13. 13
    Gertsch, J. The Intricate Influence of the Placebo Effect on Medical Cannabis and Cannabinoids. Med. Cannabis Cannabinoids 2018, 1, 6064,  DOI: 10.1159/000489291
  14. 14
    WHO CBD Report May 2018. Cannabidiol (CBD). Critical Review Report. https://www.who.int/medicines/access/controlled-substances/WHOCBDReportMay2018-2.pdf?ua=1 (accessed Oct 25, 2019).
  15. 15
    Millar, S. A.; Stone, N. L.; Yates, A. S.; O’Sullivan, S. E. A Systematic Review on the Pharmacokinetics of Cannabidiol in Humans. Front. Pharmacol. 2018, 9, 1365,  DOI: 10.3389/fphar.2018.01365
  16. 16
    Office of the Commissioner. What to Know About Products Containing Cannabis and CBD. https://www.fda.gov/consumers/consumer-updates/what-you-need-know-and-what-were-working-find-out-about-products-containing-cannabis-or-cannabis (accessed Apr 23, 2020).
  17. 17
    Gaoni, Y.; Mechoulam, R. Hashish—VII: The Isomerization of Cannabidiol to Tetrahydrocannabinols. Tetrahedron 1966, 22, 14811488,  DOI: 10.1016/S0040-4020(01)99446-3
  18. 18
    Gutman, A. L.; Etinger, M.; Fedotev, I.; Khanolkar, R. Methods for Purifying Trans-(−)-Δ9-Tetrahydrocannabinol and Trans-(+)-Δ9-Tetrahydrocannabinol. U.S. Patent 8383842, 2006.
  19. 19
    Aizpurua-Olaizola, O.; Soydaner, U.; Öztürk, E.; Schibano, D.; Simsir, Y.; Navarro, P.; Etxebarria, N.; Usobiaga, A. Evolution of the Cannabinoid and Terpene Content during the Growth of Cannabis sativa Plants from Different Chemotypes. J. Nat. Prod. 2016, 79, 324331,  DOI: 10.1021/acs.jnatprod.5b00949
  20. 20
    Basas-Jaumandreu, J.; de Las Heras, F. X. C. GC-MS Metabolite Profile and Identification of Unusual Homologous Cannabinoids in High Potency Cannabis sativa. Planta Med. 2020, 86, 338347,  DOI: 10.1055/a-1110-1045
  21. 21
    Luo, X.; Reiter, M. A.; d’Espaux, L.; Wong, J.; Denby, C. M.; Lechner, A.; Zhang, Y.; Grzybowski, A. T.; Harth, S.; Lin, W.; Lee, H.; Yu, C.; Shin, J.; Deng, K.; Benites, V. T.; Wang, G.; Baidoo, E. E. K.; Chen, Y.; Dev, I.; Petzold, C. J.; Keasling, J. D. Complete Biosynthesis of Cannabinoids and Their Unnatural Analogues in Yeast. Nature 2019, 567, 123126,  DOI: 10.1038/s41586-019-0978-9
  22. 22
    Kumari, S.; Pundhir, S.; Priya, P.; Jeena, G.; Punetha, A.; Chawla, K.; Firdos Jafaree, Z.; Mondal, S.; Yadav, G. EssOilDB: A Database of Essential Oils Reflecting Terpene Composition and Variability in the Plant Kingdom. Database 2014, 2014, bau120  DOI: 10.1093/database/bau120
  23. 23
    Degenhardt, F.; Stehle, F.; Kayser, O. The Biosynthesis of Cannabinoids. In Handbook of Cannabis and Related Pathologies. Biology, Pharmacology, Diagnosis, and Treatment; Preedy, V. R., Ed.; Elsevier: London, 2017; pp 1323.
  24. 24
    Pauli, G. F.; Chen, S.-N.; Simmler, C.; Lankin, D. C.; Gödecke, T.; Jaki, B. U.; Friesen, J. B.; McAlpine, J. B.; Napolitano, J. G. Importance of Purity Evaluation and the Potential of Quantitative 1H NMR as a Purity Assay. J. Med. Chem. 2014, 57, 92209231,  DOI: 10.1021/jm500734a
  25. 25
    Martin Emanuele, R.; Shattock-Gordon, T.; Williford, T.; Andres, M.; Andres, P. New Solid Forms of Cannabidiol and Uses Thereof. World Intellectual Property Organization. WO 2019118360 A1, 2019.
  26. 26
    Mechoulam, R.; Hanuš, L. Cannabidiol: An Overview of Some Chemical and Pharmacological Aspects. Part I: Chemical Aspects. Chem. Phys. Lipids 2002, 121, 3543,  DOI: 10.1016/S0009-3084(02)00144-5
  27. 27
    Popovic, A.; Morelato, M.; Roux, C.; Beavis, A. Review of the Most Common Chemometric Techniques in Illicit Drug Profiling. Forensic Sci. Int. 2019, 302, 109911,  DOI: 10.1016/j.forsciint.2019.109911
  28. 28
    O’Neil, M. J. The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals; Royal Society of Chemistry: Cambridge, U.K., 2013; 2707.
  29. 29
    Pauli, G. F.; Gödecke, T.; Jaki, B. U.; Lankin, D. C. Quantitative 1H NMR. Development and Potential of an Analytical Method: An Update. J. Nat. Prod. 2012, 75, 834851,  DOI: 10.1021/np200993k
  30. 30
    Hazekamp, A.; Choi, Y. H.; Verpoorte, R. Quantitative Analysis of Cannabinoids from Cannabis sativa Using 1H-NMR. Chem. Pharm. Bull. 2004, 52, 718721,  DOI: 10.1248/cpb.52.718
  31. 31
    Siciliano, C.; Bartella, L.; Mazzotti, F.; Aiello, D.; Napoli, A.; De Luca, P.; Temperini, A. 1H NMR Quantification of Cannabidiol (CBD) in Industrial Products Derived from Cannabis sativa L. (hemp) Seeds - IOPscience. IOP Conf. Ser.: Mater. Sci. Eng. 2019, 572, 012010,  DOI: 10.1088/1757-899X/572/1/012010
  32. 32
    Choules, M. P.; Bisson, J.; Simmler, C.; McAlpine, J. B.; Giancaspro, G.; Bzhelyansky, A.; Niemitz, M.; Pauli, G. F. NMR Reveals an Undeclared Constituent in Custom Synthetic Peptides. J. Pharm. Biomed. Anal. 2020, 178, 112915,  DOI: 10.1016/j.jpba.2019.112915
  33. 33
    Bisson, J.; Simmler, C.; Chen, S.-N.; Friesen, J. B.; Lankin, D. C.; McAlpine, J. B.; Pauli, G. F. Dissemination of Original NMR Data Enhances Reproducibility and Integrity in Chemical Research. Nat. Prod. Rep. 2016, 33, 10281033,  DOI: 10.1039/C6NP00022C
  34. 34
    McAlpine, J. B.; Chen, S.-N.; Kutateladze, A.; MacMillan, J. B.; Appendino, G.; Barison, A.; Beniddir, M. A.; Biavatti, M. W.; Blüml, S.; Boufridi, A.; Butler, M. S.; Capon, R. J.; Choi, Y. H.; Coppage, D.; Crews, P.; Crimmins, M. T.; Csete, M.; Dewapriya, P.; Egan, J. M.; Garson, M. J.; Genta-Jouve, G.; Gerwick, W. H.; Gross, H.; Harper, M. K.; Hermanto, P.; Hook, J. M.; Hunter, L.; Jeannerat, D.; Ji, N.-Y.; Johnson, T. A.; Kingston, D. G. I.; Koshino, H.; Lee, H.-W.; Lewin, G.; Li, J.; Linington, R. G.; Liu, M.; McPhail, K. L.; Molinski, T. F.; Moore, B. S.; Nam, J.-W.; Neupane, R. P.; Niemitz, M.; Nuzillard, J.-M.; Oberlies, N. H.; Ocampos, F. M. M.; Pan, G.; Quinn, R. J.; Reddy, D. S.; Renault, J.-H.; Rivera-Chávez, J.; Robien, W.; Saunders, C. M.; Schmidt, T. J.; Seger, C.; Shen, B.; Steinbeck, C.; Stuppner, H.; Sturm, S.; Taglialatela-Scafati, O.; Tantillo, D. J.; Verpoorte, R.; Wang, B.-G.; Williams, C. M.; Williams, P. G.; Wist, J.; Yue, J.-M.; Zhang, C.; Xu, Z.; Simmler, C.; Lankin, D. C.; Bisson, J.; Pauli, G. F. The Value of Universally Available Raw NMR Data for Transparency, Reproducibility, and Integrity in Natural Product Research. Nat. Prod. Rep. 2019, 36, 35107,  DOI: 10.1039/C7NP00064B
  35. 35
    Choules, M. P.; Klein, L. L.; Lankin, D. C.; McAlpine, J. B.; Cho, S.-H.; Cheng, J.; Lee, H.; Suh, J.-W.; Jaki, B. U.; Franzblau, S. G.; Pauli, G. F. Residual Complexity Does Impact Organic Chemistry and Drug Discovery: The Case of Rufomyazine and Rufomycin. J. Org. Chem. 2018, 83, 66646672,  DOI: 10.1021/acs.joc.8b00988
  36. 36
    Pauli, G. F.; Chen, S.-N.; Friesen, J. B.; McAlpine, J. B.; Jaki, B. U. Analysis and Purification of Bioactive Natural Products: The AnaPurNa Study. J. Nat. Prod. 2012, 75, 12431255,  DOI: 10.1021/np300066q
  37. 37
    Citti, C.; Linciano, P.; Forni, F.; Vandelli, M. A.; Gigli, G.; Laganà, A.; Cannazza, G. Analysis of Impurities of Cannabidiol from Hemp. Isolation, Characterization and Synthesis of Cannabidibutol, the Novel Cannabidiol Butyl Analog. J. Pharm. Biomed. Anal. 2019, 175, 112752,  DOI: 10.1016/j.jpba.2019.06.049
  38. 38
    Freeman, T. P.; Hindocha, C.; Green, S. F.; Bloomfield, M. A. P. Medicinal Use of Cannabis Based Products and Cannabinoids. BMJ. 2019, 365, l1141  DOI: 10.1136/bmj.l1141
  39. 39
    Office of the Commissioner. FDA Regulation of Cannabis and Cannabis-Derived Products: Q&A. https://www.fda.gov/news-events/public-health-focus/fda-regulation-cannabis-and-cannabis-derived-products-including-cannabidiol-cbd (accessed Apr 22, 2020).
  40. 40
    Office of the Commissioner. FDA and Cannabis: Research and Drug Approval Process. https://www.fda.gov/news-events/public-health-focus/fda-and-cannabis-research-and-drug-approval-process (accessed Apr 22, 2020).
  41. 41
    Biosciences, G. EPIDIOLEX (cannabidiol) oral solution, CV prescribing information; revised 12/2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210365lbl.pdf (accessed Dec 19, 2019).
  42. 42
    Office of the Commissioner. Warning Letters and Test Results for Cannabidiol-Related Products. https://www.fda.gov/news-events/public-health-focus/warning-letters-and-test-results-cannabidiol-related-products (accessed Apr 27, 2020).
  43. 43
    Jacob, A.; Todd, A. R. 119. Cannabis Indica. Part II. Isolation of Cannabidiol from Egyptian Hashish. Observations on the Structure of Cannabinol. J. Chem. Soc. 1940, 649653,  DOI: 10.1039/jr9400000649
  44. 44
    Adams, R.; Baker, B. R.; Wearn, R. B. Structure of Cannabinol. III. Synthesis of Cannabinol, 1-Hydroxy-3-N-Amyl-6,6,9-Trimethyl-6-dibenzopyran1. J. Am. Chem. Soc. 1940, 62, 22042207,  DOI: 10.1021/ja01865a083
  45. 45
    Jones, P. G.; Falvello, L.; Kennard, O.; Sheldrick, G. M.; Mechoulam, R. Cannabidiol. Acta Crystallogr., Sect. B: Struct. Crystallogr. Cryst. Chem. 1977, 33, 32113214,  DOI: 10.1107/S0567740877010577
  46. 46
    Pacifici, R.; Marchei, E.; Salvatore, F.; Guandalini, L.; Busardò, F. P.; Pichini, S. Evaluation of Cannabinoids Concentration and Stability in Standardized Preparations of Cannabis Tea and Cannabis Oil by Ultra-High Performance Liquid Chromatography Tandem Mass Spectrometry. Clin. Chem. Lab. Med. 2017, 55, 15551563,  DOI: 10.1515/cclm-2016-1060
  47. 47
    Watanabe, K.; Usami, N.; Yamamoto, I.; Yoshimura, H. Inhibitory Effect of Cannabidiol Hydroxy-Quinone, an Oxidative Product of Cannabidiol, on the Hepatic Microsomal Drug-Metabolizing Enzymes of Mice. J. Pharmacobio-Dyn. 1991, 14, 421427,  DOI: 10.1248/bpb1978.14.421
  48. 48
    Webster, G. R. B.; Sarna, L. P.; Mechoulam, R. Conversion of CBD to Delta8-THC and Delta9-THC. United States Patent 2004/0143126 A1, 2004.
  49. 49
    Merrick, J.; Lane, B.; Sebree, T.; Yaksh, T.; O’Neill, C.; Banks, S. L. Identification of Psychoactive Degradants of Cannabidiol in Simulated Gastric and Physiological Fluid. Cannabis Cannabinoid Res. 2016, 1, 102112,  DOI: 10.1089/can.2015.0004
  50. 50
    Nahler, G.; Grotenhermen, F.; Zuardi, A. W.; Crippa, J. A. S. A Conversion of Oral Cannabidiol to Delta9-Tetrahydrocannabinol Seems Not to Occur in Humans. Cannabis Cannabinoid Res. 2017, 2, 8186,  DOI: 10.1089/can.2017.0009
  51. 51
    Watanabe, K.; Itokawa, Y.; Yamaori, S.; Funahashi, T.; Kimura, T.; Kaji, T.; Usami, N.; Yamamoto, I. Conversion of Cannabidiol to Δ9-Tetrahydrocannabinol and Related Cannabinoids in Artificial Gastric Juice, and Their Pharmacological Effects in Mice. Forensic Toxicol. 2007, 25, 1621,  DOI: 10.1007/s11419-007-0021-y
  52. 52
