Priority Considerations for Medicinal Cannabis-Related Research

Introduction and Rationale

The National Academy of Sciences, Engineering, and Medicine’s 2017 publication The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research provided a significant contribution by synthesizing the existing evidence base for the therapeutic use of cannabinoids. With the tremendous interest and early data surrounding cannabinoid therapeutics, what remains is a strong need for systematic guidance regarding research priorities and future directions within this space.

This document focuses on priority areas for medicinal cannabis-related research. The authors, an international group of cannabis experts, have compiled this list, based on their extensive cannabinoid research experience. For clinicians to have confidence in recommending medicinal cannabis, anecdotal reports, however extensive and/or remarkable, are not sufficient. Evidence-based research is required.

This white paper provides an overview of current research gaps, while offering recommendations for studies that may serve to advance existing science within each area. In compiling this list of research recommendations, extensive reviews of the existing evidence (both basic and clinical) were conducted for the following conditions: Alzheimer’s disease and other dementias, amyotrophic lateral sclerosis, autism spectrum disorder, cancer, depression/anxiety/posttraumatic stress disorder, epilepsy, glaucoma, hepatitis and other liver disorders, HIV/AIDS, Huntington’s disease, inflammatory bowel disease, multiple sclerosis, muscular dystrophy, nausea, pain, Parkinson’s disease, schizophrenia and other psychoses, and sickle cell disease. This list was compiled based on the legislative actions of various U.S. jurisdictions in enacting medicinal cannabis laws.

In the review of the above-noted conditions, a number of common themes emerged that both highlighted existing gaps in the literature and pointed to important future directions. Rather than focus on each disease/disorder, we chose to focus this review on the overarching themes that were observed across the literature. Each section that follows was authored primarily by one or two of the authors who have particular expertise in the pertinent space.

Research Consideration #1: Routes of Administration

The pharmacokinetics (absorption, distribution, metabolism, and elimination) of a drug—in this case, cannabis—administered as pharmacotherapy or for recreational use varies significantly as a function of the route of administration. These pharmacokinetic differences influence the onset, peak, and duration of effects (also known as cannabinoid pharmacodynamics). These characteristics can help determine whether the drug dose delivers the expected/desired effect, the occurrence of adverse side effects, and interactions with other drugs or medications. Brief descriptions of cannabinoid pharmacokinetics and pharmacodynamics are described below for the variety of methods in which cannabinoids are administered.

References

^1.Wall ME, Perez-Reyes M. The metabolism of delta 9-tetrahydrocannabinol and related cannabinoids in man. J Clin Pharmacol. 1981;21:178S–189S.

^2.Hunt CA, Jones RT. Tolerance and disposition of tetrahydrocannabinol in man. J Pharmacol Exp Ther. 1980;215:35–44.

^3.Agurell S, Halldin M, Lindgren JE, et al. Pharmacokinetics and metabolism of delta 1-tetrahydrocannabinol and other cannabinoids with emphasis on man. Pharmacol Rev. 1986;38:21–43.

^4.Kelly P, Jones RT. Metabolism of THC in frequent and infrequent marijuana users. J Anal Toxicol. 1992;16:228–235.

^5.Huestis MA, Henningfield JE, Cone EJ. Blood cannabinoids: absorption of THC and formation of 11-OH-THC and THCCOOH during and after smoking marijuana. J Anal Toxicol. 1992;16:276–282.

^6.Newmeyer MN, Swortwood MJ, Barnes AJ, et al. Free and glucuronide whole blood cannabinoids’ pharmacokinetics after controlled smoked, vaporized, and oral cannabis administration in frequent and occasional cannabis users: identification of recent cannabis intake. Clin Chem. 2016;62:1579–1592.

^7.Bergamaschi MM, Karschner EL, Goodwin RS, et al. Impact of prolonged cannabinoid excretion in chronic daily cannabis smokers’ blood on per se drugged driving laws. Clin Chem. 2013;59:519–526.

^8.Rosenberg EC, Patra PH, Whalley BJ. Therapeutic effects of cannabinoids in animal models of seizures, epilepsy, epileptogenesis, and epilepsy-related neuroprotection. Epilepsy Behav. 2017;70:319–327.

^9.Johansson E, Halldin MM, Agurell S, et al. Terminal elimination plasma half-life of delta 1-tetrahydrocannabinol (delta 1-THC) in heavy users of marijuana. Eur J Clin Pharmacol. 1989;37:273–277.

^10.Abrams DI, Vizoso HP, Shade SB, et al. Vaporization as a smokeless cannabis delivery system: a pilot study. Clin Pharmacol Ther. 2007;82:572–578.

^11.Vandrey R, Herrmann, ES, Mitchell JM, et al. Pharmacokinetic profile of oral cannabis in humans: blood and oral fluid disposition and relation to pharmacodynamic outcomes. J Anal Toxicol. 2017;41:83–99.

^12.Karschner EL, Darwin WD, Goodwin RS, et al. Plasma cannabinoid pharmacokinetics following controlled oral Δ9-tetrahydrocannabinol and oromucosal cannabis extract administration. Clin Chem. 2011;57:166–175.

^13.Stinchcomb AL, Valiveti S, Hammell DC, et al. Human skin permeation of delta8-tetrahydrocannabinol, cannabidiol and cannabinol. J Pharm Pharmacol. 2004;56:291–297.

^14.Valiveti S, Hammell DC, Earles DC, et al. In vitro/in vivo correlation studies for transdermal delt8-THC development. J Pharm Sci. 2004;93:1154–1164.

^15.ElSohly MA, Stanford DF, Harland EC, et al. Rectal bioavailability of Δ9-tetrahydrocannabinol from the hemisuccinate ester in monkeys. J Pharm Sci. 1991;80:942–945.

^16.ElSohly MA, Little TL, Jr., Hikal A, et al. Rectal bioavailability of Δ9-tetrahydrocannabinol from various esters. Pharmacol Biochem Behav. 1991;40:497–502.

^17.Mattes RD, Shaw LM, Edling-Owens J, et al. Bypassing the first-pass effect for the therapeutic use of cannabinoids. Pharmacol Biochem Behav. 1993;44:745–747.

^18.Mattes RD, Engelman K, Shaw LM, et al. Cannabinoids and appetite stimulation. Pharmacol Biochem Behav. 1994;49:187–195.

^19.Brenneisen R, Egli A, Elsohly MA et al. The effect of orally and rectally administered delta 9-tetrahydrocannabinol on spasticity: a pilot study with 2 patients. Int J Clin Pharmacol Ther. 1996;34:446–452.

^20.Greenwich Biosciences. Epidiolex, full prescribing information. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210365lbl.pdf (last accessed March 12, 2019).

^21.Paton WDM, Pertwee RG. Effect of cannabis and certain of its constituents on pentobarbitone sleeping time and phenazone metabolism. Br J Pharmacol. 1972;44:250–261.

^22.Devinsky O, Cilio MR, Cross H. et al. Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia. 2014;55:791–802.

^23.Pertwee RG. Cannabinoid pharmacology: the first 66 years. Br J Pharmacol. 2006;147 Suppl.1:S163–S171.

^24.Zuardi A.W. Cannabidiol: from an inactive cannabinoid to a drug with wide spectrum of action. Braz J Psychiatry. 2008;30:271–280.

Research Consideration #2: Cannabinoid Concentrations

It is neither easy nor simple to describe the effects of cannabis. Each patient is an individual, and the concentrations of cannabinoids providing relief to one patient are not necessarily helpful to another. The many known compounds in cannabis that can exert differing biodynamic actions in the human body include (at last count) 262 terpenes, 120 cannabinoids, 62 ferments, 58 polyphenols, 58 steroids, 49 flavonoid glycosides, 27 amino acids and peptides, 26 metals and elements, 19 flavonoids, 17 vitamins, and 14 spirans. We lack detailed studies concerning interactions among these substances.^1–3 Recently, ∼100 additional cannabinoid compounds, mostly cannabinoid acids, have been identified, which could constitute yet another set of compounds with medicinal potential.^4,5 In addition, selective breeding can be used to generate cannabis chemotypes (sometimes called chemovars) that overexpress certain compounds or groups of compounds that are believed to be associated with desired pharmacodynamic effects.

Synergistic pharmacological interactions among the components of cannabis—one definition of the entourage effect—can certainly exist, although this concept has been largely overinterpreted, both in its original meaning (i.e., endocannabinoid-like molecules modulate the biological activity of endocannabinoids) and especially upon extrapolation to the plant (i.e., non-THC cannabinoids and terpenes modulate the therapeutic activity of THC). We do not have much good empirical data on this topic and need more, which should come from a combination of pre-clinical studies evaluating binding assays of different combinations of cannabinoids to see whether they displace each other or otherwise alter pharmacology of one another, to evaluate dose effects on pharmacology, to look at behavioral effects of cannabinoid interactions as well as THC-terpenoid interactions, and finally to perform comparative behavioral pharmacology studies in humans with isolated compounds as well as with boutique chemovars (chemically distinct plant entities with minor genetic and epigenetic changes with little or no effect on morphology or anatomy) to empirically test these entourage hypotheses.^6,7

Most of the classical therapeutic activities of (THC-rich) cannabis extracts in the mammalian body (except for some restricted CBD-driven effects such as inhibition of seizures and psychoses) are conceivably due to the THC-evoked activation of CB₁ receptors.^8–12 These include, for example, inhibition of nausea and vomiting, stimulation of appetite, attenuation of cachexia/energy expenditure, analgesia, and reduction of spasticity. Nonetheless, the notion that CBD may make cannabis extracts safer is becoming widely accepted, and so, THC/CBD balanced preparations could have a wider therapeutic window than high-THC/low-CBD preparations.¹³ The use of cannabis that does not contain CBD^14,15 may cause acute psychotic and anxiety episodes,¹⁶ which is why CBD can be a valuable modulator of THC-potent agents.¹⁷

CBD could conceivably modulate the THC effect via a cytochrome p450 3A11 isoform interaction, although the pharmacodynamic process is not known. Does THCV or another phytocannabinoid component impact the activity of THC? These are research priorities.

