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ABSTRACT

Marijuana has been touted to have significant therapeutic activity for a wide variety of conditions. Thirty three states currently permit the use of marijuana as a medication through an inconsistent patchwork of regulations. Evidence for marijuana’s efficacy is increasing, but is hindered by variable, inconsistent, and conflicting results and regulatory barriers. Despite the efforts at the state level to expand the use of marijuana, both as a medicine and for recreational purposes, Cannabis and its constituents remain C-I drugs under the Federal Controlled Substances Act. Recently the U.S. Food and Drug Administration (FDA) approved a form of cannabidiol to treat rare but serious pediatric seizure disorders and the U.S. Drug Enforcement Administration (DEA) reclassified this approved form as a Schedule V drug. This lesson will review Cannabis products’ pharmacology and therapeutics and will provide an update on the fluid regulatory oversight of marijuana.

INTRODUCTION

Over the course of thousands of years, marijuana has been viewed as a component of religious and cultural events, an important medicine, a major agricultural product, and a corrupting national menace.¹ In the United States (U.S.), it was grown as a source of fiber in the South and was listed in the U.S. Pharmacopeia (USP) between 1850 and 1941. In the 1930s marijuana began to be looked upon less favorably.

In 1937, Harry Anslinger, at the time the head of the Bureau of Narcotics and Dangerous Drugs and essentially the nation’s first drug czar, testified at a congressional hearing and referred to Cannabis as “the national menace.”² In comparing marijuana to opiates, he stated that “opium has all the good of Dr Jekyll (i.e., its analgesic properties) and the evil of Mr Hyde. This drug (marijuana) is entirely the monster Hyde, the harmful effect of which cannot be measured.”² Shortly thereafter, Congress, reflecting the popular opinion of the time, enacted the Marijuana Tax Act, making marijuana use illegal.³ Less than 60 years later, the State of California led a new trend by approving marijuana for medical use and a few years after that, Colorado became the first state to permit recreational use of the once-notorious plant product.

Marijuana use generates strong emotions among advocates and opponents alike. Evidence, largely anecdotal or small case reports, supports the use of marijuana’s constituents for a long list of disease states, while other evidence purportedly links marijuana to serious problems, including memory impairment, psychological disturbances, and a role as a gateway drug.

The expansion in the use of medical and recreational marijuana poses potential problems for pharmacists. Patients may add marijuana to their therapy without the pharmacist’s knowledge, raising the risk of interactions and lack of adherence to conventional medications. It may also produce adverse effects that the counseling pharmacist may not be able to attribute to anything in the patient’s record. The recent U.S. Food and Drug Administration (FDA) approval of a single constituent (cannabidiol) product further confounds the issue.

This manuscript provides a brief overview of marijuana’s pharmacology and therapeutics and describes the progress in developing new regulatory approaches promoting medical marijuana programs in some states and potentially at the federal level.

MARIJUANA

Marijuana refers to various preparations from different strains of the Cannabis plant. The active constituents found in the plant are obtained from the resin secreted by the flowering tops and leaves; much lower quantities are found in the stems and roots, and none in the seeds.⁴ The plant’s fibrous stalks can be used to manufacture rope and fabric (hemp).

Most active constituents in the Cannabis plant are a diverse group of lipophilic compounds collectively known as cannabinoids,⁵ although other potentially active constituents have been found.⁶ More than 100 cannabinoids have been identified, most of which are unique to species of Cannabis.⁵ The 2 most abundant and well-known cannabinoids are delta-9-tetrahydrocannabinol (delta-9-THC), which, along with the closely related but less potent delta-8-tetrahydrocannabinol (delta-8-THC), are believed to be the principal psychoactive compounds found in the plant, and the non-psychoactive cannabidiol (CBD). THC and CBD are substances of great interest for their pharmacologic and potential therapeutic activity.

Cannabinoids act on cannabinoid (CB) receptors (a member of the large G-protein coupled receptor family) in the brain and other organs, although the cannabinoids also act through other cellular mediators. At least 2 cannabinoid receptors have been identified, CB1 which is found predominately in the central nervous system and CB2 which is located mostly in cells and organs mediating immune functions and other peripheral responses.^5,6  

Pharmacology and Pharmacokinetics

Marijuana produces many well recognized effects including relaxation or sedation, contentment, a pleasurable “buzz,” increased sociability, altered perception of time, and increased appetite, especially for sweet or fatty foods.⁶ Marijuana also is reported to produce potential therapeutic effects, discussed below.