    Grotenhermen, F.; Russo, E.; Zuardi, A. W. Even High Doses of Oral Cannabidiol Do Not Cause THC-Like Effects in Humans: Comment on Merrick et al. Cannabis and Cannabinoid Research 2016; 1(1): 102–112; DOI: 10.1089/can.2015.0004. Cannabis Cannabinoid Res. 2017, 2, 14,  DOI: 10.1089/can.2016.0036
  53. 53
    Lachenmeier, D. W.; Habel, S.; Fischer, B.; Herbi, F.; Zerbe, Y.; Bock, V.; Rajcic de Rezende, T.; Walch, S. G.; Sproll, C. Are Side Effects of Cannabidiol (CBD) Products Caused by Tetrahydrocannabinol (THC) Contamination?. F1000Research 2019, 8, 1394,  DOI: 10.12688/f1000research.19931.3
  54. 54
    Mascal, M.; Hafezi, N.; Wang, D.; Hu, Y.; Serra, G.; Dallas, M. L.; Spencer, J. P. E. Synthetic, Non-Intoxicating 8,9-Dihydrocannabidiol for the Mitigation of Seizures. Sci. Rep. 2019, 9, 7778,  DOI: 10.1038/s41598-019-44056-y
  55. 55
    Ben-Shabat, S.; Hanus, L. O.; Katzavian, G.; Gallily, R. New Cannabidiol Derivatives: Synthesis, Binding to Cannabinoid Receptor, and Evaluation of Their Antiinflammatory Activity. J. Med. Chem. 2006, 49, 11131117,  DOI: 10.1021/jm050709m
  56. 56
    Bisogno, T.; Hanus, L.; De Petrocellis, L.; Tchilibon, S.; Ponde, D. E.; Brandi, I.; Moriello, A. S.; Davis, J. B.; Mechoulam, R.; Di Marzo, V. Molecular Targets for Cannabidiol and Its Synthetic Analogues: Effect on Vanilloid VR1 Receptors and on the Cellular Uptake and Enzymatic Hydrolysis of Anandamide. Br. J. Pharmacol. 2001, 134, 845852,  DOI: 10.1038/sj.bjp.0704327
  57. 57
    Hanus, L. O.; Tchilibon, S.; Ponde, D. E.; Breuer, A.; Fride, E.; Mechoulam, R. Enantiomeric Cannabidiol Derivatives: Synthesis and Binding to Cannabinoid Receptors. Org. Biomol. Chem. 2005, 3 (6), 11161123,  DOI: 10.1039/b416943c
  58. 58
    Little, P. J.; Compton, D. R.; Johnson, M. R.; Melvin, L. S.; Martin, B. R. Pharmacology and Stereoselectivity of Structurally Novel Cannabinoids in Mice. J. Pharmacol. Exp. Ther. 1988, 247, 10461051
  59. 59
    Kinney, W. A.; McDonnell, M. E.; Zhong, H. M.; Liu, C.; Yang, L.; Ling, W.; Qian, T.; Chen, Y.; Cai, Z.; Petkanas, D.; Brenneman, D. E. Discovery of KLS-13019, a Cannabidiol-Derived Neuroprotective Agent, with Improved Potency, Safety, and Permeability. ACS Med. Chem. Lett. 2016, 7, 424428,  DOI: 10.1021/acsmedchemlett.6b00009
  60. 60
    BioSpace. Kannalife, Inc. Further Elucidates Mechanism of Action Behind KLS-13019, the Company’s Leading Drug Candidate for the Potential Treatment of Neuropathic Pain. BioSpace. https://www.biospace.com/article/kannalife-inc-further-elucidates-mechanism-of-action-behind-kls-13019-the-company-s-leading-drug-candidate-for-the-potential-treatment-of-neuropathic-pain/ (accessed Apr 27, 2020).
  61. 61
    Johns, D. G.; Behm, D. J.; Walker, D. J.; Ao, Z.; Shapland, E. M.; Daniels, D. A.; Riddick, M.; Dowell, S.; Staton, P. C.; Green, P.; Shabon, U.; Bao, W.; Aiyar, N.; Yue, T.-L.; Brown, A. J.; Morrison, A. D.; Douglas, S. A. The Novel Endocannabinoid Receptor GPR55 Is Activated by Atypical Cannabinoids but Does Not Mediate Their Vasodilator Effects. Br. J. Pharmacol. 2007, 152, 825831,  DOI: 10.1038/sj.bjp.0707419
  62. 62
    Ryberg, E.; Larsson, N.; Sjögren, S.; Hjorth, S.; Hermansson, N.-O.; Leonova, J.; Elebring, T.; Nilsson, K.; Drmota, T.; Greasley, P. J. The Orphan Receptor GPR55 Is a Novel Cannabinoid Receptor. Br. J. Pharmacol. 2007, 152, 10921101,  DOI: 10.1038/sj.bjp.0707460
  63. 63
    Romero-Zerbo, S. Y.; Rafacho, A.; Díaz-Arteaga, A.; Suárez, J.; Quesada, I.; Imbernon, M.; Ross, R. A.; Dieguez, C.; Rodríguez de Fonseca, F.; Nogueiras, R.; Nadal, A.; Bermúdez-Silva, F. J. A Role for the Putative Cannabinoid Receptor GPR55 in the Islets of Langerhans. J. Endocrinol. 2011, 211, 177185,  DOI: 10.1530/JOE-11-0166
  64. 64
    Console-Bram, L.; Brailoiu, E.; Brailoiu, G. C.; Sharir, H.; Abood, M. E. Activation of GPR18 by Cannabinoid Compounds: A Tale of Biased Agonism. Br. J. Pharmacol. 2014, 171, 39083917,  DOI: 10.1111/bph.12746
  65. 65
    Morales, P.; Reggio, P. H. CBD: A New Hope?. ACS Med. Chem. Lett. 2019, 10, 694695,  DOI: 10.1021/acsmedchemlett.9b00127
  66. 66
    Pertwee, R. G. Pharmacological and Therapeutic Targets for Δ9 Tetrahydrocannabinol and Cannabidiol. Euphytica 2004, 140, 7382,  DOI: 10.1007/s10681-004-4756-9
  67. 67
    Morales, P.; Hurst, D. P.; Reggio, P. H. Molecular Targets of the Phytocannabinoids: A Complex Picture. Prog. Chem. Org. Nat. Prod. 2017, 103, 103131,  DOI: 10.1007/978-3-319-45541-9_4
  68. 68
    Brzozowska, N.; Li, K. M.; Wang, X. S.; Booth, J.; Stuart, J.; McGregor, I. S.; Arnold, J. C. ABC Transporters P-Gp and Bcrp Do Not Limit the Brain Uptake of the Novel Antipsychotic and Anticonvulsant Drug Cannabidiol in Mice. PeerJ 2016, 4, e2081  DOI: 10.7717/peerj.2081
  69. 69
    Kathmann, M.; Flau, K.; Redmer, A.; Tränkle, C.; Schlicker, E. Cannabidiol Is an Allosteric Modulator at Mu- and Delta-Opioid Receptors. Naunyn-Schmiedeberg's Arch. Pharmacol. 2006, 372, 354361,  DOI: 10.1007/s00210-006-0033-x
  70. 70
    Russo, E. B.; Burnett, A.; Hall, B.; Parker, K. K. Agonistic Properties of Cannabidiol at 5-HT1a Receptors. Neurochem. Res. 2005, 30, 10371043,  DOI: 10.1007/s11064-005-6978-1
  71. 71
    Chen, G.; Chen, Y.; Yang, N.; Zhu, X.; Sun, L.; Li, G. Interaction between Curcumin and Mimetic Biomembrane. Sci. China: Life Sci. 2012, 55, 527532,  DOI: 10.1007/s11427-012-4317-8
  72. 72
    Ingólfsson, H. I.; Thakur, P.; Herold, K. F.; Hobart, E. A.; Ramsey, N. B.; Periole, X.; de Jong, D. H.; Zwama, M.; Yilmaz, D.; Hall, K.; Maretzky, T.; Hemmings, H. C., Jr.; Blobel, C.; Marrink, S. J.; Koçer, A.; Sack, J. T.; Andersen, O. S. Phytochemicals Perturb Membranes and Promiscuously Alter Protein Function. ACS Chem. Biol. 2014, 9, 17881798,  DOI: 10.1021/cb500086e
  73. 73
    Showalter, V. M.; Compton, D. R.; Martin, B. R.; Abood, M. E. Evaluation of Binding in a Transfected Cell Line Expressing a Peripheral Cannabinoid Receptor (CB2): Identification of Cannabinoid Receptor Subtype Selective Ligands. J. Pharmacol. Exp. Ther. 1996, 278, 989999
  74. 74
    Watkinson, A.; Chapman, S. C. E.; Horne, R. Beliefs About Pharmaceutical Medicines and Natural Remedies Explain Individual Variation in Placebo Analgesia. J. Pain 2017, 18 (8), 908922,  DOI: 10.1016/j.jpain.2017.02.435
  75. 75
    Trainor, G. L. Plasma Protein Binding and the Free Drug Principle: Recent Developments and Applications. In Annual Reports in Medicinal Chemistry; Macor, J. E., Ed.; Academic Press: San Diego, CA, 2007; Vol. 42, Chapter 31, pp 489502.
  76. 76
    Tayo, B.; Taylor, L.; Sahebkar, F.; Morrison, G. A Phase I, Open-Label, Parallel-Group, Single-Dose Trial of the Pharmacokinetics, Safety, and Tolerability of Cannabidiol in Subjects with Mild to Severe Renal Impairment. Clin. Pharmacokinet. 2020, 59, 747755,  DOI: 10.1007/s40262-019-00841-6
  77. 77
    Liu, X.; Wright, M.; Hop, C. E. C. A. Rational Use of Plasma Protein and Tissue Binding Data in Drug Design. J. Med. Chem. 2014, 57, 82388248,  DOI: 10.1021/jm5007935
  78. 78
    Wheless, J. W.; Dlugos, D.; Miller, I.; Oh, D. A.; Parikh, N.; Phillips, S.; Renfroe, J. B.; Roberts, C. M.; Saeed, I.; Sparagana, S. P.; Yu, J.; Cilio, M. R. INS011-14-029 Study Investigators. Pharmacokinetics and Tolerability of Multiple Doses of Pharmaceutical-Grade Synthetic Cannabidiol in Pediatric Patients with Treatment-Resistant Epilepsy. CNS Drugs 2019, 33, 593604,  DOI: 10.1007/s40263-019-00624-4
  79. 79
    Geffrey, A. L.; Pollack, S. F.; Bruno, P. L.; Thiele, E. A. Drug-Drug Interaction between Clobazam and Cannabidiol in Children with Refractory Epilepsy. Epilepsia 2015, 56, 12461251,  DOI: 10.1111/epi.13060
  80. 80
    Bergmann, K. R.; Broekhuizen, K.; Groeneveld, G. J. Clinical Trial Simulations of the Interaction between Cannabidiol and Clobazam and Effect on Drop-Seizure Frequency. Br. J. Clin. Pharmacol. 2020, 86, 380385,  DOI: 10.1111/bcp.14158
  81. 81
    Huddart, R.; Leeder, J. S.; Altman, R. B.; Klein, T. E. PharmGKB Summary: Clobazam Pathway, Pharmacokinetics. Pharmacogenet. Genomics 2018, 28, 110115,  DOI: 10.1097/FPC.0000000000000327
  82. 82
    Calculation of Molecular Properties and Bioactivity Core. https://www.molinspiration.com/cgi-bin/properties (accessed Jul 4, 2020).
  83. 83
    Thorne, N.; Auld, D. S.; Inglese, J. Apparent Activity in High-Throughput Screening: Origins of Compound-Dependent Assay Interference. Curr. Opin. Chem. Biol. 2010, 14, 315324,  DOI: 10.1016/j.cbpa.2010.03.020
  84. 84
    Elbaz, M.; Nasser, M. W.; Ravi, J.; Wani, N. A.; Ahirwar, D. K.; Zhao, H.; Oghumu, S.; Satoskar, A. R.; Shilo, K.; Carson, W. E., 3rd; Ganju, R. K. Modulation of the Tumor Microenvironment and Inhibition of EGF/EGFR Pathway: Novel Anti-Tumor Mechanisms of Cannabidiol in Breast Cancer. Mol. Oncol. 2015, 9, 906919,  DOI: 10.1016/j.molonc.2014.12.010
  85. 85
    Solinas, M.; Massi, P.; Cantelmo, A. R.; Cattaneo, M. G.; Cammarota, R.; Bartolini, D.; Cinquina, V.; Valenti, M.; Vicentini, L. M.; Noonan, D. M.; Albini, A.; Parolaro, D. Cannabidiol Inhibits Angiogenesis by Multiple Mechanisms. Br. J. Pharmacol. 2012, 167, 12181231,  DOI: 10.1111/j.1476-5381.2012.02050.x
  86. 86
    Ohlsson, A.; Lindgren, J. E.; Andersson, S.; Agurell, S.; Gillespie, H.; Hollister, L. E. Single-Dose Kinetics of Deuterium-Labelled Cannabidiol in Man after Smoking and Intravenous Administration. Biol. Mass Spectrom. 1986, 13, 7783,  DOI: 10.1002/bms.1200130206
  87. 87
    Samara, E.; Bialer, M.; Mechoulam, R. Pharmacokinetics of Cannabidiol in Dogs. Drug Metab. Dispos. 1988, 16, 469472
  88. 88
    Stott, C. G.; White, L.; Wright, S.; Wilbraham, D.; Guy, G. W. A Phase I Study to Assess the Single and Multiple Dose Pharmacokinetics of THC/CBD Oromucosal Spray. Eur. J. Clin. Pharmacol. 2013, 69, 11351147,  DOI: 10.1007/s00228-012-1441-0
  89. 89
    Deiana, S.; Watanabe, A.; Yamasaki, Y.; Amada, N.; Arthur, M.; Fleming, S.; Woodcock, H.; Dorward, P.; Pigliacampo, B.; Close, S.; Platt, B.; Riedel, G. Plasma and Brain Pharmacokinetic Profile of Cannabidiol (CBD), Cannabidivarine (CBDV), Δ9-Tetrahydrocannabivarin (THCV) and Cannabigerol (CBG) in Rats and Mice Following Oral and Intraperitoneal Administration and CBD Action on Obsessive-Compulsive Behaviour. Psychopharmacology 2012, 219, 859873,  DOI: 10.1007/s00213-011-2415-0
  90. 90
    Huestis, M. A. Pharmacokinetics and Metabolism of the Plant Cannabinoids, Δ9-Tetrahydrocannibinol, Cannabidiol and Cannabinol. In Cannabinoids; Pertwee, R. G., Ed.; Springer: Berlin, 2005; pp 657690.
  91. 91
    Jiang, R.; Yamaori, S.; Takeda, S.; Yamamoto, I.; Watanabe, K. Identification of Cytochrome P450 Enzymes Responsible for Metabolism of Cannabidiol by Human Liver Microsomes. Life Sci. 2011, 89, 165170,  DOI: 10.1016/j.lfs.2011.05.018