We do not have enough knowledge concerning interactions and biodynamic effects caused by most cannabinoids, terpenes, and terpenoids.^18,19 We need to further validate the toxicity and potential health risks of terpenes and/or terpenoids. For example, limonene and linalool are prone to oxidation, and behave as dermal allergens.^20,21 Myrcene, limonene, and linalool can generate methacrolein and benzene as degradation products due to their oxidative liability when heated, potentially resulting in dangerous pyrolytic compounds.^22,23

We need to conduct pre-clinical testing with multiple doses of pure compounds alone and in combination and create isobolograms that can inform dose and combination selection for clinical studies based on animal models of disease. Systematically testing THC:CBD ratios in clinical trials is a challenging undertaking. The impact on measured outcomes would likely be small, so very large sample sizes would be needed. As an example, the initial clinical studies of nabiximols resulted in a “compromise” THC:CBD ratio of 1:1. For this product, mean maintenance doses of about 8 sprays (∼22 mg THC and 20 mg CBD) per day have been shown to be effective for neuropathic pain and spasticity indications. Other THC:CBD ratio recommendations have been based on anecdotal reports.²⁴

Another open question is whether the use of whole plant material, plant-based extracts, or synthetic cannabinoids is better for therapeutic treatment. Of course, for isolated pure phytocannabinoids this should not matter (i.e., pure Δ⁹-THC is a unique molecule, with the same stereochemistry whether it is isolated from cannabis or produced in a test tube). Nonetheless, there might be some differences between plant-derived and synthetic cannabinoids. Nabilone, a synthetic THC derivative, has high agonistic potency on cannabinoid CB₁ receptors, a narrow therapeutic window, and erratic digestive absorption. These issues have prevented it from becoming widely accepted, relative to dronabinol, nabiximols, or crude cannabis preparations.

Admixtures of cannabis components originating during synthesis (and optical impurity of the initial products) can have a significant impact on the final product. Studies have found that (+)CBD and its derivatives bind to the cannabinoid receptors. Differences between (+) and (−)CBD have not been pharmacologically defined. If natural (isolated from the plant) or synthetic (−)CBD, as initial products, is used for this synthesis and is not optically pure, synthetic (−)CBD may include small amounts of the (+)isomer that can pharmacologically influence the effect of (−)CBD.^25–27

According to many Internet claims, often based on overinterpreted pre-clinical murine studies, CBD has been touted as a “magic drug.” However, there is limited clinical evidence of CBD’s activity in humans, except for some specific conditions such as pediatric²⁸ and adult²⁹ epilepsies, and to a degree in schizophrenia³⁰ and social anxiety.³¹ Clearly, clinical trials of CBD, including differences in the effects between (−)CBD and (+)CBD, are warranted for a range of medical and psychiatric conditions.

It is difficult to envisage large clinical trials that examine different isolates/extracts/ratios for many different conditions. These are out of reach in terms of money, time, and human resources. Thus, there may be parallel, nonmutually exclusive paths. Clinical trials with isolates could provide data on efficacy and safety, including particular doses, times, and pharmacokinetic (PK) characteristics.

We can follow traditional drug development methods here; start with basic chemistry/characterization, identify candidates based on pharmacology, screen with pre-clinical models of disease, and then carry forward promising candidates (whether single molecules or combinations) to human trials based on pre-clinical data. Additional observational studies of extracts could provide “signs/hints” of whether extracts are better tolerated and/or have higher efficacy than isolates.

References

^1.Hanuš L, Meyer S, Taglialatela-Scafati O, et al. Phytocannabinoids: a unified critical inventory. Nat Prod Rep. 2016;33:1357–1392.

^2.ElSohly MA, Radwan MM, Gul W, et al. Phytochemistry of Cannabis sativa L. Prog Chem Org Nat Prod. 2017;103:1–36.

^3.Radwan MM, Elsohly MA, Slade D, et al. Non-cannabinoid constituents from a high potency Cannabis sativa variety. Phytochemistry. 2008;69:2627–2633.

^4.Lewis MM, Yang Y, Wasilewski E, et al. Chemical profiling of medical cannabis extracts. ACS Omega. 2017;2:6091–6103.

^5.Berman P, Futoran K, Lewitus GM, et al. A new ESI-LC/MS approach for comprehensive metabolic profiling of phytocannabinoids in cannabis. Sci Rep. 2018;8:14280.

^6.Russo EB. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharmacol. 2011;163:1344–1364.

^7.Ilan AB, Gevins A, Coleman M, et al. Neurophysiological and subjective profile of marijuana with varying concentrations of cannabinoids. Behav Pharmacol. 2005;16:487–496.

^8.Karschner EL, Darwin WD, McMahon RP, et al. Subjective and physiological effects after controlled Sativex and oral THC administration. Clin Pharmacol Ther. 2011;89:400–407.

^9.Karschner EL, Darwin WD, Goodwin RS, et al. Plasma cannabinoid pharmacokinetics following controlled oral Δ9-tetrahydrocannabinol and oromucosal cannabis extract administration. Clin Chem. 2011;57:66–75.

^10.Pacher P, Bátkai S, Kunos G. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev. 2006;58:389–462.

^11.Pertwee RG, Howlett AC, Abood ME, et al. International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB₁ and CB₂. Pharmacol Rev. 2010;62:588–631.

^12.Pacher P, Kunos G. Modulating the endocannabinoid system in human health and disease: successes and failures. FEBS J. 2013;280:1918–1943.

^13.Englund A, Freeman TP, Murray RM, et al. Can we make cannabis safer? Lancet Psychiatry. 2017;4:643–648.

^14.Turner CE, Hadley K. Constituents of Cannabis sativa L. II: absence of cannabidiol in an African variant. J Pharm Sci. 1973;62:251–255.

^15.Braut-Boucher F, Cosson L, Paris M. Ecophysiological behavior and biochemical relationships: the genus Cannabis. Herba Hungarica. 1979;18:301–310.

^16.Rottanburg D, Robins AH, Ben-Arie O, et al. Cannabis-associated psychosis with hypomanic features. Lancet. 1982;2:1364–1366.

^17.Schubart CD, Sommer IEC, van Gastel WA, et al. Cannabis with high cannabidiol content is associated with fewer psychotic experiences. Schizophr Res. 2011;130:216–221.

^18.Hazekamp A, Fischedick JT. Cannabis—from cultivar to chemovar. Drug Test Anal. 2012;4:660–667.

^19.Fischedick JT. Identification of terpenoid chemotypes among high (−)-trans-Δ⁹-tetrahydrocannabinol-producing Cannabis sativa L. cultivars. Cannabis Cannabinoid Res. 2017;2:34–47.

^20.Lewis MA, Russo EB, Smith KM. Pharmacological foundations of cannabis chemovars. Planta Med. 2018;84:225–233.

^21.Pinkas A, Gonçalves CL, Aschner M. Neurotoxicity of fragrance compounds: a review. Environ Res. 2017;158:342–349.

^22.Audrain H, Kenward C, Lovell CR, et al. Allergy to oxidized limonene and linalool is frequent in the U.K. Br J Dermatol. 2014;171:292–297.

^23.Meehan-Atrash J, Luo W, Strongin RM. Toxicant formation in dabbing: the Terpene story. ACS Omega. 2017;2:6112−6117.

^24.Reynolds P. Medicinal Cannabis: the evidence. CLEAR Cannabis Law Reform. Norwich, United Kingdom. 2015. Available at https://s3.eu-west-2.amazonaws.com/assets.clear-uk.org/medicinal-cannabis-the-evidence-190416.pdf (last accessed April 15, 2019).

^25.Fride E, Feigin C, Ponde DE, et al. (+)-Cannabidiol analogues which bind cannabinoid receptors but exert peripheral activity only. Eur J Pharmacol. 2004;506:179–188.

^26.Fride E, Ponde D, Breuer A, et al. Peripheral, but not central effects of cannabidiol derivatives: mediation by CB1 and unidentified receptors. Neuropharmacology. 2005;48:1117–1129.

^27.Hanuš L, Tchilibon S, Ponde DE, et al. Enantiomeric cannabidiol derivatives: synthesis and binding to cannabinoid receptors. Org Biomol Chem. 2005;3:1116–1123.

^28.Anderson CL, Evans VF, DeMarse TB, et al. Cannabidiol for the treatment of drug-resistant epilepsy in children: current state of research. J Pediatr Neurol. 2017;15:143–150.

^29.Cunha JM, Carlini EA, Pereira AE, et al. Chronic administration of CBD to healthy volunteers and epileptic patients. Pharmacologia. 1980;21:175–185.

^30.McGuire P, Robson P, Cubala WJ, et al. Cannabidiol (CBD) as an adjunctive therapy in schizophrenia: a multicenter randomized controlled trial. Am J Psychiatry. 2018;175:225–231.