CB receptors bind phyto-cannabinoids, synthetic drugs, and endogenous substances (endocannabinoids) such as anandamide and 2-arachidonylglycerol, to varying degrees.⁶ Cells release endocannabinoids in a stimulus-dependent manner by cleavage of membrane lipid precursors and likely function as neurotransmitters or neuromodulators.⁷ After release, they are rapidly inactivated by cellular uptake through a carrier-mediated mechanism and enzymatic hydrolysis by fatty acid amide hydrolase (FAAH).⁷ Synthetic drugs targeting the uptake and breakdown of endocannabinoids are also in development.

Many of the phyto-cannabinoids are weak or partial agonists or antagonists of the CB receptors, but the therapeutic effects of the phyto-cannabinoids may be due, at least partially, to mechanisms other than the endocannabinoid system.^6,8

The most common route of administration of marijuana is inhalation (i.e., smoking). This is the most efficient route (comparable to intravenous injection) with both THC and CBD rapidly reaching peak plasma concentrations within 3-10 minutes and reaching maximum concentrations that are higher than those achieved by oral ingestion.⁹ There is substantial intra‐ and inter-subject variability from inhalation. Among the factors accounting for the variability are loss of active ingredient in sidestream smoke, individual variation in puff rate and depth, pyrolysis (thermal decomposition of biomass at high temperatures), metabolism in the lung, the type of inhalational device used, the size of inhaled particles, and the deposition site within the respiratory system.^9,10

Experienced users are better able to regulate the amount of THC delivered to the lung.¹⁰ Some advocates of medical marijuana note the ability to self-titrate and endorse smoking as superior to oral dosing, since the patient who smokes has better control over the delivered dose. This is significant since a few states prohibit the use of smokable marijuana.

In addition to smoking, many medical marijuana preparations are oral dosage forms including beverages, lozenges, gums, tinctures, sublingual sprays, and baked goods. When cannabis is ingested, its onset of action is delayed and variable, with subjective effects lasting 5 to 12 hours. Peak effects are produced within 1 hour in some subjects, while in others the peak is delayed for 4 to 6 hours.^19,11 Oral bioavailability of THC, whether given in the pure form or as THC in marijuana, is low and extremely variable¹¹ and is subject to first-pass metabolism and erratic absorption from the stomach and bowel. After oral doses, the formation of the active THC metabolite, 11-hydroxy-THC, may exceed that of delta-9-THC and contribute to the sustained pharmacologic effects of oral THC or marijuana.⁷

Oromucosal formulations (e.g., sprays) are rapidly absorbed through the oral mucosa and produce higher plasma drug concentrations than oral but reduced relative to the inhaled route.⁹

Many topical products are also used; these have an onset of approximately 15-30 minutes and a duration of about 2 hours.⁶

THC and other cannabinoids are metabolized by cytochrome P450 isozymes primarily in the liver and to a lesser extent in the small intestine and brain.⁹ THC is predominantly metabolized by CYP3A4, CYP2C9, and CYP2C19 mainly to the active 11‐hydroxy‐THC and the inactive 11‐carboxy‐THC and is subsequently glucuronidated and excreted in the urine and feces.⁹ CBD is metabolized primarily by isozymes CYP3A4, CYP2C19, and to a lesser extent by CYP1A1, CYP1A2, CYP2C9, and CYP2D6.⁹ The main metabolite is 7‐hydroxy cannabidiol.⁷ Regular smoking, but not oral ingestion of marijuana, appears to induce CYP1A2 and CYP3A4, an effect also observed with tobacco smoking.¹²

Pharmacists should also note that lipophilic cannabinoids are able to cross the placenta and are excreted in human breast milk raising a concern for toxicity to the developing fetus.^9,13 The fetal concentration is about one-third of the maternal plasma concentration after inhaled THC. After oral intake, the fetal concentration is about one-tenth the plasma concentration and may pose a smaller risk.⁷