  92. 92
    Ujváry, I.; Hanuš, L. Human Metabolites of Cannabidiol: A Review on Their Formation, Biological Activity, and Relevance in Therapy. Cannabis Cannabinoid Res. 2016, 1, 90101,  DOI: 10.1089/can.2015.0012
  93. 93
    Taylor, L.; Gidal, B.; Blakey, G.; Tayo, B.; Morrison, G. A Phase I, Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose, Multiple Dose, and Food Effect Trial of the Safety, Tolerability and Pharmacokinetics of Highly Purified Cannabidiol in Healthy Subjects. CNS Drugs 2018, 32, 10531067,  DOI: 10.1007/s40263-018-0578-5
  94. 94
    Harvey, D. J.; Mechoulam, R. Metabolites of Cannabidiol Identified in Human Urine. Xenobiotica 1990, 20, 303320,  DOI: 10.3109/00498259009046849
  95. 95
    Watanabe, K.; Usami, N.; Osada, S.; Narimatsu, S.; Yamamoto, I.; Yoshimura, H. Cannabidiol Metabolism Revisited: Tentative Identification of Novel Decarbonylated Metabolites of Cannabidiol Formed by Human Liver Microsomes and Recombinant Cytochrome P450 3A4. Forensic Toxicol. 2019, 37, 449455,  DOI: 10.1007/s11419-019-00467-0
  96. 96
    Harvey, D. J.; Samara, E.; Mechoulam, R. Urinary Metabolites of Cannabidiol in Dog, Rat and Man and Their Identification by Gas Chromatography-Mass Spectrometry. J. Chromatogr., Biomed. Appl. 1991, 562, 299322,  DOI: 10.1016/0378-4347(91)80587-3
  97. 97
    Wray, L.; Stott, C.; Jones, N.; Wright, S. Cannabidiol Does Not Convert to Δ9-Tetrahydrocannabinol in an In Vivo Animal Model. Cannabis Cannabinoid Res. 2017, 2, 282287,  DOI: 10.1089/can.2017.0032
  98. 98
    Palazzoli, F.; Citti, C.; Licata, M.; Vilella, A.; Manca, L.; Zoli, M.; Vandelli, M. A.; Forni, F.; Cannazza, G. Development of a Simple and Sensitive Liquid Chromatography Triple Quadrupole Mass Spectrometry (LC-MS/MS) Method for the Determination of Cannabidiol (CBD), Δ9-Tetrahydrocannabinol (THC) and Its Metabolites in Rat Whole Blood after Oral Administration of a Single High Dose of CBD. J. Pharm. Biomed. Anal. 2018, 150, 2532,  DOI: 10.1016/j.jpba.2017.11.054
  99. 99
    Guy, G. W.; Flint, M. E. A Single Centre, Placebo-Controlled, Four Period, Crossover, Tolerability Study Assessing, Pharmacodynamic Effects, Pharmacokinetic Characteristics and Cognitive Profiles of a Single Dose of Three Formulations of Cannabis Based Medicine Extracts (CBMEs) (GWPD9901), Plus a Two Period Tolerability Study Comparing Pharmacodynamic Effects and Pharmacokinetic Characteristics of a Single Dose of a Cannabis Based Medicine Extract Given via Two Administration Routes (GWPD9901 EXT). J. Cannabis Ther. 2004, 3, 3577,  DOI: 10.1300/J175v03n03_03
  100. 100
    Atsmon, J.; Cherniakov, I.; Izgelov, D.; Hoffman, A.; Domb, A. J.; Deutsch, L.; Deutsch, F.; Heffetz, D.; Sacks, H. PTL401, a New Formulation Based on Pro-Nano Dispersion Technology, Improves Oral Cannabinoids Bioavailability in Healthy Volunteers. J. Pharm. Sci. 2018, 107, 14231429,  DOI: 10.1016/j.xphs.2017.12.020
  101. 101
    Consroe, P.; Kennedy, K.; Schram, K. Assay of Plasma Cannabidiol by Capillary Gas Chromatography/ion Trap Mass Spectroscopy Following High-Dose Repeated Daily Oral Administration in Humans. Pharmacol., Biochem. Behav. 1991, 40, 517522,  DOI: 10.1016/0091-3057(91)90357-8
  102. 102
    Wall, M. E.; Brine, D. R.; Perez-Reyes, M. Metabolism of Cannabinoids in Man. In The Pharmacology of Marihuana; Braude, M. C., Szara, S., Eds.; Raven Press: New York, 1976; pp 93113.
  103. 103
    Stott, C. G.; White, L.; Wright, S.; Wilbraham, D.; Guy, G. W. A Phase I Study to Assess the Effect of Food on the Single Dose Bioavailability of the THC/CBD Oromucosal Spray. Eur. J. Clin. Pharmacol. 2013, 69, 825834,  DOI: 10.1007/s00228-012-1393-4
  104. 104
    Stout, S. M.; Cimino, N. M. Exogenous Cannabinoids as Substrates, Inhibitors, and Inducers of Human Drug Metabolizing Enzymes: A Systematic Review. Drug Metab. Rev. 2014, 46 (1), 8695,  DOI: 10.3109/03602532.2013.849268
  105. 105
    Zendulka, O.; Dovrtělová, G.; Nosková, K.; Turjap, M.; Šulcová, A.; Hanuš, L.; Juřica, J. Cannabinoids and Cytochrome P450 Interactions. Curr. Drug Metab. 2016, 17, 206226,  DOI: 10.2174/1389200217666151210142051
  106. 106
    Benowitz, N. L.; Nguyen, T. L.; Jones, R. T.; Herning, R. I.; Bachman, J. Metabolic and Psychophysiologic Studies of Cannabidiol-Hexobarbital Interaction. Clin. Pharmacol. Ther. 1980, 28, 115120,  DOI: 10.1038/clpt.1980.139
  107. 107
    Garberg, H. T.; Solberg, R.; Barlinn, J.; Martinez-Orgado, J.; Løberg, E.-M.; Saugstad, O. D. High-Dose Cannabidiol Induced Hypotension after Global Hypoxia-Ischemia in Piglets. Neonatology 2017, 112, 143149,  DOI: 10.1159/000471786
  108. 108
    Murphy, S. K.; Itchon-Ramos, N.; Visco, Z.; Huang, Z.; Grenier, C.; Schrott, R.; Acharya, K.; Boudreau, M.-H.; Price, T. M.; Raburn, D. J.; Corcoran, D. L.; Lucas, J. E.; Mitchell, J. T.; McClernon, F. J.; Cauley, M.; Hall, B. J.; Levin, E. D.; Kollins, S. H. Cannabinoid Exposure and Altered DNA Methylation in Rat and Human Sperm. Epigenetics 2018, 13, 12081221,  DOI: 10.1080/15592294.2018.1554521
  109. 109
    Reece, A. S.; Hulse, G. K. Impacts of Cannabinoid Epigenetics on Human Development: Reflections on Murphy et. al. ‘Cannabinoid Exposure and Altered DNA Methylation in Rat and Human Sperm Epigenetics 2018; 13: 1208-1221’. Epigenetics 2019, 14, 10411056,  DOI: 10.1080/15592294.2019.1633868
  110. 110
    Carvalho, R. K.; Santos, M. L.; Souza, M. R.; Rocha, T. L.; Guimarães, F. S.; Anselmo-Franci, J. A.; Mazaro-Costa, R. Chronic Exposure to Cannabidiol Induces Reproductive Toxicity in Male Swiss Mice. J. Appl. Toxicol. 2018, 38, 12151223,  DOI: 10.1002/jat.3631
  111. 111
    Ewing, L. E.; Skinner, C. M.; Quick, C. M.; Kennon-McGill, S.; McGill, M. R.; Walker, L. A.; ElSohly, M. A.; Gurley, B. J.; Koturbash, I. Hepatotoxicity of a Cannabidiol-Rich Cannabis Extract in the Mouse Model. Molecules 2019, 24, 1694,  DOI: 10.3390/molecules24091694
  112. 112
    Russo, C.; Ferk, F.; Mišík, M.; Ropek, N.; Nersesyan, A.; Mejri, D.; Holzmann, K.; Lavorgna, M.; Isidori, M.; Knasmüller, S. Low Doses of Widely Consumed Cannabinoids (Cannabidiol and Cannabidivarin) Cause DNA Damage and Chromosomal Aberrations in Human-Derived Cells. Arch. Toxicol. 2019, 93, 179188,  DOI: 10.1007/s00204-018-2322-9
  113. 113
    Devinsky, O.; Patel, A. D.; Cross, J. H.; Villanueva, V.; Wirrell, E. C.; Privitera, M.; Greenwood, S. M.; Roberts, C.; Checketts, D.; VanLandingham, K. E.; Zuberi, S. M. GWPCARE3 Study Group. Effect of Cannabidiol on Drop Seizures in the Lennox-Gastaut Syndrome. N. Engl. J. Med. 2018, 378, 18881897,  DOI: 10.1056/NEJMoa1714631
  114. 114
    Gaston, T. E.; Bebin, E. M.; Cutter, G. R.; Liu, Y.; Szaflarski, J. P. UAB CBD Program. Interactions between Cannabidiol and Commonly Used Antiepileptic Drugs. Epilepsia 2017, 58, 15861592,  DOI: 10.1111/epi.13852
  115. 115
    Groeneveld, G. J.; Martin, J. H. Parasitic Pharmacology: A Plausible Mechanism of Action for Cannabidiol. Br. J. Clin. Pharmacol. 2020, 86, 189191,  DOI: 10.1111/bcp.14028
  116. 116
    American Epilepsy Foundation. AES Position Statement on Cannabis as a Treatment for Patients with Epileptic Seizures; American Epilepsy Foundation, 2019. https://www.aesnet.org/sites/default/files/file_attach/42981132_cannabis_position_statement_updated_2.19.19.pdf (accessed Dec 19, 2019).
  117. 117
    MacKeen, D. What Are the Benefits of CBD? N. Y. Times 2019 (October 16).
  118. 118
    Popejoy, S. Is CBD for Aging a Potential Fountain of Youth? CBGenius. https://www.cbgenius.net/2019/06/18/is-cbd-for-aging-a-potential-fountain-of-youth/ (accessed Jul 4, 2020).
  119. 119
    Freeman, J. Does CBD Oil Really Help Treat Arthritis Pain? Rheumatoid Arthritis. https://www.rheumatoidarthritis.org/cbd-oil/ (accessed Jul. 4, 2020).
  120. 120
    Skrobin, N., The Fresh Toast. Cannabis: Optimal Treatment Method for Post-Concussion Syndrome Symptoms. Chicago Tribune 2019 (August 30).
  121. 121
    Johnson, J. CBD for Weight Loss: Does It Work? https://www.medicalnewstoday.com/articles/324733 (accessed Jul 4, 2020).
  122. 122
    Kubala, J.. 7 Benefits and Uses of CBD Oil (Plus Side Effects). https://www.healthline.com/nutrition/cbd-oil-benefits (accessed Jul 4, 2020).
  123. 123
    Bonaccorso, S.; Ricciardi, A.; Zangani, C.; Chiappini, S.; Schifano, F. Cannabidiol (CBD) Use in Psychiatric Disorders: A Systematic Review. NeuroToxicology 2019, 74, 282298,  DOI: 10.1016/j.neuro.2019.08.002
  124. 124
    Hiemstra, B.; Keus, F.; Wetterslev, J.; Gluud, C.; van der Horst, I. C. C. DEBATE-Statistical Analysis Plans for Observational Studies. BMC Med. Res. Methodol. 2019, 19 (1), 233,  DOI: 10.1186/s12874-019-0879-5
  125. 125
    The Skyline Agency. CBD Oil & Cannabinol Tincture Products from Medterra CBD. https://medterracbd.com/product-cbd-oil-tincture (accessed Jul 7, 2020).
  126. 126
    Moerman, D. E.; Jonas, W. B. Deconstructing the Placebo Effect and Finding the Meaning Response. Ann. Intern. Med. 2002, 136, 471476,  DOI: 10.7326/0003-4819-136-6-200203190-00011
  127. 127
    Benedetti, F. Placebo Effects: From the Neurobiological Paradigm to Translational Implications. Neuron 2014, 84, 623637,  DOI: 10.1016/j.neuron.2014.10.023
  128. 128
    Hopp, C. Past and Future Research at National Center for Complementary and Integrative Health with Respect to Botanicals. HerbalGram 2015, 107, 4451
  129. 129
    Geller, S. E.; Shulman, L. P.; van Breemen, R. B.; Banuvar, S.; Zhou, Y.; Epstein, G.; Hedayat, S.; Nikolic, D.; Krause, E. C.; Piersen, C. E.; Bolton, J. L.; Pauli, G. F.; Farnsworth, N. R. Safety and Efficacy of Black Cohosh and Red Clover for the Management of Vasomotor Symptoms: A Randomized Controlled Trial. Menopause 2009, 16, 11561166,  DOI: 10.1097/gme.0b013e3181ace49b
  130. 130
    Sorkin, B. C.; Kuszak, A. J.; Bloss, G.; Fukagawa, N. K.; Hoffman, F. A.; Jafari, M.; Barrett, B.; Brown, P. N.; Bushman, F. D.; Casper, S. J.; Chilton, F. H.; Coffey, C. S.; Ferruzzi, M. G.; Hopp, D. C.; Kiely, M.; Lakens, D.; MacMillan, J. B.; Meltzer, D. O.; Pahor, M.; Paul, J.; Pritchett-Corning, K.; Quinney, S. K.; Rehermann, B.; Setchell, K. D. R.; Sipes, N. S.; Stephens, J. M.; Taylor, D. L.; Tiriac, H.; Walters, M. A.; Xi, D.; Zappalá, G.; Pauli, G. F. Improving Natural Product Research Translation: From Source to Clinical Trial. FASEB J. 2020, 34, 4165,  DOI: 10.1096/fj.201902143R
  131. 131
    Brown, J. D. Cannabidiol as Prophylaxis for SARS-CoV-2 and COVID-19? Unfounded Claims versus Potential Risks of Medications during the Pandemic. Res. Social Adm. Pharm. 2020,  DOI: 10.1016/j.sapharm.2020.03.020