^31.Bergamaschi MM, Queiroz RH, Chagas MH, et al. Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naïve social phobia patients. Neuropsychopharmacology. 2011;36:1219–1226.

Research Consideration #3: Dosing of Cannabis and Cannabinoids

Guidance regarding dosing of cannabis/cannabinoids is a somewhat complex proposition. A drug dose refers to the precise amount of one or more substances to be taken at one time for a desired therapeutic effect. Traditionally in medicine, therapeutic agents, most often singular chemical entities, are developed for a target indication and for specific clinical populations. Through the process of evaluation in clinical trials, target doses that best balance therapeutic efficacy with safety and adverse events are identified. In following this model, the best information on dosing recommendations for cannabinoids is derived from cannabinoid medicines that have been developed through the clinical trial process and have been formally approved as medicine by regulatory bodies such as the U.S. FDA or Health Canada.

For example, the recommended dose of THC as dronabinol for appetite stimulation is 2.5 mg twice daily 1 h before lunch and dinner.¹ For chemotherapy-induced nausea and vomiting, the recommended dronabinol dose is 5 mg/m² 1 to 3 h before chemotherapy and then every 2 to 4 h as needed for a total of four to six doses. Dronabinol is available in 2.5, 5.0, and 10 mg dosage formulations. Nabilone, a synthetic analogue of THC that has increased potency and oral bioavailability compared with dronabinol, is available as a 1 mg capsule in the United States, and as 0.25 and 0.5 mg capsules in Canada, with a recommended dose of 1 or 2 mg twice daily in the treatment of adverse side effects of chemotherapy, but should not exceed 6 mg.²

Nabiximols is a whole cannabis plant extract product that contains both THC and CBD.³ It is delivered as a sublingual oromucosal spray. Each 100 μL spray contains 2.7 mg of THC and 2.5 mg of CBD. The manufacturers suggest that “the number of sprays each day depends on the individual.” It is recommended that sprays should be dosed at least 15 min apart with an average daily dose of 1–12 sprays per day. In a chemotherapy-induced nausea and vomiting trial, 4.6 sprays a day of nabiximols in addition to standard antiemetics improved outcomes more than placebo.⁴ This would be the equivalent of 12.4 mg of THC.

Epidiolex^®, recently approved by the U.S. FDA, is a plant-derived oral CBD preparation that has shown benefit in clinical trials in children with refractory seizure disorders.⁵ The suggested dose in children is 10–20 mg/kg per day. It is recommended to commence at a dose of 2.5 mg/kg per day in two divided doses and increase to tolerance. Other trials of Epidiolex have investigated doses as high as 50 mg/kg daily.^6–9 Earlier CBD studies using preparations other than Epidiolex evaluated doses of 10 mg/kg in Huntington’s disease,⁶ 300 mg in Parkinson’s disease,⁷ 600 mg in social anxiety,⁸ 400–800 mg in schizophrenia,⁹ and 400–800 mg in opiate addiction,¹⁰ but insufficient research has been conducted to establish specific dose recommendations for these health conditions.

The dosing of botanical cannabis is less clear, in large part, due to the variability in the chemical constituency of the plant and resultant products and variation based on different routes of administration.¹¹ Picking appropriate dosing has also been complicated by the availability of botanical cannabis for both medicinal and nonmedicinal purposes made possible through legislative action rather than through the conduct of traditional clinical trials. With respect to the chemical composition of a botanical cannabis product, the most common characteristics described are the THC and CBD content, often provided as a % of the whole product for raw plant material or highly concentrated extracts (e.g., wax, shatter), as mg per dose for “edibles,” and as mg/mL for liquid solutions (aka tinctures).

For raw botanical products, it is important to note that the % THC or CBD concentration simply refers to the concentration of drug in that matrix, but the dose is determined by the amount that is consumed and the method of consumption. For example, a person who inhales a 100 mL puff of smoked cannabis containing 5% THC receives the same THC dose as someone who inhales a 25 mL puff of smoked cannabis that has 20% THC. However, in this scenario, the dose of substances other than THC is likely to be different, and there are hundreds of known chemical constituents in the cannabis plant that have been hypothesized to modulate the effects of one another (i.e., the so-called entourage effect¹²). In another scenario, if two individuals inhale 100 mL puffs from the same cannabis, but one smokes and the other uses a vaporizer, the smoker will get a smaller THC dose because some of the THC will be lost during combustion.¹³

Several studies of botanical cannabis have been conducted to evaluate the therapeutic potential for a variety of health conditions, but the evaluation of cannabis to alleviate pain has been predominant.^14–17 Much of this research was done in laboratory studies in the United States using cannabis obtained from the National Institute on Drug Abuse (NIDA). The THC content of cannabis assayed in these trials ranged from 1.7% to 6% THC (equivalent to 17–60 mg of THC per 1 g cannabis cigarette). Canadian studies have used herbal cannabis products containing 9.4% to 12.5% THC. These studies have consistently demonstrated that cannabis can reduce neuropathic pain.^18–21 No clinical studies have explored the role of CBD in pain conditions.

Interestingly, variations in the potency of cannabis did not always produce variation in outcomes. In fact, in animal models, THC has been shown to have a biphasic effect, such as being anxiolytic in low dose and anxiogenic in higher concentrations.²² In addition, research has shown that cannabis users will adjust the manner in which they smoke cannabis (e.g., depth or intensity of puffing) to compensate for differences in the potency of different varieties of cannabis as a means of titrating THC dose.^13,23

The State of Colorado was the first to establish 10 mg THC as a “unit dose” for oral cannabis products not intended for medicinal use.²⁴ In controlled scientific studies, this dose of THC has been associated with discriminable and predominantly pleasant drug effects, with little impairment via oral and smoked routes of administration. However, the same dose via vaporization or doses of 25 mg THC or higher across other routes of administration have been associated with an increased likelihood of adverse effects such as nausea, dizziness, anxiety, paranoia, and sedation among infrequent cannabis users. This research was limited to cannabis that had a very low level of CBD, which has been hypothesized to mitigate some of the adverse effects of THC.^12,23 CBD is now being increasingly found in chemovars available in dispensaries and for research purposes; thus, the THC-modulating effects of concurrent administration of varying ratios of CBD will likely become clearer in the near future, but for now, no data exist to enable a provider to provide guidance with respect to the best ratio of THC:CBD to treat any health condition or to help reduce the likelihood or severity of unwanted side effects.

The actual THC content of a utilized botanical cannabis product depends on the concentration in the particular chemovar, which can vary considerably. Eighty percent of Israeli cannabis patients are licensed to obtain 20–30 g of cannabis monthly; 4% have allowances up to 150 g a month.²⁵ In Canada, there is no set limit to cannabis authorization, although possession limits are set at 150 g; however, the average amount reported by patients who are registered in the federal access program is less than 1 g daily.²⁶

In starting a naive patient on a cannabis regimen, the current mantra is to “start low and go slow” (despite its grammatical incorrectness!).²³ One might start with a 2.5 mg THC equivalent dose at bedtime to limit adverse events and allow for the development of tolerance. Half that dose might be considered in the very young, the elderly, or people with cardiovascular health problems. Some would even advocate that patients consider starting with even lower doses (e.g., in the increasingly popular “microdosing”²⁷ range) down to as low as 1 mg. Ultimately, however, there is considerable individual variability in response to cannabis, and the “right” dose for a given individual at any one time will be dependent on his or her use history and the intent for the use at that moment.

To discuss optimal dosing of cannabis is akin to trying to describe the treatment of cancer. Just as there are hundreds of different malignancies, all requiring differing treatment interventions, so are there hundreds if not thousands of cannabis chemovars that will all have varying concentrations of cannabinoids and other bioactive chemicals. Hence, it is impossible to define a broadly applicable therapeutic dose of cannabis as these things need to be evaluated using defined and reliable formulations for specific therapeutic conditions. As the botanical is quite safe, the recommended patient-determined titration of dose until the optimal desired effect is the best that can currently be advised for an inhaled product.¹¹

More guidance might be reasonable for orally ingested edibles or tinctures and oils, but again, individual variability in response will preclude the ability to define a one-size-fits-all recommendation. Whether this is an area that is amenable to further research is difficult to assess as there are so many variables and moving parts that the effort seems Sisyphean.

References

^1.Marinol (dronabinol) [package insert]. Abbvie, Inc.: N. Chicago, IL, 2017.

^2.Cesamet (nabilone) [package insert]. Meda Pharmaceuticals: Somerset, NJ, 2013.

^3.Sativex (nabiximols) [Summary of Product Characteristics]. GW Pharmaceuticals plc: Cambridge, United Kingdom, 2015.

^4.Duran M, Perez E, Abanades S, et al. Preliminary efficacy and safety of an oromucosal standardized cannabis extract in chemotherapy-induced nausea and vomiting. Br J Clin Pharmacol. 2010;70:656–663.

^5.Epidiolex (cannabidiol) [prescribing information]. Greenwich Biosciences: Carlsbad, CA, 2018.

^6.Consroe P, Laguna J, Allender J, et al. Controlled clinical trial of cannabidiol in Huntington’s disease. Pharmacol Biochem Behav. 1991;40:701–708.

^7.Chagas MH, Zuardi AW, Tumas V, et al. Effects of cannabidiol in the treatment of patients with Parkinson’s disease: an exploratory double-blind trial. J Psychopharmacol. 2014;28:1088–1098.