THERAPEUTICS OVERVIEW

Cannabis sativa was 1 of the first plants to be used by humans in both medicine and religious rites.⁶ Fiber and woven hemp fabrics are believed to trace back to 7,000 BC.Evidence for the medicinal use of cannabis can be found in descriptions dating to the reign of Chinese Emperor Chen Nung 5,000 years ago. Cannabis was recommended for malaria, constipation, rheumatic pains, gout, and “female disorders.”¹⁴ References to the plant can also be found in Assyrian records, Egyptian hieroglyphics, and Greek and Roman medical treatises.^14,15 Ancient Greek physicians Dioscorides and Galen found the juice from the seeds to be analgesic,¹⁵ an effect that is actively being reevaluated in this century.

Many Cannabis-containing products were marketed in the US in the 1900s, and manufacturers included Parke-Davis, Eli Lilly, and Squibb. From 1850 to 1941, cannabis was listed in the U.S. Pharmacopeia (USP) and National Formulary (NF).¹⁴ Popular medical uses included treatment of inflammation, cough, cramps, insomnia, arthritis, gout, epilepsy, and even venereal disease.¹⁴ 

A critical question for contemporary pharmacists is what conditions are amenable to treatment by marijuana/cannabinoids? The answer is murky. Anecdotal and lower quality studies document its efficacy in a wide range of disorders and regulations in different states permit marijuana to be used for a large and inconsistent potpourri of conditions (see below). But definitive clinical evidence is difficult to come by because of experimental, ethical and regulatory constraints.

While numerous individual reports describe promising activity, meta-analyses of most of the published research studies have shown variable, inconsistent, and conflicting results and modest to weak effects on a number of disease states; conclusions are also hindered by short term investigations, small sample sizes, and subjective effects.^10,16 Some studies have examined a single cannabinoid (e.g., THC/dronabinol) and others investigated mixtures or smoked marijuana, making comparisons difficult. Another variable in interpreting the published studies is that, generally, marijuana preparations obtained from dispensaries are more potent than products used in clinical trials.¹⁰

A helpful resource is the report “The Health Effects of Cannabis and Cannabinoids”⁶ compiled by a committee of experts and published by the National Academy of Sciences in 2017. Previously, the formerly named Institute of Medicine had published reports in 1982 and 1999, but available evidence about the short- and long-term health effects of cannabis had remained “elusive.” The committee creating the National Academy report was tasked with conducting a comprehensive review of the current evidence of health effects of Cannabis.

The therapeutic conclusions reached by the Committee are shown in Table 1. The strongest evidence in the Committee’s view was in reducing chemotherapy-associated nausea and vomiting, treating pain, and relieving subjective spasticity associated with multiple sclerosis. A lower level of confidence supported efficacy for improving short term sleep outcomes.

Other recent meta-analyses have reached slightly different conclusions. The authors of 1 meta-analysis of clinical research concluded that cannabinoids efficacy is variable, being associated with

• modest benefits for chemotherapy-related nausea and vomiting
• small and inconsistent benefits for pain and spasticity
• inconclusive benefits for other indications such as improvement of appetite and weight, decreased tic severity, improved mood or sleep, and
• no benefit for anxiety or depression.¹⁷

A different report concluded that the therapeutic areas with the best potential for exploitation of Cannabis-related medicinal agents were pain, epilepsy, feeding disorders, multiple sclerosis, and glaucoma.¹⁸ Another concluded that the medical conditions with the current “best” clinical evidence supported a benefit for cannabinoids (single or plant-derived) for multiple sclerosis patient-reported symptoms of spasticity, pain or painful spasms, multiple sclerosis bladder frequency, and chronic cancer pain/neuropathic pain.¹⁹ 

Treatment of chronic pain and spasticity by cannabinoids was supported by moderate-quality evidence in another recent meta-analysis.²⁰ Improvements in nausea and vomiting because of chemotherapy, weight gain in HIV infection, sleep disorders, and Tourette syndrome were also associated with cannabinoids, but the evidence was judged to be of low quality.²⁰ These reviews illustrate that cannabinoid preparations have great potential in many treatment areas, but further research is necessary to provide more definitive evidence.