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  6. Giuseppina Chianese, Carmina Sirignano, Emanuele Benetti, Vittoria Marzaroli, Juan A. Collado, Lauren de la Vega, Giovanni Appendino, Eduardo Muñoz, Orazio Taglialatela-Scafati. A Nrf-2 Stimulatory Hydroxylated Cannabidiol Derivative from Hemp (Cannabis sativa). Journal of Natural Products 2022, 85 (4) , 1089-1097. https://doi.org/10.1021/acs.jnatprod.1c01198
  7. Escarlin Perez, Jasmin Ceja-Vega, Michael Krmic, Alondra Gamez Hernandez, Jamie Gudyka, Riley Porteus, Sunghee Lee. Differential Interaction of Cannabidiol with Biomembranes Dependent on Cholesterol Concentration. ACS Chemical Neuroscience 2022, 13 (7) , 1046-1054. https://doi.org/10.1021/acschemneuro.2c00040
  8. Takashi Ohtsuki, J. Brent Friesen, Shao-Nong Chen, James B. McAlpine, Guido F. Pauli. Selective Preparation and High Dynamic-Range Analysis of Cannabinoids in “CBD Oil” and Other Cannabis sativa Preparations. Journal of Natural Products 2022, 85 (3) , 634-646. https://doi.org/10.1021/acs.jnatprod.1c00976
  9. Iain W. H. Oswald, Marcos A. Ojeda, Ryan J. Pobanz, Kevin A. Koby, Anthony J. Buchanan, Josh Del Rosso, Mario A. Guzman, Thomas J. Martin. Identification of a New Family of Prenylated Volatile Sulfur Compounds in Cannabis Revealed by Comprehensive Two-Dimensional Gas Chromatography. ACS Omega 2021, 6 (47) , 31667-31676. https://doi.org/10.1021/acsomega.1c04196
  10. Erin C. Berthold, Shyam H. Kamble, Siva Rama Raju Kanumuri, Michelle A. Kuntz, Alexandria S. Senetra, Yi-Hua Chiang, Sushobhan Mukhopadhyay, Christopher R. McCurdy, Abhisheak Sharma. Pharmacokinetic Interaction of Kratom and Cannabidiol in Male Rats. Pharmaceutics 2024, 16 (3) , 318. https://doi.org/10.3390/pharmaceutics16030318
  11. Andrea Jess Josiah, Sreejarani Kesavan Pillai, Werner Cordier, Margo Nell, Namrita Lall, Danielle Twilley, Suprakas Sinha Ray. One‐Step Synthesis of Metal Oxide Nanoparticles Using Cannabidiol: Characterisation and Cytotoxicity Assessment in Human Keratinocyte Cells. ChemistrySelect 2024, 9 (8) https://doi.org/10.1002/slct.202304373
  12. Andrejs Sitovs, Konstantins Logviss, Liga Lauberte, Valentyn Mohylyuk. Oral delivery of cannabidiol: Revealing the formulation and absorption challenges. Journal of Drug Delivery Science and Technology 2024, 92 , 105316. https://doi.org/10.1016/j.jddst.2023.105316
  13. Wenjiao Yang, Xudong Gong, Haiguo Sun, Chunhui Wu, Jin Suo, Jing Ji, Xiangrui Jiang, Jingshan Shen, Yang He, Haji Akber Aisa. Discovery of a CB2 and 5-HT1A receptor dual agonist for the treatment of depression and anxiety. European Journal of Medicinal Chemistry 2024, 265 , 116048. https://doi.org/10.1016/j.ejmech.2023.116048
  14. Andrzej L. Dawidowicz, Rafal Typek, Michal P. Dybowski, Piotr Holowinski, Michal Rombel. Cannabigerol (CBG) signal enhancement in its analysis by gas chromatography coupled with tandem mass spectrometry. Forensic Toxicology 2024, 42 (1) , 31-44. https://doi.org/10.1007/s11419-023-00673-x
  15. Sreejarani Kesavan Pillai, Nazia Hassan Kera, Phumelele Kleyi, Marinda de Beer, Matin Magwaza, Suprakas Sinha Ray. Stability, biofunctional, and antimicrobial characteristics of cannabidiol isolate for the design of topical formulations. Soft Matter 2024, 24 https://doi.org/10.1039/D3SM01466E
  16. Sanne M. Buijs, C. Louwrens Braal, Stefan A. J. Buck, Noud F. van Maanen, Lonneke M. van der Meijden-Erkelens, Heleen A. Kuijper-Tissot van Patot, Esther Oomen-de Hoop, Lotte Saes, Sophia J. van den Boogerd, Liesbeth E. M. Struik, Quirine C. van Rossum-Schornagel, Ron H. J. Mathijssen, Stijn L. W. Koolen, Agnes Jager. CBD-oil as a potential solution in case of severe tamoxifen-related side effects. npj Breast Cancer 2023, 9 (1) https://doi.org/10.1038/s41523-023-00570-x
  17. Marjan Talebi, Mohammad Mehdi Sadoughi, Seyed Abdulmajid Ayatollahi, Elaheh Ainy, Roghayeh Kiani, Alireza Zali, MirMohammad Miri. Therapeutic potentials of cannabidiol: Focus on the Nrf2 signaling pathway. Biomedicine & Pharmacotherapy 2023, 168 , 115805. https://doi.org/10.1016/j.biopha.2023.115805
  18. Ana Julia de Lima Bomfim, Stefany Mirrelle Fávero Zuze, Daiene de Morais Fabrício, Rebeca Mendes de Paula Pessoa, José Alexandre S. Crippa, Marcos Hortes N. Chagas. Effects of the Acute and Chronic Administration of Cannabidiol on Cognition in Humans and Animals: A Systematic Review. Cannabis and Cannabinoid Research 2023, 8 (6) , 955-973. https://doi.org/10.1089/can.2023.0086
  19. Hesam Khodadadi, Évila Lopes Salles, Ahmet Alptekin, Daniel Mehrabian, Martin Rutkowski, Ali S. Arbab, W. Andrew Yeudall, Jack C. Yu, John C. Morgan, David C. Hess, Kumar Vaibhav, Krishnan M. Dhandapani, Babak Baban. Inhalant Cannabidiol Inhibits Glioblastoma Progression Through Regulation of Tumor Microenvironment. Cannabis and Cannabinoid Research 2023, 8 (5) , 824-834. https://doi.org/10.1089/can.2021.0098
  20. Irene Cheah, Ingrid Gelissen, Jennifer Hunter, Joanna Harnett. Adverse events associated with the use of cannabis-based products in people living with cancer: A scoping review protocol. European Journal of Integrative Medicine 2023, 62 , 102279. https://doi.org/10.1016/j.eujim.2023.102279
  21. Michal P. Dybowski, Andrzej L. Dawidowicz, Michal Rombel, Rafal Typek. GC vs. HPLC in quantitation of CBD, CBG, ∆9-THC and CBN in plasma using different sample preparation methods. Journal of Pharmaceutical and Biomedical Analysis 2023, 234 , 115563. https://doi.org/10.1016/j.jpba.2023.115563
  22. C.N. Scholfield, Neti Waranuch, Chuenjid Kongkaew. Systematic Review on Transdermal/Topical Cannabidiol Trials: A Reconsidered Way Forward. Cannabis and Cannabinoid Research 2023, 8 (4) , 589-602. https://doi.org/10.1089/can.2021.0154
  23. Erin C. Berthold, Shyam H. Kamble, Siva Rama Raju Kanumuri, Michelle A. Kuntz, Alexandria S. Senetra, Yi-Hua Chiang, Lance R. McMahon, Christopher R. McCurdy, Abhisheak Sharma. Comparative Pharmacokinetics of Commercially Available Cannabidiol Isolate, Broad-Spectrum, and Full-Spectrum Products. European Journal of Drug Metabolism and Pharmacokinetics 2023, 48 (4) , 427-435. https://doi.org/10.1007/s13318-023-00839-3
  24. Luigi Bellocchio, Assunta Patano, Alessio Danilo Inchingolo, Francesco Inchingolo, Gianna Dipalma, Ciro Gargiulo Isacco, Elisabetta de Ruvo, Biagio Rapone, Antonio Mancini, Felice Lorusso, Antonio Scarano, Giuseppina Malcangi, Angelo Michele Inchingolo. Cannabidiol for Oral Health: A New Promising Therapeutical Tool in Dentistry. International Journal of Molecular Sciences 2023, 24 (11) , 9693. https://doi.org/10.3390/ijms24119693
  25. Grace Tsz Yan Yau, Waiting Tai, Jonathon Carl Arnold, Hak-Kim Chan, Philip Chi Lip Kwok. Cannabidiol for the Treatment of Brain Disorders: Therapeutic Potential and Routes of Administration. Pharmaceutical Research 2023, 40 (5) , 1087-1114. https://doi.org/10.1007/s11095-023-03469-1
  26. William R. Swindell, Krzysztof Bojanowski, Parvesh Singh, Manpreet Randhawa, Ratan K. Chaudhuri. Bakuchiol and Ethyl (Linoleate/Oleate) Synergistically Modulate Endocannabinoid Tone in Keratinocytes and Repress Inflammatory Pathway mRNAs. JID Innovations 2023, 3 (3) , 100178. https://doi.org/10.1016/j.xjidi.2022.100178
  27. Benjamin G. Chavez, John C. D’Auria. Turning a new leaf on cannabinoids. Nature Plants 2023, 9 (5) , 687-688. https://doi.org/10.1038/s41477-023-01415-y
  28. T. Srinivasa Reddy, Roby Zomer, Nitin Mantri. Nanoformulations as a strategy to overcome the delivery limitations of cannabinoids. Phytotherapy Research 2023, 37 (4) , 1526-1538. https://doi.org/10.1002/ptr.7742
  29. Elham Assadpour, Atefe Rezaei, Sabya Sachi Das, Balaga Venkata Krishna Rao, Sandeep Kumar Singh, Mohammad Saeed Kharazmi, Niraj Kumar Jha, Saurabh Kumar Jha, Miguel A. Prieto, Seid Mahdi Jafari. Cannabidiol-Loaded Nanocarriers and Their Therapeutic Applications. Pharmaceuticals 2023, 16 (4) , 487. https://doi.org/10.3390/ph16040487
  30. Aleksandra Zielińska, Piotr Eder, Jacek Karczewski, Marlena Szalata, Szymon Hryhorowicz, Karolina Wielgus, Milena Szalata, Agnieszka Dobrowolska, Atanas G. Atanasov, Ryszard Słomski, Eliana B. Souto. Tocilizumab-coated solid lipid nanoparticles loaded with cannabidiol as a novel drug delivery strategy for treating COVID-19: A review. Frontiers in Immunology 2023, 14 https://doi.org/10.3389/fimmu.2023.1147991
  31. Wim Buijs. The scientific controversy on the conversion of CBD into THC in the human stomach: Molecular modelling and experimental results compared. Forensic Chemistry 2023, 32 , 100467. https://doi.org/10.1016/j.forc.2023.100467
  32. Janet Hardy, Ristan Greer, Georgie Huggett, Alison Kearney, Taylan Gurgenci, Phillip Good. Phase IIb Randomized, Placebo-Controlled, Dose-Escalating, Double-Blind Study of Cannabidiol Oil for the Relief of Symptoms in Advanced Cancer (MedCan1-CBD). Journal of Clinical Oncology 2023, 41 (7) , 1444-1452. https://doi.org/10.1200/JCO.22.01632
  33. Stefano Martini, Alessandra Gemma, Marco Ferrari, Marco Cosentino, Franca Marino. Effects of Cannabidiol on Innate Immunity: Experimental Evidence and Clinical Relevance. International Journal of Molecular Sciences 2023, 24 (4) , 3125. https://doi.org/10.3390/ijms24043125
  34. Giorgia della Rocca, Fabiola Paoletti, Maria Beatrice Conti, Roberta Galarini, Elisabetta Chiaradia, Monica Sforna, Cecilia Dall'Aglio, Angela Polisca, Alessandra Di Salvo. Pharmacokinetics of cannabidiol following single oral and oral transmucosal administration in dogs. Frontiers in Veterinary Science 2023, 9 https://doi.org/10.3389/fvets.2022.1104152
  35. Susan Miller, Walter Moos, Barbara Munk, Stephen Munk, Charles Hart, David Spellmeyer. Backgrounder—Part 2. 2023, 27-64. https://doi.org/10.1016/B978-0-12-824304-6.00010-9
  36. Nivedita Bhardwaj, Nancy Tripathi, Ram A. Vishwakarma, Shreyans K. Jain. Advances in natural products driven drug discovery from medicinal plants for neuropathic pain. 2023, 133-162. https://doi.org/10.1016/bs.armc.2023.10.003
  37. Laura C. Laurella, Albertina G. Moglioni, M. Florencia Martini. Molecular study of endo and phytocannabinoids on lipid membranes of different composition. Colloids and Surfaces B: Biointerfaces 2023, 221 , 113020. https://doi.org/10.1016/j.colsurfb.2022.113020
  38. Rui Filipe Malheiro, Helena Carmo, Félix Carvalho, João Pedro Silva. Cannabinoid-mediated targeting of mitochondria on the modulation of mitochondrial function and dynamics. Pharmacological Research 2023, 187 , 106603. https://doi.org/10.1016/j.phrs.2022.106603
  39. Rafal Typek, Piotr Holowinski, Andrzej L. Dawidowicz, Michal P. Dybowski, Michal Rombel. Chromatographic analysis of CBD and THC after their acylation with blockade of compound transformation. Talanta 2023, 251 , 123777. https://doi.org/10.1016/j.talanta.2022.123777
  40. Nicoleta Mirela Blebea. Phytocannabinoids and synthetic cannabinoids – pharmacotherapeutic aspects. Farmacist.ro 2023, 1 (210) , 10. https://doi.org/10.26416/Farm.210.1.2023.7757