^8.Bergamaschi MM, Queiroz RH, Chagas MH, et al. Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naïve social phobia patients. Neuropsychopharmacology. 2011;36:1219–1226.

^9.Leweke FM, Piomelli D, Pahlisch F, et al. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry. 2012;2:e94.

^10.Prud’homme M, Cata R, Jutras-Aswad D. Cannabidiol as an intervention for addictive behaviors: a systematic review of the evidence. Subst Abuse. 2015;33–38.

^11.Carter GT, Weydt P, Kyashna-Tocha M, et al. Medicinal cannabis: rational guidelines for dosing. IDrugs. 2004;7:464–470.

^12.Russo EB. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharmacol. 2011;163:1344–1364.

^13.Abrams DI, Vizoso HP, Shade SB, et al. Vaporization as a smokeless cannabis delivery system: a pilot study. Clin Pharmacol Ther. 2007;82:572–578.

^14.Whiting PF, Wolff RF, Deshpande S, et al. Cannabinoids for medical use: a systematic review and meta-analysis. JAMA. 2015;313:2456–2473.

^15.Nugent SM, Morasco BJ, O’Neil ME, et al. The effects of cannabis among adults with chronic pain and an overview of general harms: a systematic review. Ann Intern Med. 2017;167:319–331.

^16.Häuser W, Petzke F, Fitzcharles MA. Efficacy, tolerability and safety of cannabis-based medicines for chronic pain management—an overview of systematic reviews. Eur J Pain. 2018;22:455–470.

^17.Aviram J, Samuelly-Leichtag G. Efficacy of cannabis-based medicines for pain management: a systematic review and meta-analysis of randomized controlled trials. Pain Physician. 2017;20:E755–E796.

^18.Abrams DI, Jay CA, Shade SB, et al. Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trial. Neurology. 2007;68:515–521.

^19.Ellis RJ, Toperoff W, Vaida F, et al. Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial. Neuropsychopharmacology. 2009;34:672–680.

^20.Ware MA, Wang T, Shapiro S, et al. Smoked cannabis for chronic neuropathic pain: a randomized controlled trial. CMAJ. 2010;182:E694–E701.

^21.Wilsey B, Marcotte T, Deutsch R, et al. Low-dose vaporized cannabis significantly improves neuropathic pain. J Pain. 2013;14:136–148.

^22.Rey AA, Purrio M, Viveros MP, et al. Biphasic effects of cannabinoids in anxiety responses: CB1 and GABA B receptors in the balance of GABAergic and glutamatergic neurotransmission. Neuropsychopharmacology. 2012;37:2624.

^23.MacCallum CA, Russo EB. Practical considerations in medical cannabis administration and dosing. Eur J Intern Med. 2018;49:12–19.

^24.Denver Public Health. Facts about marijuana edibles and your health. 2016. Available at http://denverpublichealth.org/home/health-information-and-reports/fact-sheets/marijuana/marijuana-edibles (last accessed September 1, 2018).

^25.Schleider LB, Mechoulam R, Lederman V, et al. Prospective analysis of safety and efficacy of medical cannabis in large unselected population of patients with cancer. Eur J Intern Med. 2018;49:37–43.

^26.Government of Canada. Cannabis market data. 2018. Available at https://www.canada.ca/en/health-canada/services/drugs-medication/cannabis/licensed-producers/market-data.html (last accessed January 7, 2019).

^27.Johnstad PG. Powerful substances in tiny amounts: an interview study of psychedelic microdosing. Nordisk Alkohol Nark. 2018;35:39–51.

Research Consideration #4: Study Design

Research is needed to understand and characterize more fully the properties and potential utility of any drug substance, and cannabis is no different. The methods most appropriate for any given study will depend on the aims of the research. For example, research related to the study of cannabis can include therapeutic drug development, regulatory science, public health evaluation, economic impact, epidemiology, safety versus efficacy, or other issues. Within these broad research categories, research methods have been established to ensure scientific rigor and should be followed. Any research study that involves administration of an experimental drug must include administration of an appropriate control substance (placebo, vehicle, positive control). Furthermore, the use of validated and reliable measures is essential. Here we provide a general overview of research approaches that relate to cannabis and a discussion of relevant research methods with reference to more comprehensive guidelines.

Therapeutic drug development is the cannabis research area for which research methods are best established, and perhaps is of greatest interest at the moment. Governing bodies such as the U.S. Food and Drug Administration, Health Canada, or the European Medicines Agency oversee drug development and have well-defined requirements for establishing the safety and efficacy of a novel therapeutic. Internationally, there is wide agreement on what evidence is needed to approve a new drug for labeling and, thus, a standard approach to drug development research has been established. Initially, this process includes drug discovery, determination of the pharmacology, identification of a target therapeutic use, the conduct of pre-clinical toxicology and pharmacokinetic studies, and evaluation for a signal of therapeutic potential in pre-clinical models of human disease states. If this initial work suggests that a novel therapeutic agent appears safe and has therapeutic promise, then a progression of human clinical trials commences. Drug development with novel cannabinoid molecules would follow this trajectory as is.

Development of botanical cannabis, on the contrary, would be a little different because so much is already known about the toxicology, pharmacokinetics, and safety of cannabis. However, pre-clinical research could not be avoided entirely because, before the initiation of human research, the drug product must be very clearly defined and manufacturing methods must be established that meet regulatory requirements for human administration. Data are needed to demonstrate consistency and stability in the end product within and across multiple batches/lots of product. The route of administration and precision in dose delivery must also be demonstrated. These requirements are where therapeutic development of botanical cannabis poses unique challenges, given its incredibly diverse chemical profile and the heterogeneity in product that typically occurs both within and across harvests of cultivated plants.

Once a drug product has been defined and pre-clinical research conducted, a series of human clinical trials should follow. First, Phase 1 studies are conducted in healthy volunteers to establish the pharmacokinetics and pharmacodynamics of the drug in humans following acute and chronic dose administration. These studies are typically performed with small numbers of research volunteers (usually 8–14 per study), and always include a placebo control. Phase 1 studies can be designed to evaluate the effects of variations in dose, frequency of dosing, or perhaps different formulations of the drug. Phase 1 studies are used to define the bioavailability of the drug, type and time course of drug effects, and identification of potential adverse effects. Thus, end-points usually include the measurement of the drug and metabolites in blood/plasma, subjective drug effects, cardiovascular effects, and adverse events. These data are then used to inform dosing conditions for Phase 2 studies, which are the first studies evaluating the drug in a target clinical population. The primary aim of Phase 2 studies is to determine whether the drug is both safe and has the intended therapeutic effect in individuals who have a defined health condition for which the drug is believed to produce therapeutic benefit. In Phase 2 studies, a primary therapeutic end-point and relevant secondary end-points must be defined before study initiation, and sample sizes are calculated to determine how many people are needed to participate to detect a clinically meaningful effect on those outcomes.

Phase 2 studies typically include multiple dose regimens (vary in amount and/or frequency of drug administration) to identify the dosing scheme that maximizes clinical benefit while minimizing the frequency and/or severity of adverse effects. If a Phase 2 study demonstrates the drug results in significant improvement on clinically important end-points compared with placebo, then Phase 3 trials are initiated.

Phase 3 trials are required to demonstrate the safety and efficacy of a drug in large clinical populations that vary in sex, age, geographic location, and other important demographic characteristics, as appropriate, based on the target clinical indication. If there are other approved medications for the target clinical indication, Phase 3 studies often will include a direct comparison of the novel drug with the established standard of care. Typically, at this stage of development, a single dosing regimen was identified during Phase 2, but in some cases, two dose regimens may be evaluated in Phase 3 to better understand risk versus benefit in a larger population.

In parallel with Phase 3 trials, development of cannabis or any cannabinoid medication will also require a separate abuse liability evaluation. These studies involve administration of therapeutic and supratherapeutic doses of the agent being studied to individuals who currently use other drugs with known abuse liability for nonmedicinal purposes. Important end-points for abuse liability testing are subjective ratings of drug liking, willingness to take it again, valuation of the drug by the study participants, and self-administration behavior. If significant therapeutic benefit of the drug is demonstrated, and shown to outweigh the potential risks of use, then a drug may be submitted to the appropriate regulatory authorities for marketing approval. Outcomes of the abuse liability study will be used to determine regulatory restrictions placed on the drug if approved.

With all of that said, we now must address the fact that cannabis has been legislatively approved for both medicinal and nonmedicinal use widely. This has happened in the absence of much of the required research just described. Because of this, research on the safety and efficacy of cannabis at the patient level remains needed, but can be obtained via other methods. One approach is to conduct observational studies. Often referred to as Phase 4 or postmarketing surveillance research, observational studies do not include placebo groups, but rather record health-related and other specific information about individuals using a drug. In this case, individuals using cannabis can be recruited to provide information about the cannabis products they use and validated health outcome assessments are obtained.

The impact of cannabis use in observational research can be enhanced by comparing cannabis users to individuals who do not use cannabis but are similar to the cannabis users with respect to demographic and relevant health characteristics and/or by evaluating the same individual over time and obtaining assessments during periods when cannabis is used and not used. It is also possible to obtain this type of data by evaluating patient medical records. The challenge of this approach is that medical records often do not include data on cannabis use due to it being an illicit drug historically, and when information on cannabis use is included, the requisite details needed to determine cannabis product type, dose, route of administration, and frequency of use are likely not provided.