Although not studied as extensively as some other indications, neurodegenerative diseases are a promising clinical target for cannabinoids. Patients with Parkinson’s Disease and Huntington’s Disease have a reduced CB1 receptors expression in motor areas, and cannabinoid agonists show promising activity in animal models of stroke.¹⁸

Cannabidiol

CBD, the non-psychoactive cannabinoid, has received increasing attention as a therapeutic agent, especially as a treatment for intractable seizures. CBD has shown anticonvulsant properties, both in preclinical and clinical studies.^21,22 Clinical evidence suggests efficacy in refractory seizures in both children and adults with a favorable side effect profile.

CBD’s mechanism of action is not established, but CBD does not directly bind to, nor activate, CB1 or CB2 receptors at concentrations pharmacologically relevant to its anticonvulsant effect.⁸ It has been proposed that the reduced neuronal hyperexcitabilty produced by CBD is due to multiple actions.^8,21,22 CBD shares many properties with other anti-seizure compounds and non-cannabinoid mechanisms may be producing the anti-seizure activity, including decreasing synaptic release of glutamate, stimulating alpha-3 and alpha-1 glycine receptors, activating 5-HT_1a receptors, altering GABA, adenosine and norepinephrine signaling, or modulation of intra-cellular calcium through GPR-55, TRPV, and VDAC.^8,21,22

Few guidelines assist the clinician in the use of marijuana/cannabinoids, and state regulations approving marijuana use are silent on guidance. One experienced practitioner²³ has suggested a “start low – go slow – stay low” approach. Specifically, he recommends beginning with a dose of 2.5 mg THC-equivalent once a day and increasing to 2.5 mg twice a day on day 3, with an increase as needed and as tolerated to 15 mg THC-equivalent/day divided into 2 or 3 doses. Doses exceeding 20-30 mg/day may increase adverse events or induce tolerance without improving efficacy.²³

Adverse Effects

Some reported adverse effects of marijuana include decreased short-term memory; impaired motor skills and driving abilities; dry mouth; tachycardia, palpitations, hypertension and other adverse cardiovascular events; reduced immunologic competence; bronchitis (when smoked); and depression, psychotic behavior and altered cognitive function with high dose chronic use.^6,24 Substantial cognitive and psychomotor impairment is associated with blood THC concentrations in excess of 5 ng/mL.⁹

Marijuana is also associated with impaired driving and an increased risk of a motor vehicle crashes, especially for fatal collisions.²⁵ A blood level as low as 1-2 mcg/L may increase the risk 1.5 to 2.5-fold.¹⁹

Pharmacists and pharmacy technicians should be on the lookout for potential pharmacodynamic and pharmacokinetic drug interactions.^9,26,27 Cannabinoids can increase sedation produced by other CNS depressants, and can also interact with SSRIs, cardiovascular agents (e.g., anti-hypertensive, anti-arrhythmic, and anticoagulants, and amphetamines, cocaine, atropine, or other sympathomimetic agents), and anti-seizure drugs. Pharmacists should also warn about combining marijuana with substrates of CYP3A4, CYP2C9, and CYP2C19 (e.g., ketoconazole, clobazam, protease inhibitors, clozapine, monoamine oxidase inhibitors, phenytoin, tricyclic antidepressants, warfarin).

The risk of overdose and death due to marijuana is extremely low,⁶ although there have been reports of an increased risk of heart failure, cerebrovascular accident, coronary artery disease, sudden cardiac death, and hypertension in patients with cannabis use.^{28, 28a} This contrasts with the potent abused full-agonist “synthetic cannabinoids” (e.g., K2, Spice) which produce a higher risk of toxicity including tachycardia, agitation, vomiting, stroke (rare), kidney damage, seizures, psychotic episodes, and death.²⁹

REGULATION OF MARIJUANA

Marijuana is listed as a C-I drug in the Federal Controlled Substances Act (CSA), the schedule reserved for drugs with the highest public health concern. How did a drug that was listed in the USP for almost 100 years that had a longer history of medical use become so tightly controlled?