  41. Nicoleta Mirela Blebea, Gabriel Hancu, Robert Alexandru Vlad, Andreea Pricopie. Applications of Capillary Electrophoresis for the Determination of Cannabinoids in Different Matrices. Molecules 2023, 28 (2) , 638. https://doi.org/10.3390/molecules28020638
  42. Thomas Azwell, Chloe Ciotti, Arthur Adams, Guido F. Pauli. Variation among hemp (Cannabis sativus L.) analytical testing laboratories evinces regulatory and quality control issues for the industry. Journal of Applied Research on Medicinal and Aromatic Plants 2022, 31 , 100434. https://doi.org/10.1016/j.jarmap.2022.100434
  43. Henry Blanton, Linda Yin, Joshua Duong, Khalid Benamar. Cannabidiol and Beta-Caryophyllene in Combination: A Therapeutic Functional Interaction. International Journal of Molecular Sciences 2022, 23 (24) , 15470. https://doi.org/10.3390/ijms232415470
  44. Amelia Seifalian, Julian Kenyon, Vik Khullar. Dysmenorrhoea: Can Medicinal Cannabis Bring New Hope for a Collective Group of Women Suffering in Pain, Globally?. International Journal of Molecular Sciences 2022, 23 (24) , 16201. https://doi.org/10.3390/ijms232416201
  45. Sebastian W. Nielsen, Simone Dyring Hasselsteen, Helena Sylow Heilmann Dominiak, Dejan Labudovic, Lars Reiter, Susanne Oksbjerg Dalton, Jørn Herrstedt. Oral cannabidiol for prevention of acute and transient chemotherapy-induced peripheral neuropathy. Supportive Care in Cancer 2022, 30 (11) , 9441-9451. https://doi.org/10.1007/s00520-022-07312-y
  46. Michael Geci, Mark Scialdone, Jordan Tishler. The Dark Side of Cannabidiol: The Unanticipated Social and Clinical Implications of Synthetic Δ 8 -THC. Cannabis and Cannabinoid Research 2022, 9 https://doi.org/10.1089/can.2022.0126
  47. Sharon Lustenberger, Grzegorz Boczkaj, Roberto Castro-Muñoz. Cannabinoids: Challenges, opportunities and current techniques towards its extraction and purification for edibles. Food Bioscience 2022, 49 , 101835. https://doi.org/10.1016/j.fbio.2022.101835
  48. Carla David, Alejandro Elizalde-Hernández, Andressa Barboza, Gabriela Cardoso, Mateus Santos, Rafael Moraes. Cannabidiol in Dentistry: A Scoping Review. Dentistry Journal 2022, 10 (10) , 193. https://doi.org/10.3390/dj10100193
  49. Damijana Mojca Jurič, Klara Bulc Rozman, Metoda Lipnik-Štangelj, Dušan Šuput, Miran Brvar. Cytotoxic Effects of Cannabidiol on Neonatal Rat Cortical Neurons and Astrocytes: Potential Danger to Brain Development. Toxins 2022, 14 (10) , 720. https://doi.org/10.3390/toxins14100720
  50. Shallu Tomer, Wenli Mu, Gajendra Suryawanshi, Hwee Ng, Li Wang, Wally Wennerberg, Valerie Rezek, Heather Martin, Irvin Chen, Scott Kitchen, Anjie Zhen. Cannabidiol modulates expression of type I IFN response genes and HIV infection in macrophages. Frontiers in Immunology 2022, 13 https://doi.org/10.3389/fimmu.2022.926696
  51. Yuli Qian, John S. Markowitz. Prediction of Carboxylesterase 1-mediated In Vivo Drug Interaction between Methylphenidate and Cannabinoids using Static and Physiologically Based Pharmacokinetic Models. Drug Metabolism and Disposition 2022, 50 (7) , 968-979. https://doi.org/10.1124/dmd.121.000823
  52. Alessia D’Aloia, Michela Ceriani, Renata Tisi, Simone Stucchi, Elena Sacco, Barbara Costa. Cannabidiol Antiproliferative Effect in Triple-Negative Breast Cancer MDA-MB-231 Cells Is Modulated by Its Physical State and by IGF-1. International Journal of Molecular Sciences 2022, 23 (13) , 7145. https://doi.org/10.3390/ijms23137145
  53. Simona De Vita, Claudia Finamore, Maria Giovanna Chini, Gabriella Saviano, Vincenzo De Felice, Simona De Marino, Gianluigi Lauro, Agostino Casapullo, Francesca Fantasma, Federico Trombetta, Giuseppe Bifulco, Maria Iorizzi. Phytochemical Analysis of the Methanolic Extract and Essential Oil from Leaves of Industrial Hemp Futura 75 Cultivar: Isolation of a New Cannabinoid Derivative and Biological Profile Using Computational Approaches. Plants 2022, 11 (13) , 1671. https://doi.org/10.3390/plants11131671
  54. José Luis Cortes-Altamirano, Ariadna Yáñez-Pizaña, Samuel Reyes-Long, González-Maciel Angélica, Cindy Bandala, Herlinda Bonilla-Jaime, Alfonso Alfaro-Rodríguez. Potential Neuroprotective Effect of Cannabinoids in COVID-19 Patients. Current Topics in Medicinal Chemistry 2022, 22 (16) , 1326-1345. https://doi.org/10.2174/1568026622666220405143003
  55. Michael J. Viereckl, Kelsey Krutsinger, Aaron Apawu, Jian Gu, Bryana Cardona, Donovan Barratt, Yuyan Han. Cannabidiol and Cannabigerol Inhibit Cholangiocarcinoma Growth In Vitro via Divergent Cell Death Pathways. Biomolecules 2022, 12 (6) , 854. https://doi.org/10.3390/biom12060854
  56. Sara L. MacPhail, Miguel A. Bedoya-Pérez, Rhys Cohen, Vicki Kotsirilos, Iain S. McGregor, Elizabeth A. Cairns. Medicinal Cannabis Prescribing in Australia: An Analysis of Trends Over the First Five Years. Frontiers in Pharmacology 2022, 13 https://doi.org/10.3389/fphar.2022.885655
  57. Ochuko L. Erukainure, Motlalepula G. Matsabisa, Veronica F. Salau, Kolawole A. Olofinsan, Sunday O. Oyedemi, Chika I. Chukwuma, Adeline Lum Nde, Md. Shahidul Islam. Cannabidiol improves glucose utilization and modulates glucose-induced dysmetabolic activities in isolated rats' peripheral adipose tissues. Biomedicine & Pharmacotherapy 2022, 149 , 112863. https://doi.org/10.1016/j.biopha.2022.112863
  58. Giovanni Appendino, Orazio Taglialatela-Scafati, Eduardo Muñoz. Cannabidiol (CBD) From Non-Cannabis Plants: Myth or Reality?. Natural Product Communications 2022, 17 (5) , 1934578X2210988. https://doi.org/10.1177/1934578X221098843
  59. Robert B. Child, Mark J. Tallon. Cannabidiol (CBD) Dosing: Plasma Pharmacokinetics and Effects on Accumulation in Skeletal Muscle, Liver and Adipose Tissue. Nutrients 2022, 14 (10) , 2101. https://doi.org/10.3390/nu14102101
  60. Thope Moqejwa, Thashree Marimuthu, Pierre P. D. Kondiah, Yahya E. Choonara. Development of Stable Nano-Sized Transfersomes as a Rectal Colloid for Enhanced Delivery of Cannabidiol. Pharmaceutics 2022, 14 (4) , 703. https://doi.org/10.3390/pharmaceutics14040703
  61. Eugenia Mazzara, Jacopo Torresi, Gelsomina Fico, Alessio Papini, Nicola Kulbaka, Stefano Dall’Acqua, Stefania Sut, Stefania Garzoli, Ahmed M. Mustafa, Loredana Cappellacci, Dennis Fiorini, Filippo Maggi, Claudia Giuliani, Riccardo Petrelli. A Comprehensive Phytochemical Analysis of Terpenes, Polyphenols and Cannabinoids, and Micromorphological Characterization of 9 Commercial Varieties of Cannabis sativa L.. Plants 2022, 11 (7) , 891. https://doi.org/10.3390/plants11070891
  62. Yanhong Wang, Yuzhu Hong, Jiyu Yan, Breanna Brown, Xiaoyang Lin, Xiaolin Zhang, Ning Shen, Minghua Li, Jianfeng Cai, Marcia Gordon, David Morgan, Qingyu Zhou, Chuanhai Cao. Low-Dose Delta-9-Tetrahydrocannabinol as Beneficial Treatment for Aged APP/PS1 Mice. International Journal of Molecular Sciences 2022, 23 (5) , 2757. https://doi.org/10.3390/ijms23052757
  63. Miguel Olivas-Aguirre, Liliana Torres-López, Kathya Villatoro-Gómez, Sonia Mayra Perez-Tapia, Igor Pottosin, Oxana Dobrovinskaya. Cannabidiol on the Path from the Lab to the Cancer Patient: Opportunities and Challenges. Pharmaceuticals 2022, 15 (3) , 366. https://doi.org/10.3390/ph15030366
  64. Long Chi Nguyen, Dongbo Yang, Vlad Nicolaescu, Thomas J. Best, Haley Gula, Divyasha Saxena, Jon D. Gabbard, Shao-Nong Chen, Takashi Ohtsuki, John Brent Friesen, Nir Drayman, Adil Mohamed, Christopher Dann, Diane Silva, Lydia Robinson-Mailman, Andrea Valdespino, Letícia Stock, Eva Suárez, Krysten A. Jones, Saara-Anne Azizi, Jennifer K. Demarco, William E. Severson, Charles D. Anderson, James Michael Millis, Bryan C. Dickinson, Savaş Tay, Scott A. Oakes, Guido F. Pauli, Kenneth E. Palmer, , David O. Meltzer, Glenn Randall, Marsha Rich Rosner. Cannabidiol inhibits SARS-CoV-2 replication through induction of the host ER stress and innate immune responses. Science Advances 2022, 8 (8) https://doi.org/10.1126/sciadv.abi6110
  65. Krzysztof Laudanski, Justin Wain. Considerations for Cannabinoids in Perioperative Care by Anesthesiologists. Journal of Clinical Medicine 2022, 11 (3) , 558. https://doi.org/10.3390/jcm11030558
  66. Chiara Corpetti, Alessandro Del Re, Luisa Seguella, Irene Palenca, Sara Rurgo, Barbara De Conno, Marcella Pesce, Giovanni Sarnelli, Giuseppe Esposito. Cannabidiol inhibits SARS‐Cov ‐2 spike (S) protein‐induced cytotoxicity and inflammation through a PPARγ ‐dependent TLR4 / NLRP3 /Caspase‐1 signaling suppression in Caco‐2 cell line. Phytotherapy Research 2021, 35 (12) , 6893-6903. https://doi.org/10.1002/ptr.7302
  67. Wenwen Duan, Ying Sun, Meng Wu, Zhiyuan Zhang, Taotao Zhang, Huan Wang, Fei Li, Lingyun Yang, Yueming Xu, Zhi-Jie Liu, Tian Hua, Hong Nie, Jianjun Cheng. Carbon-silicon switch led to the discovery of novel synthetic cannabinoids with therapeutic effects in a mouse model of multiple sclerosis. European Journal of Medicinal Chemistry 2021, 226 , 113878. https://doi.org/10.1016/j.ejmech.2021.113878
  68. Justin E. LaVigne, Ryan Hecksel, Attila Keresztes, John M. Streicher. Cannabis sativa terpenes are cannabimimetic and selectively enhance cannabinoid activity. Scientific Reports 2021, 11 (1) https://doi.org/10.1038/s41598-021-87740-8
  69. Peter S. Cogan. Regarding the Mechanisms of Promiscuous Cannabinoid Pharmacology: An Elephant Has Entered the Room. Cannabis and Cannabinoid Research 2021, 6 (6) , 457-461. https://doi.org/10.1089/can.2020.0115
  70. Bulbul Ahmed, Mohamed Hijri. Potential impacts of soil microbiota manipulation on secondary metabolites production in cannabis. Journal of Cannabis Research 2021, 3 (1) https://doi.org/10.1186/s42238-021-00082-0
  71. Sukvinder Kaur Bhamra, Ankita Desai, Parmis Imani‐Berendjestanki, Maeve Horgan. The emerging role of cannabidiol ( CBD ) products; a survey exploring the public's use and perceptions of CBD. Phytotherapy Research 2021, 35 (10) , 5734-5740. https://doi.org/10.1002/ptr.7232
  72. Zi-Yi Huang, Min-Ru Jiao, Xiu Gu, Zi-Ran Zhai, Jian-Qi Li, Qing-Wei Zhang. Asymmetric Synthesis of 1,2-Limonene Epoxides by Jacobsen Epoxidation. Pharmaceutical Fronts 2021, 03 (03) , e113-e118. https://doi.org/10.1055/s-0041-1740241
  73. Diego Caprioglio, Daiana Mattoteia, Orazio Taglialatela-Scafati, Eduardo Muñoz, Giovanni Appendino. Cannabinoquinones: Synthesis and Biological Profile. Biomolecules 2021, 11 (7) , 991. https://doi.org/10.3390/biom11070991
  74. Lisa A. Stott, Cheryl A. Brighton, Jason Brown, Richard Mould, Kirstie A. Bennett, Robert Newman, Heather Currinn, Flavia Autore, Alicia P. Higueruelo, Benjamin G. Tehan, Cliona MacSweeney, Michael A. O'Brien, Steve P. Watson. Characterisation of inverse agonism of the orphan-G protein-coupled receptor GPR52 by cannabinoid ligands Cannabidiol and O-1918. Heliyon 2021, 7 (6) , e07201. https://doi.org/10.1016/j.heliyon.2021.e07201
  75. Lewis J. Martin, Samuel D. Banister, Michael T. Bowen. Understanding the complex pharmacology of cannabidiol: Mounting evidence suggests a common binding site with cholesterol. Pharmacological Research 2021, 166 , 105508. https://doi.org/10.1016/j.phrs.2021.105508
  • Abstract