In parallel to observational research on the impact of cannabis use at the patient level, public health research is needed to evaluate the impact of cannabis use at the population level. Public health and economic research relies on the collection of important data from large, representative samples of individuals in a defined geographic region. These data sets include national surveys and records of public health (across a number of domains), health care utilization, socioeconomic status, workplace and motor vehicle accidents, crime, community health and resources, unemployment, education, and measures of industry health and economics. These data sets are typically available either publicly or by request. Advanced training in biostatistics and/or economics is required to appropriately evaluate outcomes from these data. With the appropriate expertise, these data sets can yield highly important information about the impact of cannabis legalization and/or use on key public health and economic indicators.

A related and equally important area of research needed on cannabis and cannabinoids is regulatory science. Research here encompasses a variety of disciplines and methods. Due to this, we are unable to go into extensive detail on methodology for each topic, but rather highlight key needs and identify the relevant disciplines from which expertise is needed. First, analytical chemistry research is needed to establish standard methods for product test methods. Currently, testing of cannabis products varies and research has not been conducted to determine the validity and reliability of test methods being utilized. Plant science and toxicological research is needed to establish standards for the use of chemicals in cannabis cultivation and processing (e.g., pesticides, solvents). Pre-clinical and human behavioral pharmacology studies are needed to better understand the effects of individual chemical components of the cannabis plant and their interactions, as well as differences in use across various routes of administration and types of delivery devices. Behavioral and social science research is needed to establish regulations for cannabis product marketing, including both advertising and product labeling, to minimize cannabis misuse and harm.

Behavioral and toxicological research is needed to develop methods of reliably detecting whether an individual is acutely impaired. This is critical for enforcement of driving under the influence laws, maintaining safe workplaces and determining culpability in other accidents or criminal activity as there currently is no method for differentiating individuals who use cannabis in responsible versus irresponsible ways in situations where impairment poses a public health risk. Indeed, the research needs with respect to cannabis regulatory science reach far and wide, extend beyond the key areas broadly highlighted here, and deserve urgent attention.

Of note, the conduct of all of the studies described must be done in accordance with established international regulations for research. This includes both pre-clinical and clinical research. For reference, regulations for the responsible conduct of research with animals are provided here,^1,2 and guidance for human research is provided here.^3,4 A summary of additional guidance and regulations regarding the conduct of clinical trials for therapeutic drug development can be found here.^5–7 Approval from local regulatory agencies and ethics review boards must also be obtained before initiating any research studies involving living beings or identifiable personal health information. For those considering therapeutic development of cannabis, guidance on botanical drug development can be found here⁸ (FDA botanical guidelines).

References

^1.Office of Laboratory Animal Welfare, National Institutes of Health. PHS policy on humane care and use of laboratory animals. 2015. Available at https://olaw.nih.gov/policies-laws/phs-policy.htm (last accessed October 30, 2018).

^2.United States Department of Agriculture Animal Care. Animal welfare act and animal welfare regulations. 2017. Available at https://www.aphis.usda.gov/animal_welfare/downloads/AC_BlueBook_AWA_FINAL_2017_508comp.pdf (last accessed October 30, 2018).

^3.World Medical Association. WMA declaration of Helsinki-ethical principles for medical research involving human subjects. Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 and amended by the 64th WMA General Assembly, Fortaleza, Brazil, October 2013. Available at https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/ (last accessed October 30, 2018).

^4.Office of the Secretary, Department of Health, Education, and Welfare. Ethical Principles and Guidelines for the Protection of Human Subjects of Research. The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The Belmont Report. April 18, 1979. Available at https://www.hhs.gov/ohrp/sites/default/files/the-belmont-report-508c_FINAL.pdf (last accessed October 30, 2018).

^5.International Conference for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. ICH Guidelines. Available at https://www.ich.org/products/guidelines.html (last accessed October 30, 2018).

^6.European Medicines Agency. Clinical trials regulation. Available at https://www.ema.europa.eu/en/human-regulatory/research-development/clinical-trials/clinical-trial-regulation (last accessed August 6, 2019).

^7.United States Food and Drug Administration. Regulations: good clinical practice and clinical trials. 2018. Available at https://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/ucm155713.htm (last accessed October 30, 2018).

^8.U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Botanical Drug Development: Guidance for Industry. December 2016. Available at https://www.fda.gov/downloads/Drugs/Guidances/UCM458484.pdf (last accessed October 30, 2018).

Research Consideration #5: Long-Term Effects

Proponents of medical cannabis see its widespread acceptance as welcome news that is long overdue. At the same time, its opponents cringe at the risks that will be unleashed on an unsuspecting public. As more people use cannabis, the stakes of legalization are increasing rapidly. Every day, there are more people using medicinal cannabis to treat a wide variety of ailments and symptoms that include pain, anxiety, nausea, insomnia, posttraumatic stress disorder (PTSD), and depression. If cannabis is therapeutically effective, these patients are benefiting. However, if not, millions of patients are wasting their time, their money, and being exposed to health risks unnecessarily.

For some symptoms, there is good evidence that medical cannabis is effective. However, for many symptoms and conditions, an adequate evidence base does not exist yet. We also know very little about the long-term risks of medical cannabis. Virtually all published studies about cannabis’s risks, ranging from heart disease to schizophrenia, have been conducted in people using cannabis recreationally. Those people may use in very large amounts, over long periods of time. They may also combine cannabis with other drugs such as heroin and cocaine, in ways that most medical users do not. Thus, it is difficult to generalize observations of harms in that population to, say, someone who uses a square of cannabis-infused chocolate to sleep at night.

When most of us decide to use a medication, we do so with a good sense of its risks and potential benefits. We know what it is likely to do for us, and we are aware of what it might do to us. However, most people using medicinal cannabis now are doing so without enough knowledge to make informed decisions, because we just do not have the data.

The thin evidence base for cannabis has led to calls for more randomized controlled trials, and it is true that more high-quality trials are needed. However, those trials will take time, and we cannot afford to wait for evidence about its risks and potential benefits. People are using medicinal cannabis today, and we need more data, now.

Therefore, in addition to more—and better—randomized controlled trials, we need to further explore ways of crowdsourcing the science of medicinal cannabis. That is, we need to learn from people who are using medicinal cannabis today, and who could be teaching us about what it is doing for them, and to them. Specifically, we need registries that collect the experiences of large numbers of patients, as they use cannabis in real-world ways, over long periods of time. There are at least four ways that crowdsourced data could help to answer clinically important questions about medicinal cannabis.

First, crowdsourcing data are arguably the best way to provide long-term information about the benefits and safety of cannabis. Clinical trials in this field will likely never be large enough—or well funded enough—to follow patients for years. Longitudinal data about safety and efficacy will need to come from registries. In those studies, we will need to examine both well-understood risks, such as addiction and dependence, and suspected risks such as myocardial infarction, stroke, and schizophrenia. In particular, longitudinal registries are the only way to reliably identify risks that are rare and therefore are unlikely to be detected in small clinical trials that enroll a few dozen people.

The long-term longitudinal studies that registries make possible can also provide valuable insights into patterns of use and the susceptibility of symptoms over time. For instance, these sorts of data can help to define symptom rebound after prolonged use. Again, short-term randomized controlled trials are ill suited to answer such questions.

Third, large sample sizes of diverse patients in a registry are needed to answer pressing questions about interactions between cannabinoids and medications, as many patients are taking multiple medications, in varying combinations and at several doses. Large samples are needed for an analysis that can tease out side effects, interactions, and risk factors.

Registry data can shed light on the relative benefits of the wide variety of ways that cannabis is used in real-world settings. For a given indication, patients might use varying combinations of cannabinoids, at different doses, by several routes of administration. Characterizing and testing each of those in a randomized controlled trial would be prohibitively time-consuming, and expensive. However, insights can be obtained, with a reasonable degree of accuracy, with the crowdsourced data that come from registries.

Although they are no substitutes for randomized controlled trials, registries are nevertheless a quick way of figuring out what types of trials we should be doing. They can tell us which symptoms might respond, and which doses might be effective. These data can also give us hints of risks that might exist.

An additional research methodology that is pertinent to this space is the open-label extension of randomized trials. Open-label extension studies typically follow a double-blind, randomized, placebo-controlled trial of a new drug. At the end of the double-blind phase, participants are invited to enroll in an extension study. The study will normally be longer than the randomized trial and often extends for a year or longer. All participants in the extension study are given the study drug, and both they and the investigators are unblinded to drug and dose. The objective is primarily to gather information about the safety and tolerability of the new drug in long-term, day-to-day use. In cannabis studies, the regulatory approval of this approach would have to be negotiated with the appropriate oversight agencies, but this “approximation” of real-world use could be valuable in adding to the evidence basis for cannabis/cannabinoid use.

At present, people are utilizing a wide variety of cannabis formulations for a multitude of medical indications. Sometimes it will work, and sometimes it will not. And—if we are being honest—sometimes people will think that it works when in fact the effects are driven by a placebo effect.

Nevertheless, we can harness these thousands of little experiments going on every day. We can get a sense of what could work, what might work, and what probably will not work. And—what is probably just as important—we can learn about whether cannabis is safe and what its long-term effects may be on medical conditions and symptoms.