In the 1920’s, concerns about marijuana contributing to crime, drug abuse, degenerate behavior, and sexual depravity began to spread in certain parts of the country. These concerns were particularly related to its use by immigrant Mexican laborers and African-American musicians, and became more widespread at the time of the Great Depression, likely fueled by economic concerns.³ These fears and associated political pressures resulted in the passage of the Marijuana Tax Act in 1937, with little debate or public attention and despite opposition by the American Medical Association.³ The provisions of the act resembled the earlier Harrison Act regulating opiate distribution, and required registration and payment of a fee (tax) for all the drug’s sellers and buyers.³

With the passage of the CSA in 1970, marijuana was temporarily placed in Schedule I where it continues to reside more than 4 decades later. A drug is classified as C-I if the U.S. Drug Enforcement Administration (DEA) concludes that it has high potential for abuse; does not have a recognized medical use; and cannot be safely “prescribed” by a health care practitioner, nor possessed in any amount.

STATE INITIATIVES

Although still illegal under the Federal CSA, many states, beginning with California in 1996, have enacted laws which permit the sale, use, possession and, in some cases, cultivation, of marijuana for medical purposes. In June of 2018, Oklahoma became the 31^st state and in the November 2018 election Missouri and Utah became the 32^nd and 33^rd states (plus D.C.) to enact medical marijuana laws. Table 2 lists states with approved medical marijuana programs.

Laws permiting medical marijuana in the different states are not uniform and pharmacists need to be aware of the peculiarities within their own states.³¹ Table 3 lists some characteristics where differences may exist among the states.

All states list the specific medical conditions that qualify for medical marijuana, but the lists differ.³⁰ All or nearly all states provide for the use of marijuana for certain disorders:

• cancer (especially to reduce the nausea accompanying chemotherapy)
• AIDS/HIV (especially to improve appetite and cachexia)
• seizure disorders
• some kinds of pain, and
• muscle spasms (usually associated with a major neurological disease such as multiple sclerosis).

A much smaller number of states recognize other disorders such as glaucoma, post-traumatic stress disorder, Crohn’s disease, Tourette’s disease, Alzheimer’s disease, sickle cell anemia, psoriasis, and others. Some states have an additional clause permitting wide discretion in qualifying conditions. For example, the Florida regulations approve marijuana for “a terminal condition diagnosed by a physician other than the qualified physician issuing the physician certification.” California permits possession by patients diagnosed with any debilitating illness where the medical use of marijuana has been "deemed appropriate and has been recommended by a physician." States have a blanket limit on sale and possession amounts, commonly a 30-day supply (which vary among the states), and do not depend on the intended use. States generally make medical marijuana available through retail dispensaries, which are subject to different degrees of oversight, and some states permit patients/caregivers to grow their own.

Seventeen states have programs specifically approving the use of a form of cannabidiol for medical uses, usually seizure disorders.³² Only 3 states (as of November 2018) have not followed the same path of other states for the use of any marijuana product for medical use (Idaho, Kansas, and Nebraska). Many of the states recognizing CBD specify the dosage form/source that qualifies for the exemption³² and normally in a form that has high CBD concentrations and very low THC concentrations (typically less than 1% and often as little as 0.3%, but up to 5% in some states). For example, Texas allows the use of cannabis oil that is no more than 0.5% THC and at least 10% CBD for the treatment of intractable epilepsy if approved by 2 certified specialists.

LEGALLY AVAILABLE MARIJUANA PRODUCTS

Although Cannabis products are generally considered to be illegal substances, some products derived from or related to marijuana can be legally obtained by prescription in the U.S. or Canada.

Dronabinol (Marinol): The FDA approved this synthetic form of delta-9-THC s in 1985 and it is available as an oral dosage form.³³ THC is marketed as a soft gelatin capsule containing 2.5 or 10 mg of active ingredient. The usual dosage is 2.5 mg before lunch and supper but may be increased to a maximum of 20 mg/day. It is approved for the relief of nausea and vomiting associated with cancer chemotherapy and to assist with the loss of appetite in patients with HIV. The active ingredient is dissolved in sesame oil to discourage smoking.³³ It is currently classified as a Schedule III drug.

Adverse central nervous system effects (e.g., dizziness, drowsiness, confusion, and feeling “stoned”) have been reported.