    Figure 1

    Figure 1. (A) Tetrahydrodiphenyl skeleton of CBD in the context of the base structures of three other main classes of cannabinoids (dibenzopyrans, benzopyrans, and acyclic prenyl-olivetols) and (B) five principal structural variations that occur in all cannabinoid classes. Different combinations of these four classes, with variations such as these presented as well as additional redox-driven metabolic modifications, explain why CBD and THC are just two molecules within the complex metabolome of cannabinoids.

    Figure 2

    Figure 2. The biosynthetic pathway of cannabinoids is the result of the intersection of three metabolic pathways in Cannabis sp.

    Figure 3

    Figure 3. Not only is the axial hydrogen, H-4″ax, involved in multiple J-couplings within the monoterpene moiety, but its 1H NMR resonance is also affected by the close resonance behavior of its coupling partners. The resulting pronounced higher order effects of the ddddddq-type multiplet encode the spin parameters of half of the molecule in such a way that the H-4″ax resonance alone becomes diagnostic for the entire CBD molecule. See section S1, Supporting Information, for the detailed results of the underlying 1H iterative full spin analysis (HiFSA).

    Figure 4

    Figure 4. Structures of the active ingredients of FDA-approved drugs containing CBD or related compounds.

    Figure 5

    Figure 5. Acid instability of cannabidiol as reported by Zynerba Pharmaceuticals. (47)

    Figure 6

    Figure 6. Selected bioactive synthetic analogs of cannabidiol.

    Figure 7

    Figure 7. Interference profiling of CBD. (A) CBD shows moderate activity at several receptors. Ki values were reported from testing by PDSP. Full data are in Supporting Information. (B) CBD shows concentration-dependent, detergent-sensitive inhibition of AmpC in a colloidal aggregation counterscreen. TIPT, positive aggregation control; 2-BTBA, positive nonaggregator control. Data are the mean ± SD of four intrarun technical replicates. (C) CBD shows detergent-sensitive inhibition of MDH in an orthogonal aggregation counterscreen. Compounds were tested at 33 or 100 μM final concentrations in either the presence (blue) or absence (magenta) of buffer containing freshly added 0.01% Triton X-100 (v/v). Data are the mean ± SD of at least three intrarun technical replicates. (D) CBD forms detectible colloidal aggregates at approximately 12.5 μM by DLS. (E) CBD does not produce detectable H2O2 in a HRP-PR redox-cycling counterscreen. Compounds were assayed at 250 μM final concentrations, 1 mM DTT, enzyme. H2O2, positive control; NSC-663284 and 4-amino-1-naphthol, positive control compounds. Data are mean ± SD of at least three intrarun technical replicates.

    Figure 8

    Figure 8. Major metabolites of cannabidiol.

  • References

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    Jump To

    This article references 131 other publications.