Research Consideration #6: Effects of Drug/Drug Interactions

Knowledge of the pharmacokinetics and metabolism of cannabinoids, particularly THC and to a lesser degree CBD, in humans is fairly well established. However, not much is reported on the human metabolism of the majority of less predominant cannabinoids. The cannabinoids are metabolized by a series of enzymes in the gastrointestinal tract and liver that modify them (and other organic compounds) by adding chemical moieties that allow them to be secreted into the gut or through the urine. There are two main enzymatic systems that process these ingested (or injected, inhaled, etc.) products. These two enzyme structures are classified into Phase I and Phase II systems. Phase I enzymes typically add an oxygen atom to the exogenous organic compound. The cytochrome P450 enzymes (CYP450) are a set of proteins that perform this first step of metabolism. The second phase is performed by a group of enzymes called the uridine-diphosphate glucuronosyltransferases (UGTs). These enzymes typically link a glucuronide molecule to the exogenous structure. This sugar-like molecule allows the body to secrete the cannabinoid into the urine or bile.¹ This process can be inhibited by many different drugs, botanicals, or foods. Many of the cannabinoids modulate the activity of these CYP450 enzymes.

A full understanding of how individual cannabinoids interact with other drugs is vital if cannabis-derived medicinals are to be used more broadly in clinical care. There are good data that the CYP system is vital for metabolism of both CBD and THC.^1,2 Δ-9 THC is metabolized by both CYP1A2 and CYP2C9 into 11-OH-Δ-9-THC and 11-nor-9carbocy-Δ-9-THC and these are then glucuronided by the UGT system.¹ The same metabolic steps clear CBD.¹

There is strong evidence that both CBD and THC inhibit different CYP isoenzymes resulting in effects of metabolism of other medications.^3,4 This is becoming a major issue for treatment of epilepsy, as patients with seizures are typically on multiple pharmacological agents that are metabolized by this system. This will also be an issue for treatment of psychiatric disorders (e.g., anxiety, PTSD) and cancer patients; both groups often are treated with multiple agents for their conditions. While there have been four large Phase 3 trials that have demonstrated efficacy for a purified CBD preparation (Epidiolex-Greenwich Pharma) and strong support of its efficacy from a number of open-label studies^5–8—and in fact, Epidiolex has now received FDA approval—the question of the efficacy of CBD versus its role to lower the metabolism of other antiepileptic drugs continues to be raised.

Data from the Greenwich/GW trial of CBD for Dravet syndrome have provided evidence for alterations of at least one commonly used antiepileptic drug, clobazam.⁹ Clobazam, metabolized by CYP2C19 and CYP3A4, is a novel benzodiazepine with 1–5 side chains on the main benzene ring of the molecule. Two studies^9,10 have demonstrated that there is a substantial increase in both clobazam and N-desmethylclobazam (the active metabolite of clobazam) upon treatment with CBD, although the range of elevation was highly variable (from 0% to 80% increase of clobazam levels to 150–600% increase of N-clobazam levels^9,10) and with unclear relationship to CBD dosing or level, although this was not well analyzed in these articles. In addition, pediatric epilepsy studies utilizing CBD have presented data demonstrating an increase in liver enzymes (particularly aspartate transaminase and alanine transaminase) in patients taking valproic acid, but without comment on change in valproate levels. Clearly, these data demonstrate that there are important interactions between CBD and antiepileptic drugs metabolized by the CYP system, indicating that further study is needed.

There are two questions that the interaction data raise. First, what is the best approach to performing clinical trials with cannabis preparations? Should medications with known interactions be excluded from use during trials or should detailed pharmacokinetic interaction studies be performed? The Epidiolex CBD data do not show a clear 1:1 relationship between increasing clobazam (or N-clobazam) dose and outcome. Many patients were able to be weaned off or decrease the dose of clobazam, while still experiencing good efficacy. This raises the suggestion that the effect of CBD may not be only on metabolism or pharmacokinetics but at the target of the medicine as well. Hence, removing these medications from clinical trials would limit the trials and prevent “real-world” clinical experiences from moving forward. Moving forward with trials that allow all typical concomitant medications into the trial would be prudent, but ensuring that thorough analysis of the drug/drug interactions and genetics of the CYP system is obtained is needed to both understand the potential nuances of the interactions and to potentially predict how any individual would respond.

The second question the interaction data raise relates to the efficacy of cannabis as a stand-alone agent or as an adjuvant to other compounds. Is there a need for THC or CBD to modify the activity of other drugs (or even each other)? Studies that are powered to detect the role of cannabis to be effective as a solo agent or with other drugs are needed. Designing studies that require controlling for these types of factors lead to difficulty in enrolling patients and powering appropriately. Generation of data that support the important interaction and efficacy information needs to be considered when any study is designed.

It is known that foods and other botanicals also can interact with the P450 system. Many people interested in natural remedies are apt to use cannabis products as part of their care plan. These individuals are then also at risk for interactions between pharmaceuticals and botanicals or nutraceuticals that could be dangerous. Studying these interactions would also be important for future trials, particularly ones outside the pharmaceutical realm where these issues will be more likely to be considered.

Overall, there are many therapeutic areas for which cannabis may or may not show efficacy. As studies emerge that report on the dosage and efficacy of cannabis, further studies on the pharmacodynamic interactions between cannabis and other drugs and nutraceuticals are needed. These studies should both measure levels of parent compound and metabolites and how these interact with each other. This field should also appeal to individuals who are interested in pharmacogenomics as correlating polymorphisms in the CYP and UGT system with level of metabolism and interactions between cannabis and drugs could provide a path forward that allows a cleaner and individualized approach to treatments.

References

^1.Huestis MA. Human cannabinoid pharmacokinetics. Chem Biodivers. 2007;4:1770–1804.

^2.Su MK, Seely KA, Moran JH, et al. Metabolism of classical cannabinoids and the synthetic cannabinoid JWH-018. Clin Pharmacol Ther. 2015;97:562–564.

^3.Yamaori S, Okamoto Y, Yamamoto I, et al. Cannabidiol, a major phytocannabinoid, as a potent atypical inhibitor for CYP2D6. Drug Metab Dispos. 2011;39:2049–2056.

^4.Jiang R, Yamaori S, Okamoto Y, et al. Cannabidiol Is a potent inhibitor of the catalytic activity of cytochrome P450 2C19. Drug Metab Pharmacokinet. 2013;28:332–338.

^5.Devinsky O, Cross JH, Laux L, et al. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med. 2017;376:2011–2020.

^6.Devinsky O, Patel AD, Cross JH, et al. Effect of cannabidiol on drop seizures in the Lennox-Gastaut Syndrome. N Engl J Med. 2018;378:1888–1897.

^7.Thiele EA, Marsh ED, French JA, et al. Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2018;391:1085–1096.

^8.Devinsky O, Marsh E, Friedman D, et al. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol. 2016;15:270–278.

^9.Devinsky O, Patel AD, Thiele EA, et al. Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome. Neurology. 2018;90:e1204–e1211.

^10.Geffrey AL, Pollack SF, Bruno PL, et al. Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy. Epilepsia. 2015;56:1246–1251.

Research Consideration #7: Individual Variability in Cannabinoid Effects

Cannabis is a plant of a complex chemical profile with more than 500 identified compounds, of which 120 are cannabinoids.^1,2 Although they have close chemical structures, cannabinoids have different pharmacological effects from other compounds. THC and CBD are the most pharmacologically studied cannabinoids with different biological effects. Moreover, the same dose of cannabinoids affects individuals differently. This individual variability of cannabinoid effects may be attributed to one or more of the following factors: genes, gender, and/or metabolism.

Since the major activity of cannabis (mainly THC-rich) is mediated through the cannabinoid receptors CB1 and CB2, it follows that variability in the genes controlling these receptors in different people would be a factor in the reason for the variability in individual responses to cannabis and cannabinoids. Cannabinoid receptor CB1 variants in drug users have been associated with substance use disorder^3–11 and cannabis dependence (CD).^12,13 Furthermore, the gene controlling the endocannabinoid system enzyme fatty acid amide hydrolase (FAAH) has shown an association with CD phenotypes. FAAH is the enzyme expressed in the brain and liver that inactivates anandamide (an endogenous CB1 agonist). Covault et al. and Filbey et al. studied and characterized the neural mechanisms that underlie the effects of the cannabinoid receptors 1 (CNR1) and FAAH genes on CD.^5,14

Individuals with certain disease conditions such as irritable bowel syndrome (IBS), migraine, and fibromyalgia responded positively to exogenous cannabinoid treatment, possibly due to clinical endocannabinoid deficiency.¹⁵ However, objective proof and clinical data are lacking. Also, high doses of CBD, which elevates the level of anandamide (centrally acting endocannabinoid), were shown to provide significant improvement in schizophrenic patients.¹⁶ This indicates the involvement of the endocannabinoid system and that agents inhibiting anandamide deactivation (such as CBD) are of significant clinical utility.

Many reports indicate that cannabis acts differently in men and women. Frattore and Fratta published a comprehensive review on the importance of sex differences in cannabinoid action in humans and animals.¹⁷ They reported the biological and behavioral differences of cannabinoids between males and females. Females are more susceptible to cannabis abuse and dependence than men, with greater tendency to relapse.¹⁸ Female sex hormones, especially estrogen, may play a role in the CB1 receptor densities.^18–20 Estrogen may modulate the activity of FAAH, which may affect the endocannabinoid activity.²¹ All these are factors that may explain the gender differences in the response to cannabis and cannabinoids. A greater understanding of the mechanistic reasons for these differences will improve the development of sex-specific ways to treat CD and the use of cannabis-based therapeutics.