Nabilone (Cesamet): This drug is a synthetic, substituted cannabinoid originally developed by Eli Lilly and approved by the FDA (C-II) in 2006.³⁴ Nabilone is used to treat nausea and vomiting from cancer chemotherapy; the usual dose is 1 to 2 mg twice daily. It has a duration of action of 8 to 12 hours. Adverse effects include drowsiness, dizziness, vertigo, dry mouth, ataxia, euphoria, difficulty concentrating, and decreased blood pressure.³⁴ When compared with standard antiemetic agents (e.g., metoclopramide, prochlorperazine), cannabinoids such as nabilone and dronabinol were at least as effective, with good patient acceptance.³⁴

Delta-9-THC/Cannabidiol (Sativex): Sativex (ingredients known as nabiximols in the US) was approved in Canada for treatment of neuropathic pain in patients with multiple sclerosis and as an adjunct for pain in cancer patients. It is approved in 23 countries for multiple sclerosis-associated spasticity.³⁵ Sativex is derived from an extract of specifically bred cannabis varieties and is a 1:1 standardized mixture of delta-9-THC and CBD, plus other plant-derived substances. It differs from other products in that it is an oral/mucosal spray that allows more flexible dosing; each spray delivers a fixed dose of 2.7 mg THC and 2.5 mg cannabidiol.

Sativex recently completed Phase III clinical trials in the US for cancer pain³⁵ and, significantly, the FDA gave it “fast track” (expedited review) status. The results of the trial were somewhat disappointing, since the drug did not achieve statistically significant pain improvement overall, but analysis of the results appeared to show some improvement in US patients whom the manufacturer characterized as “less frail.”³⁵ The approval of this drug for the US market remains uncertain.

Cannabidiol (CBD) (Epidiolex): In October 2018, the FDA approved an oral cannabidiol solution (GW Pharma’s Epidiolex) for the treatment of seizures associated with Lennox-Gastaut (LGS) and Dravet syndrome (severe myoclonic epilepsy of infancy) in patients 2 years of age and older.³⁶ LGS and Dravet are rare, severe pediatric seizure disorders. Both are characterized by frequent and prolonged seizures, developmental delays, and may have increased mortality. Few (if any) alternatives are approved for their treatment.

Epidiolex must be dispensed with a patient Medication Guide describing the drug’s uses and risks.³⁷ The pharmacy technician should ensure the patient has received the appropriate Medication Guide to provide guidance on how to minimize the risk of experiencing a serious adverse drug event. The most common adverse effects reported from clinical trials are sleepiness, sedation and lethargy; fatigue, malaise and weakness; insomnia and poor-quality sleep; infections; elevated liver enzymes; decreased appetite; diarrhea; and rash. The most serious risks include suicidal ideation and attempts to commit suicide, which are not uncommon with anti-seizure drugs; agitation; new or worsening depression; aggression; and panic attacks. Epidiolex also caused liver injury, which was generally mild.

Pharmacists are reminded that the drug has been approved to treat the 2 seizure disorders but may anticipate that prescribers could prescribe it for off-label use. However, it is estimated that the cost of Epidolex may be as high as $32,000/year.

THE PHARMACIST’S ROLE

One variable among states is the degree of pharmacist participation in marijuana therapy. In most cases there is none. That is, unlike they do with prescription and over the counter drugs, pharmacists have no role in oversight of medical marijuana distribution which is ordinarily from a dispensary which may or may not be registered and with relatively lax regulations on personnel.³¹ For example, in many states a dispensary operator is only required to pass a criminal background check. However, at least 6 states (Arkansas, Connecticut, Minnesota, New York, Pennsylvania, Oklahoma) recognize the need for pharmacist involvement, although to different degrees. 

The most pharmacist involvement is in Connecticut. In Connecticut, a marijuana dispensary must be licensed by the Department of Consumer Protection (the agency responsible for regulating pharmacies in this state) and the number of dispensaries is restricted (currently 18 for the entire state). In addition, only a licensed pharmacist in good standing can dispense marijuana. Pharmacists are also required to enter information regarding the dispensing of marijuana into the state’s prescription monitoring program database (as is required for all controlled substances).³⁸  

In Minnesota, registered patients are required to meet with a pharmacist at the distribution center for consultation on their treatment goals and guidance on their medical cannabis dosage and dosage form.³⁹ The selection of the appropriate product, dose, and dosage form are determined by the pharmacist in consultation with the patient.