    1. 1
      Cannabidiol Market Size Analysis. CBD Industry Growth Report, 2025. https://www.grandviewresearch.com/industry-analysis/cannabidiol-cbd-market (accessed Apr 22, 2020).
    2. 2
      Dorbian, I. CBD Market Could Reach $20 Billion By 2024, Says New Study. Forbes May 20, 2019.
    3. 3
      Nelson, K. M.; Dahlin, J. L.; Bisson, J.; Graham, J.; Pauli, G. F.; Walters, M. A. The Essential Medicinal Chemistry of Curcumin. J. Med. Chem. 2017, 60 (5), 16201637,  DOI: 10.1021/acs.jmedchem.6b00975
    4. 4
      Dietz, B. M.; Chen, S.-N.; Alvarenga, R. F. R.; Dong, H.; Nikolić, D.; Biendl, M.; van Breemen, R. B.; Bolton, J. L.; Pauli, G. F. DESIGNER Extracts as Tools to Balance Estrogenic and Chemopreventive Activities of Botanicals for Women’s Health. J. Nat. Prod. 2017, 80, 22842294,  DOI: 10.1021/acs.jnatprod.7b00284
    5. 5
      Yang, Y.; Zhang, Z.; Li, S.; Ye, X.; Li, X.; He, K. Synergy Effects of Herb Extracts: Pharmacokinetics and Pharmacodynamic Basis. Fitoterapia 2014, 92, 133147,  DOI: 10.1016/j.fitote.2013.10.010
    6. 6
      Caesar, L. K.; Cech, N. B. Synergy and Antagonism in Natural Product Extracts: When 1 + 1 Does Not Equal 2. Nat. Prod. Rep. 2019, 36, 869888,  DOI: 10.1039/C9NP00011A
    7. 7
      Friesen, J. B.; Liu, Y.; Chen, S.-N.; McAlpine, J. B.; Pauli, G. F. Selective Depletion and Enrichment of Constituents in “Curcumin” and Other Curcuma longa Preparations. J. Nat. Prod. 2019, 82, 621630,  DOI: 10.1021/acs.jnatprod.9b00020
    8. 8
      Zuardi, A. W.; Crippa, J. A. S.; Hallak, J. E. C.; Moreira, F. A.; Guimarães, F. S. Cannabidiol, a Cannabis sativa Constituent, as an Antipsychotic Drug. Braz. J. Med. Biol. Res. 2006, 39, 421429,  DOI: 10.1590/S0100-879X2006000400001
    9. 9
      Mogil, J. S. Laboratory Environmental Factors and Pain Behavior: The Relevance of Unknown Unknowns to Reproducibility and Translation. Lab Anim. 2017, 46, 136141,  DOI: 10.1038/laban.1223
    10. 10
      Morrison, G.; Crockett, J.; Blakey, G.; Sommerville, K. A Phase 1, Open-Label, Pharmacokinetic Trial to Investigate Possible Drug-Drug Interactions Between Clobazam, Stiripentol, or Valproate and Cannabidiol in Healthy Subjects. Clin. Pharmacol. Drug Dev. 2019, 8, 10091031,  DOI: 10.1002/cpdd.665
    11. 11
      Ghovanloo, M.-R.; Shuart, N. G.; Mezeyova, J.; Dean, R. A.; Ruben, P. C.; Goodchild, S. J. Inhibitory Effects of Cannabidiol on Voltage-Dependent Sodium Currents. J. Biol. Chem. 2018, 293, 1654616558,  DOI: 10.1074/jbc.RA118.004929
    12. 12
      Watkins, A. R. Cannabinoid Interactions with Ion Channels and Receptors. Channels 2019, 13, 162167,  DOI: 10.1080/19336950.2019.1615824
    13. 13
      Gertsch, J. The Intricate Influence of the Placebo Effect on Medical Cannabis and Cannabinoids. Med. Cannabis Cannabinoids 2018, 1, 6064,  DOI: 10.1159/000489291
    14. 14
      WHO CBD Report May 2018. Cannabidiol (CBD). Critical Review Report. https://www.who.int/medicines/access/controlled-substances/WHOCBDReportMay2018-2.pdf?ua=1 (accessed Oct 25, 2019).
    15. 15
      Millar, S. A.; Stone, N. L.; Yates, A. S.; O’Sullivan, S. E. A Systematic Review on the Pharmacokinetics of Cannabidiol in Humans. Front. Pharmacol. 2018, 9, 1365,  DOI: 10.3389/fphar.2018.01365
    16. 16
      Office of the Commissioner. What to Know About Products Containing Cannabis and CBD. https://www.fda.gov/consumers/consumer-updates/what-you-need-know-and-what-were-working-find-out-about-products-containing-cannabis-or-cannabis (accessed Apr 23, 2020).
    17. 17
      Gaoni, Y.; Mechoulam, R. Hashish—VII: The Isomerization of Cannabidiol to Tetrahydrocannabinols. Tetrahedron 1966, 22, 14811488,  DOI: 10.1016/S0040-4020(01)99446-3
    18. 18
      Gutman, A. L.; Etinger, M.; Fedotev, I.; Khanolkar, R. Methods for Purifying Trans-(−)-Δ9-Tetrahydrocannabinol and Trans-(+)-Δ9-Tetrahydrocannabinol. U.S. Patent 8383842, 2006.
    19. 19
      Aizpurua-Olaizola, O.; Soydaner, U.; Öztürk, E.; Schibano, D.; Simsir, Y.; Navarro, P.; Etxebarria, N.; Usobiaga, A. Evolution of the Cannabinoid and Terpene Content during the Growth of Cannabis sativa Plants from Different Chemotypes. J. Nat. Prod. 2016, 79, 324331,  DOI: 10.1021/acs.jnatprod.5b00949
    20. 20
      Basas-Jaumandreu, J.; de Las Heras, F. X. C. GC-MS Metabolite Profile and Identification of Unusual Homologous Cannabinoids in High Potency Cannabis sativa. Planta Med. 2020, 86, 338347,  DOI: 10.1055/a-1110-1045
    21. 21
      Luo, X.; Reiter, M. A.; d’Espaux, L.; Wong, J.; Denby, C. M.; Lechner, A.; Zhang, Y.; Grzybowski, A. T.; Harth, S.; Lin, W.; Lee, H.; Yu, C.; Shin, J.; Deng, K.; Benites, V. T.; Wang, G.; Baidoo, E. E. K.; Chen, Y.; Dev, I.; Petzold, C. J.; Keasling, J. D. Complete Biosynthesis of Cannabinoids and Their Unnatural Analogues in Yeast. Nature 2019, 567, 123126,  DOI: 10.1038/s41586-019-0978-9
    22. 22
      Kumari, S.; Pundhir, S.; Priya, P.; Jeena, G.; Punetha, A.; Chawla, K.; Firdos Jafaree, Z.; Mondal, S.; Yadav, G. EssOilDB: A Database of Essential Oils Reflecting Terpene Composition and Variability in the Plant Kingdom. Database 2014, 2014, bau120  DOI: 10.1093/database/bau120
    23. 23
      Degenhardt, F.; Stehle, F.; Kayser, O. The Biosynthesis of Cannabinoids. In Handbook of Cannabis and Related Pathologies. Biology, Pharmacology, Diagnosis, and Treatment; Preedy, V. R., Ed.; Elsevier: London, 2017; pp 1323.
    24. 24
      Pauli, G. F.; Chen, S.-N.; Simmler, C.; Lankin, D. C.; Gödecke, T.; Jaki, B. U.; Friesen, J. B.; McAlpine, J. B.; Napolitano, J. G. Importance of Purity Evaluation and the Potential of Quantitative 1H NMR as a Purity Assay. J. Med. Chem. 2014, 57, 92209231,  DOI: 10.1021/jm500734a
    25. 25
      Martin Emanuele, R.; Shattock-Gordon, T.; Williford, T.; Andres, M.; Andres, P. New Solid Forms of Cannabidiol and Uses Thereof. World Intellectual Property Organization. WO 2019118360 A1, 2019.
    26. 26
      Mechoulam, R.; Hanuš, L. Cannabidiol: An Overview of Some Chemical and Pharmacological Aspects. Part I: Chemical Aspects. Chem. Phys. Lipids 2002, 121, 3543,  DOI: 10.1016/S0009-3084(02)00144-5
    27. 27
      Popovic, A.; Morelato, M.; Roux, C.; Beavis, A. Review of the Most Common Chemometric Techniques in Illicit Drug Profiling. Forensic Sci. Int. 2019, 302, 109911,  DOI: 10.1016/j.forsciint.2019.109911
    28. 28
      O’Neil, M. J. The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals; Royal Society of Chemistry: Cambridge, U.K., 2013; 2707.
    29. 29
      Pauli, G. F.; Gödecke, T.; Jaki, B. U.; Lankin, D. C. Quantitative 1H NMR. Development and Potential of an Analytical Method: An Update. J. Nat. Prod. 2012, 75, 834851,  DOI: 10.1021/np200993k
    30. 30
      Hazekamp, A.; Choi, Y. H.; Verpoorte, R. Quantitative Analysis of Cannabinoids from Cannabis sativa Using 1H-NMR. Chem. Pharm. Bull. 2004, 52, 718721,  DOI: 10.1248/cpb.52.718
    31. 31
      Siciliano, C.; Bartella, L.; Mazzotti, F.; Aiello, D.; Napoli, A.; De Luca, P.; Temperini, A. 1H NMR Quantification of Cannabidiol (CBD) in Industrial Products Derived from Cannabis sativa L. (hemp) Seeds - IOPscience. IOP Conf. Ser.: Mater. Sci. Eng. 2019, 572, 012010,  DOI: 10.1088/1757-899X/572/1/012010
    32. 32
      Choules, M. P.; Bisson, J.; Simmler, C.; McAlpine, J. B.; Giancaspro, G.; Bzhelyansky, A.; Niemitz, M.; Pauli, G. F. NMR Reveals an Undeclared Constituent in Custom Synthetic Peptides. J. Pharm. Biomed. Anal. 2020, 178, 112915,  DOI: 10.1016/j.jpba.2019.112915
    33. 33