Perhaps the most obvious reason for individual variability in cannabinoid effects is the metabolic differences among individuals. Fast metabolizers will convert Δ⁹-THC to its inactive metabolite Δ⁹-THC-9-COOH, resulting in low levels of Δ⁹-THC in their circulation. It follows that the higher the circulating Δ⁹-THC or the active metabolite 11-OH-Δ⁹-THC, the higher the psychological effects. Measuring the CYP450 activity might be an important clinical test to define a safe and effective dose of cannabinoid (more for THC than CBD).

The following are areas that need to be explored (Table 1).

References

^1.ElSohly MA, Radwan MM, Gul W, et al. Phytochemistry of Cannabis sativa L. Prog Chem Org Nat Prod. 2017;103:1–36.

^2.Wang M, Wang YH, Avula B, et al. Quantitative determination of cannabinoids in cannabis and cannabis products using ultra-high-performance supercritical fluid chromatography and diode array/mass spectrometric detection. J Forensic Sci. 2017;62:602–611.

^3.Ballon, N, Leroy S, Roy C, et al. (AAt)n repeat in the cannabinoid receptor gene (CNR1): association with cocaine addiction in an African-Caribbean population. Pharmacogenomics J. 2006;6:126–30.

^4.Comings DE, Muhleman D, Gade R, et al. Cannabinoid receptor gene (CNR1): association with i.v. drugs use. Mol Psychiatry. 1997;2:161–168.

^5.Covault J, Gelernter J, Kranzler H. Association study of cannabinoid receptor gene (CNR1) alleles and drug dependence. Mol Psychiatry. 2001;6:501–502.

^6.Herman AI, Kranzler HR, Cubells JF, et al. Association study of the CNR1 gene exon 3 alternative promoter region polymorphisms and substance dependence. Am J Med Genet B Neuropsychiatr Genet. 2006;141B:499–503.

^7.Racz I, Bilkei-Gorzo A, Toth ZE, et al. A critical role for the cannabinoid CB1 receptors in alcohol dependence and stress-stimulated ethanol drinking. J Neurosci. 2003;23:2453–2458.

^8.Schmidt LG, Samochowiec J, Finckh U, et al. Association of a CB1 cannabinoid receptor gene (CNR1) polymorphism with severe alcohol dependence. Drug Alcohol Depend. 2002;65:221–224.

^9.Zhang PW, Ishiguro H, Ohtsuki T, et al. Human cannabinoid receptor 1: 5’exons, candidate regulatory regions, polymorphisms, haplotypes and association with polysubstance abuse. Mol Psychiatry. 2004;9:916–931.

^10.Zuo L, Kranzler HR, Lou X, et al. CNR1 variation modulates risk for drug and alcohol dependence. Biol Psychiatry. 2007;62:616–262.

^11.Zuo L, Kranzler HR, Lou X, et al. Interaction between two independent CNR1 variants increase risk for cocaine dependence in European Americans: a replication study in family-based sample and population-based sample. Neuropsychopharmacology. 2009;34:1504–1513.

^12.Agrawal A, Lynskey MT. Candidate genes for cannabis use disorders: findings, challenges and directions. Addiction. 2009;104:518–532.

^13.Hopfer CJ, Young SE, Purcell S, et al. Cannabis receptor haplotype associated with fewer cannabis dependence symptoms in adolescents. Am J Med Genet B Neuropsychiatr Genet. 2006;141B:895–901.

^14.Filbey, FM, Schacht JP, Myers US, et al. Individual and additive effects of the CNR1 and FAAH genes on brain response to marijuana cues. Neuropsychopharmacology. 2010;35:967–75.

^15.Russo EB. Clinical endocannabinoid deficiency reconsidered: current research supports the theory in migraine, fibromyalgia, irritable bowel, and other treatment-resistant syndromes. Cannabis Cannabinoid Res. 2016;1:154–165.

^16.Leweke, FM, Piomelli D, Pahlisch F, et al. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry. 2012;2:e94.

^17.Fattore L, Fratta W. How important are sex differences in cannabinoid action? Br J Pharmacol. 2010;160:544–548.

^18.Craft, RM, Marusich JA, Wiley JL. Sex differences in cannabinoid pharmacology: a reflection of differences in the endocannabinoid system. Life Sci. 2013;92:476–481.

^19.López HH. Cannabinoid–hormone interactions in the regulation of motivational processes. Horm Behav. 2010;58:100–110.

^20.Cooper ZD, Craft RM. Sex-dependent effects of cannabis and cannabinoids: a translational perspective. Neuropsychopharmacology. 2018;43:34–51.

^21.Lazzarin N, Valensise H, Bari M, et al. Fluctuations of fatty acid amide hydrolase and anandamide levels during the human ovulatory cycle. Gynecol Endocrinol. 2004;18:212–218.

Research Consideration #8: Comparative Efficacy

There are several therapeutic areas where the efficacy of cannabis or cannabinoids has been compared head to head with other agents in randomized controlled trials. These studies are valuable to examine because they offer an insight into the use of other drug products as active controls, and they also allow some perspective on how cannabinoids measure up when tested directly against existing therapies in controlled experimental settings.

A qualitative and limited review of PubMed was conducted using keywords cannab* and (appetite or nausea or pain or sleep or anxiety) and trial. Abstracts in English were searched for comparative trials. Only studies of therapeutic efficacy were included (e.g., treatment of cannabis use disorder was excluded). Only studies using clinically available cannabinoids were included (e.g., levonantradol was excluded). No attempt was made to identify unpublished data.

The conditions for which comparative studies of cannabinoids have been conducted include pain, sleep, nausea, appetite, and asthma. The studies dated from as early as 1979.

Conclusion

The purpose of this short review was to explore the comparative efficacy of cannabinoids with other conventional therapies, and we have found that historically, some cannabinoids have been compared with a wide range of drugs in head-to-head trials. The studies were generally small, making it hard to draw strong conclusions about the relative efficacy of cannabinoids. We only focused on trials where cannabinoids have been directly compared with other conventional therapies, as opposed to extrapolating data from cannabinoid-only trials and comparing effect sizes with other medications. This would be a very complex undertaking.

While comparative work has been conducted for nausea, for example, in patients undergoing cancer chemotherapy—showing that cannabis can help with nausea equal to or better than older antiemetics—newer antiemetics may be more effective. Clinicians considering cannabinoid therapy expect to understand whether the efficacy is better than standard pharmacotherapy. While placebo-controlled trials are needed in many of the chronic diseases for which cannabinoids are purportedly used, several therapies already exist. Comparative trials will be needed in due course, and formulations need to be developed with this in mind (Table 2).

References

^1.Bestard JA, Toth CC. An open-label comparison of nabilone and gabapentin as adjuvant therapy or monotherapy in the management of neuropathic pain in patients with peripheral neuropathy. Pain Pract. 2011;11:353–68.

^2.Marini I, Bartolucci ML, Bortolotti F, et al. Palmitoylethanolamide versus a nonsteroidal anti-inflammatory drug in the treatment of temporomandibular joint inflammatory pain. J Orofac Pain. 2012;26:99–104.

^3.Frank B, Serpell MG, Hughes J, et al. Comparison of analgesic effects and patient tolerability of nabilone and dihydrocodeine for chronic neuropathic pain: randomised, crossover, double blind study. BMJ. 2008;336:199–201.

^4.Ware MA, Fitzcharles MA, Joseph L, et al. The effects of nabilone on sleep in fibromyalgia: results of a randomized controlled trial. Anesth Analg. 2010;110:604–10.

^5.Ekert H, Waters KD, Jurk IH, et al. Amelioration of cancer chemotherapy-induced nausea and vomiting by delta-9-tetrahydrocannabinol. Med J Aust. 1979;15:657–659.

^6.Ungerleider JT, Andrysiak T, Fairbanks L, et al. Cannabis and cancer chemotherapy: a comparison of oral delta-9-THC and prochlorperazine. Cancer. 1982;50:636–645.

^7.Neidhart JA, Gagen MM, Wilson HE, et al. Comparative trial of the antiemetic effects of THC and haloperidol. J Clin Pharmacol. 1981;21:38S–42S.

^8.Lane M, Smith FE, Sullivan RA, et al. Dronabinol and prochlorperazine alone and in combination as antiemetic agents for cancer chemotherapy. Am J Clin Oncol. 1990;13:480–484.

^9.Herman TS, Einhorn LH, Jones SE, et al. Superiority of nabilone over prochlorperazine as an antiemetic in patients receiving cancer chemotherapy. N Engl J Med. 1979;300:1295–1297.

^10.Ahmedzai S, Carlyle DL, Calder IT, et al. Anti-emetic efficacy and toxicity of nabilone, a synthetic cannabinoid, in lung cancer chemotherapy. Br J Cancer. 1983;48:657–663.

^11.Niiranen A, Mattson K. A cross-over comparison of nabilone and prochlorperazine for emesis induced by cancer chemotherapy. Am J Clin Oncol. 1985;8:336–340.

^12.Pomeroy M, Fennelly JJ, Towers M. Prospective randomized double-blind trial of nabilone versus domperidone in the treatment of cytotoxic-induced emesis. Cancer Chemother Pharmacol. 1986;17:285–288.