      Bisson, J.; Simmler, C.; Chen, S.-N.; Friesen, J. B.; Lankin, D. C.; McAlpine, J. B.; Pauli, G. F. Dissemination of Original NMR Data Enhances Reproducibility and Integrity in Chemical Research. Nat. Prod. Rep. 2016, 33, 10281033,  DOI: 10.1039/C6NP00022C
    34. 34
      McAlpine, J. B.; Chen, S.-N.; Kutateladze, A.; MacMillan, J. B.; Appendino, G.; Barison, A.; Beniddir, M. A.; Biavatti, M. W.; Blüml, S.; Boufridi, A.; Butler, M. S.; Capon, R. J.; Choi, Y. H.; Coppage, D.; Crews, P.; Crimmins, M. T.; Csete, M.; Dewapriya, P.; Egan, J. M.; Garson, M. J.; Genta-Jouve, G.; Gerwick, W. H.; Gross, H.; Harper, M. K.; Hermanto, P.; Hook, J. M.; Hunter, L.; Jeannerat, D.; Ji, N.-Y.; Johnson, T. A.; Kingston, D. G. I.; Koshino, H.; Lee, H.-W.; Lewin, G.; Li, J.; Linington, R. G.; Liu, M.; McPhail, K. L.; Molinski, T. F.; Moore, B. S.; Nam, J.-W.; Neupane, R. P.; Niemitz, M.; Nuzillard, J.-M.; Oberlies, N. H.; Ocampos, F. M. M.; Pan, G.; Quinn, R. J.; Reddy, D. S.; Renault, J.-H.; Rivera-Chávez, J.; Robien, W.; Saunders, C. M.; Schmidt, T. J.; Seger, C.; Shen, B.; Steinbeck, C.; Stuppner, H.; Sturm, S.; Taglialatela-Scafati, O.; Tantillo, D. J.; Verpoorte, R.; Wang, B.-G.; Williams, C. M.; Williams, P. G.; Wist, J.; Yue, J.-M.; Zhang, C.; Xu, Z.; Simmler, C.; Lankin, D. C.; Bisson, J.; Pauli, G. F. The Value of Universally Available Raw NMR Data for Transparency, Reproducibility, and Integrity in Natural Product Research. Nat. Prod. Rep. 2019, 36, 35107,  DOI: 10.1039/C7NP00064B
    35. 35
      Choules, M. P.; Klein, L. L.; Lankin, D. C.; McAlpine, J. B.; Cho, S.-H.; Cheng, J.; Lee, H.; Suh, J.-W.; Jaki, B. U.; Franzblau, S. G.; Pauli, G. F. Residual Complexity Does Impact Organic Chemistry and Drug Discovery: The Case of Rufomyazine and Rufomycin. J. Org. Chem. 2018, 83, 66646672,  DOI: 10.1021/acs.joc.8b00988
    36. 36
      Pauli, G. F.; Chen, S.-N.; Friesen, J. B.; McAlpine, J. B.; Jaki, B. U. Analysis and Purification of Bioactive Natural Products: The AnaPurNa Study. J. Nat. Prod. 2012, 75, 12431255,  DOI: 10.1021/np300066q
    37. 37
      Citti, C.; Linciano, P.; Forni, F.; Vandelli, M. A.; Gigli, G.; Laganà, A.; Cannazza, G. Analysis of Impurities of Cannabidiol from Hemp. Isolation, Characterization and Synthesis of Cannabidibutol, the Novel Cannabidiol Butyl Analog. J. Pharm. Biomed. Anal. 2019, 175, 112752,  DOI: 10.1016/j.jpba.2019.06.049
    38. 38
      Freeman, T. P.; Hindocha, C.; Green, S. F.; Bloomfield, M. A. P. Medicinal Use of Cannabis Based Products and Cannabinoids. BMJ. 2019, 365, l1141  DOI: 10.1136/bmj.l1141
    39. 39
      Office of the Commissioner. FDA Regulation of Cannabis and Cannabis-Derived Products: Q&A. https://www.fda.gov/news-events/public-health-focus/fda-regulation-cannabis-and-cannabis-derived-products-including-cannabidiol-cbd (accessed Apr 22, 2020).
    40. 40
      Office of the Commissioner. FDA and Cannabis: Research and Drug Approval Process. https://www.fda.gov/news-events/public-health-focus/fda-and-cannabis-research-and-drug-approval-process (accessed Apr 22, 2020).
    41. 41
      Biosciences, G. EPIDIOLEX (cannabidiol) oral solution, CV prescribing information; revised 12/2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210365lbl.pdf (accessed Dec 19, 2019).
    42. 42
      Office of the Commissioner. Warning Letters and Test Results for Cannabidiol-Related Products. https://www.fda.gov/news-events/public-health-focus/warning-letters-and-test-results-cannabidiol-related-products (accessed Apr 27, 2020).
    43. 43
      Jacob, A.; Todd, A. R. 119. Cannabis Indica. Part II. Isolation of Cannabidiol from Egyptian Hashish. Observations on the Structure of Cannabinol. J. Chem. Soc. 1940, 649653,  DOI: 10.1039/jr9400000649
    44. 44
      Adams, R.; Baker, B. R.; Wearn, R. B. Structure of Cannabinol. III. Synthesis of Cannabinol, 1-Hydroxy-3-N-Amyl-6,6,9-Trimethyl-6-dibenzopyran1. J. Am. Chem. Soc. 1940, 62, 22042207,  DOI: 10.1021/ja01865a083
    45. 45
      Jones, P. G.; Falvello, L.; Kennard, O.; Sheldrick, G. M.; Mechoulam, R. Cannabidiol. Acta Crystallogr., Sect. B: Struct. Crystallogr. Cryst. Chem. 1977, 33, 32113214,  DOI: 10.1107/S0567740877010577
    46. 46
      Pacifici, R.; Marchei, E.; Salvatore, F.; Guandalini, L.; Busardò, F. P.; Pichini, S. Evaluation of Cannabinoids Concentration and Stability in Standardized Preparations of Cannabis Tea and Cannabis Oil by Ultra-High Performance Liquid Chromatography Tandem Mass Spectrometry. Clin. Chem. Lab. Med. 2017, 55, 15551563,  DOI: 10.1515/cclm-2016-1060
    47. 47
      Watanabe, K.; Usami, N.; Yamamoto, I.; Yoshimura, H. Inhibitory Effect of Cannabidiol Hydroxy-Quinone, an Oxidative Product of Cannabidiol, on the Hepatic Microsomal Drug-Metabolizing Enzymes of Mice. J. Pharmacobio-Dyn. 1991, 14, 421427,  DOI: 10.1248/bpb1978.14.421
    48. 48
      Webster, G. R. B.; Sarna, L. P.; Mechoulam, R. Conversion of CBD to Delta8-THC and Delta9-THC. United States Patent 2004/0143126 A1, 2004.
    49. 49
      Merrick, J.; Lane, B.; Sebree, T.; Yaksh, T.; O’Neill, C.; Banks, S. L. Identification of Psychoactive Degradants of Cannabidiol in Simulated Gastric and Physiological Fluid. Cannabis Cannabinoid Res. 2016, 1, 102112,  DOI: 10.1089/can.2015.0004
    50. 50
      Nahler, G.; Grotenhermen, F.; Zuardi, A. W.; Crippa, J. A. S. A Conversion of Oral Cannabidiol to Delta9-Tetrahydrocannabinol Seems Not to Occur in Humans. Cannabis Cannabinoid Res. 2017, 2, 8186,  DOI: 10.1089/can.2017.0009
    51. 51
      Watanabe, K.; Itokawa, Y.; Yamaori, S.; Funahashi, T.; Kimura, T.; Kaji, T.; Usami, N.; Yamamoto, I. Conversion of Cannabidiol to Δ9-Tetrahydrocannabinol and Related Cannabinoids in Artificial Gastric Juice, and Their Pharmacological Effects in Mice. Forensic Toxicol. 2007, 25, 1621,  DOI: 10.1007/s11419-007-0021-y
    52. 52
      Grotenhermen, F.; Russo, E.; Zuardi, A. W. Even High Doses of Oral Cannabidiol Do Not Cause THC-Like Effects in Humans: Comment on Merrick et al. Cannabis and Cannabinoid Research 2016; 1(1): 102–112; DOI: 10.1089/can.2015.0004. Cannabis Cannabinoid Res. 2017, 2, 14,  DOI: 10.1089/can.2016.0036
    53. 53
      Lachenmeier, D. W.; Habel, S.; Fischer, B.; Herbi, F.; Zerbe, Y.; Bock, V.; Rajcic de Rezende, T.; Walch, S. G.; Sproll, C. Are Side Effects of Cannabidiol (CBD) Products Caused by Tetrahydrocannabinol (THC) Contamination?. F1000Research 2019, 8, 1394,  DOI: 10.12688/f1000research.19931.3
    54. 54
      Mascal, M.; Hafezi, N.; Wang, D.; Hu, Y.; Serra, G.; Dallas, M. L.; Spencer, J. P. E. Synthetic, Non-Intoxicating 8,9-Dihydrocannabidiol for the Mitigation of Seizures. Sci. Rep. 2019, 9, 7778,  DOI: 10.1038/s41598-019-44056-y
    55. 55
      Ben-Shabat, S.; Hanus, L. O.; Katzavian, G.; Gallily, R. New Cannabidiol Derivatives: Synthesis, Binding to Cannabinoid Receptor, and Evaluation of Their Antiinflammatory Activity. J. Med. Chem. 2006, 49, 11131117,  DOI: 10.1021/jm050709m
    56. 56
      Bisogno, T.; Hanus, L.; De Petrocellis, L.; Tchilibon, S.; Ponde, D. E.; Brandi, I.; Moriello, A. S.; Davis, J. B.; Mechoulam, R.; Di Marzo, V. Molecular Targets for Cannabidiol and Its Synthetic Analogues: Effect on Vanilloid VR1 Receptors and on the Cellular Uptake and Enzymatic Hydrolysis of Anandamide. Br. J. Pharmacol. 2001, 134, 845852,  DOI: 10.1038/sj.bjp.0704327
    57. 57
      Hanus, L. O.; Tchilibon, S.; Ponde, D. E.; Breuer, A.; Fride, E.; Mechoulam, R. Enantiomeric Cannabidiol Derivatives: Synthesis and Binding to Cannabinoid Receptors. Org. Biomol. Chem. 2005, 3 (6), 11161123,  DOI: 10.1039/b416943c