^13.Meiri E, Jhangiani H, Vredenburgh JJ, et al. Efficacy of dronabinol alone and in combination with ondansetron versus ondansetron alone for delayed chemotherapy-induced nausea and vomiting. Curr Med Res Opin. 2007;23:533–543.

^14.Strasser F, Luftner D, Possinger K, et al. Comparison of orally administered cannabis extract and delta-9-tetrahydrocannabinol in treating patients with cancer-related anorexia-cachexia syndrome: a multicenter, phase III, randomized, double-blind, placebo-controlled clinical trial from the Cannabis-In-Cachexia-Study-Group. J Clin Oncol. 2006;24:3394–3400.

^15.Jatoi A, Windschitl HE, Loprinzi CL, et al. Dronabinol versus megestrol acetate versus combination therapy for cancer-associated anorexia: a North Central Cancer Treatment Group study. J Clin Oncol. 2002;20:567–573.

^16.Gong H, Jr., Tashkin DP, Calvarese B. Comparison of bronchial effects of nabilone and terbutaline in healthy and asthmatic subjects. J Clin Pharmacol. 1983;23:127–133.

Research Consideration #9: Need for Clinical Data

The legalization of cannabis and certain cannabinoid preparations (e.g., CBD oil) in many U.S. states for conditions ranging from Alzheimer’s disease to migraines, and autism to PTSD, has created a situation where there is belief among medical patients that there are data to support such therapeutic use. In the majority of cases, such data are nonexistent. While the phrase “cart before the horse” has become cliché in the medical cannabis arena, it remains accurate.

We are in dire need of data to support or refute the clinical efficacy of cannabis and individual cannabinoid preparations for the vast majority of conditions for which it is currently used. The reason we know that a purified plant-derived CBD extract (Epidiolex) at doses ranging from ∼10 to 20 mg/kg in children with Dravet and Lennox/Gastaut syndromes is effective is due to a large amount of pharmaceutical funding for randomized controlled trials (RCTs). The same goes for data to support the use of a 1:1 ratio of THC to CBD (nabiximols) in multiple sclerosis, nabilone for nausea and vomiting induced by cancer chemotherapy, and dronabinol (THC) for chemotherapy-induced nausea and vomiting and anorexia associated with weight loss in adult AIDS patients.

The funding required to understand fully the effects of cannabis, or individual cannabinoid combinations, on clinical outcomes can be sizeable. While pharmaceutical companies have significantly contributed to our understanding of cannabinoid therapeutics, we cannot and should not rely on them to determine the efficacy of cannabis/cannabinoids for the litany of conditions for which they have been legalized in various U.S. jurisdictions.

There is a strong need for research to address, and support or refute, legislative actions. We need to conduct not just one, but many clinical trials of specific and well-defined cannabinoid preparations on state-approved medical conditions. These should include short- and long-term safety and tolerability studies, dose-finding studies, both small and large efficacy studies, and comparative efficacy studies. To say, for example, that medical cannabis is legalized in a given state for anxiety tells us nothing about clinical efficacy (for which there are very little data), what cannabis to use, and at what dose. In fact, studies have consistently documented anxiogenic effects of THC (particularly at high doses) and anxiolytic effects of CBD.^1,2 Only well-designed clinical trials can provide the evidence needed to properly care for those in need, while reducing the risk of serious adverse consequences associated with experimentation.

Some might argue that epidemiological data on the patterns of cannabis use among those already using state-sanctioned medical cannabis should suffice as a guide for product choice, dosing, and efficacy. Were product manufacturing regulated and human decision-making sound, epidemiological data could be sufficient. Unfortunately, we know that there is little oversight in the manufacture of cannabis products, leading to the sale of mislabeled and likely inconsistently manufactured THC and CBD preparations throughout the country.^3,4 We also know that many individuals with mental health conditions choose to use substances that are associated with long-term negative consequences (e.g., cocaine).⁵ Therefore, in populations with PTSD, the use of high THC cannabis preparations, which we know to cause acute euphoria and may lead to dependence,⁶ is extremely problematic.

Future research should start by examining the efficacy of cannabis/cannabinoid preparations for those conditions for which there are no good existing pharmacological treatments. It is for those populations that well-controlled studies that determine short- and long-term safety and efficacy, including dosing guidelines, are most needed. Studies should be adequately powered to detect hypothesized effects, and effect sizes and associated clinical significance should be thoroughly examined. Consistent with recent guidance from the Food and Drug Administration,⁷ it is also important to integrate patient perspectives and needs throughout the clinical examination of potential therapeutic effects, including the identification of end-points and selection of outcome measures.

References

^1.Crippa JA, Zuardi AW, Martin-Santos R, et al. Cannabis and anxiety: a critical review of the evidence. Hum Psychopharmacol. 2009;24:515–523.

^2.Loflin MJE, Babson KA, Bonn-Miller MO. Cannabinoids as therapeutic for PTSD. Curr Opin Psychol. 2017;14:78–83.

^3.Bonn-Miller MO, Loflin MJE, Thomas BF, et al. Labeling accuracy of cannabidiol extracts sold online. JAMA. 2017;318:1708–1709.

^4.Vandrey R, Raber JC, Raber ME, et al. Cannabinoid dose and label accuracy in edible medical cannabis products. JAMA. 2015;313:2491–2493.

^5.National Institute on Drug Abuse Research Report Series. Comorbidity: addiction and other illnesses. 2008. Available at https://www.drugabuse.gov/sites/default/files/rrcomorbidity.pdf (last accessed October 29, 2018).

^6.Budney AJ, Roffman R, Stephens RS, et al. Marijuana dependence and its treatment. Addict Sci Clin Pract. 2007;4:4–16.

^7.US Food and Drug Administration. CDER patient-focused drug development. 2018. Available at https://www.fda.gov/Drugs/DevelopmentApprovalProcess/ucm579400.htm (last accessed October 28, 2018).

Conclusions

The overall field of “cannabis medicine,” in which the cannabinoids offer potential promise in the treatment of a myriad of disease states and symptom complexes, is one of the most vast and exciting areas of health care mankind has ever faced. The concept that a natural substance that has been cultivated and used for millennia can now be associated with specific biologic effects through an increasingly well-characterized diverse receptor system in the human body opens potential for improvement in quality of life and suppression of disease that perhaps no other group of compounds—natural or synthetic—can offer. Unfortunately, the social and political history of the index plant over the past century has greatly complicated our ability to perform rigorous research in this potentially high-yield area. Studies of phytocannabinoids are exorbitantly expensive, and when funding is available, logistical and regulatory obstacles can delay study execution for months to years.

Many of these issues cannot be addressed by scientists, but are matters of public policy and market economics. This review has been intended to inform the interested researcher of where and how large the data gaps in this space lie, in the hopes that—whatever the obstacles—when funding and interest are available, the greatest possible impact can be made with the prosecution of rigorous, sound, biologically plausible research.

Authors’ Disclosure Statements

Drs. ElSohly, Good, Hanuš, and Viscusi, and Mses. Skinner and Spahr have nothing to disclose. Dr. Abrams reports personal fees from Axim Biotechnologies, Insys Therapeutics, Intec, Maui Wellness Group, Scriptyx, Tikun Olam, and Vivo Cannabis, outside the submitted work. Dr. Bonn-Miller is an employee of Canopy Growth Corporation and former employee of Zynerba Pharmaceuticals. He also reports personal fees and nonfinancial support from the Realm of Caring Foundation and Tilray. All are outside the submitted work. Dr. Casarett reports personal fees from Curio Wellness, Melix, Zelda Therapeutics, Root Bioscience, and nonfinancial support from EVIO Labs, all outside this submitted work. Dr. Dart reports compensation from Rocky Mountain Poison and Drug Center. Dr. Guzmán reports personal fees from Zelda Therapeutics, Canna Foundation, and nonfinancial support from VivaCell Biotechnology. Dr. Guzmán holds a patent licensed to GW Pharmaceuticals and patents issued to GW Pharmaceuticals, Yissum, and Madrid Complutense University/CIBERNED, outside the submitted work. Dr. Hill reports personal fees from Hazelden Publishing, outside the submitted work. Dr. Huestis reports personal fees from Intelligent Fingerprinting, Cannabix, National Medical Services Laboratory, Thermo Fisher Scientific, Fresh Hemp Foods, Nextar Israel, Pneuma, Inc., NBA, Sports Medicine Research Testing Laboratories, and Thomas Jefferson University’s Institute of Emerging Health Professions, outside the submitted work. Dr. Marsh reports personal fees from Stoke Therapeutics, Eisai Pharmaceuticals during this document’s development; grants from GW Pharmaceuticals, Zogenix Pharmaceuticals, State of PA, National Institutes of Health, Rett Syndrome Research Trust, International Rett Syndrome Foundation, and other support from GW Pharmaceuticals and Zogenix Pharmaceuticals, outside the submitted work. Dr. Pollack reports personal fees from FSD Pharma, outside the submitted work. Dr. Sisley reports grants from the Colorado Department of Public Health and Environment and nonfinancial support from the Colorado State University-Pueblo and Humboldt State University, outside of the submitted work. Dr. Vandrey reports personal fees from Zynerba Pharmaceuticals, Battelle Memorial Institute, Canopy Growth Corporation, Insys Therapeutics, outside the submitted work. Dr. Ware reports personal fees from Canopy Health Innovations and grants from CanniMed, outside the submitted work, and compensation from Canopy Growth Corporation.

Abbreviations Used