In New York medical marijuana products may not be dispensed unless a registered pharmacist is on the premises and supervising the facility’s activities.⁴⁰ The pharmacist must complete a four-hour course which includes the pharmacology of marijuana; contraindications; adverse effects; adverse reactions; overdose prevention; drug interactions; dosing; routes of administration; risks and benefits; warnings and precautions; abuse and dependence. In addition, any counseling may only be performed by a pharmacist or intern. Before dispensing medical marijuana, the dispensary is also required to consult the state’s Prescription monitoring program to ensure that the patient will not receive a renewal supply more than 7 days early (patients are permitted to receive a 30-day supply). The dispensary also must file an electronic record with the state of all approved medical marihuana products that have been dispensed; this includes a record of the payment method.

In Pennsylvania, a dispensary must always have a physician or pharmacist on duty when the facility is open to receive patients and caregivers.⁴¹ The physician or pharmacist must have successfully completed a 4-hour training course. If a dispensary has more than 1 location, a certified registered nurse practitioner or physician assistant may be on duty instead of a physician or pharmacist.

Arkansas recently amended its medical marijuana regulations to require that a dispensary needs to hire a pharmacist consultant.⁴² Among the consultant’s duties are to assist the dispensary in the development and implementation of processes for patient education and support provided by the dispensary. Focus areas may include

• methods, forms, and routes and techniques of medical marijuana administration
• strains of medical marijuana
• adverse effects and drug interactions
• policies and procedures for refusing to provide medical marijuana to an individual who appears to be impaired or abusing medical marijuana.

The consultant must be accessible to the dispensary through telephonic means and by telephone or video conference for patient consultation during operating hours.

In Oklahoma, voters approved medical marijuana in June 2018. Its State Board of Health recently added requirements to the state’s medical marijuana act, which is facing legal challenges.⁴³ One requirement would ban the sale (but not cultivation) of smokable, but not of vapable, marijuana while the other would require that dispensary managers be licensed pharmacists.

Utah is expected to require that a pharmacist is on staff in dispensaries in its regulations following passage of its medical marijuana law in November 2018.

RECREATIONAL MARIJUANA

In addition to its use as a therapeutic agent, marijuana also has a long history of use for recreational purposes. Starting with Colorado in 2012, states have been expanding the scope of permissible marijuana use beyond medical purposes. As of November 2018, 10 states (Alaska, California, Colorado, Maine, Massachusetts, Oregon, Nevada, Vermont, Washington, and Michigan in the 2018 election) plus the District of Columbia have passed laws permitting personal use and possession of marijuana by adults and most states permit sales. Not all these laws have been fully implemented, and others are still being modified.⁴⁴ Many other states have decriminalized marijuana possession (typically imposing civil fines instead of incarceration for possession of small quantities). As is the case with medical marijuana, each state has different characteristics within their regulations. While medical marijuana laws can often markedly differ from state to state, the recreational regulations tend to be more uniform. In general, states have patterned recreational marijuana use after retail sale and use of alcohol. For example, the purchaser must ordinarily be at least 21 years of age; the amount that can be possessed in public is generally around 1 ounce, although higher amounts are permitted in some states (in contrast some states permit possession of as much as 8-24 ounces of medical marijuana); retailers must be licensed by the state; driving under the influence of marijuana is prohibited, as is use in or near schools and other public locations; local municipalities can prohibit use and sale of marijuana; and most states permit purchases by non-residents.

FEDERAL LAW

While 33 states and the District of Columbia have chosen to permit sale and use of marijuana for medical use, these laws conflict with federal law. Under the CSA, marijuana is a Schedule I Controlled Substance, meaning that it has a high potential for abuse and no currently accepted medical use.⁴⁵

In fact, the DEA takes a broad view of what marijuana means,⁴⁶ including all parts of the plant, the resin, and every compound found in the plant being subject to control.[*] Consequently, every state law authorizing medical or recreational marijuana is disallowed under federal law.

Gonzales v. Raich,⁴⁷ a case decided by the U.S. Supreme Court in 2005, dealt with a situation in which federal DEA agents raided homes of seriously ill patients and seized their supply of marijuana plants that they were using on a physician’s recommendation under California’s medical marijuana law. The patients sued the U.S. arguing that this was an unlawful exercise of the government’s authority, essentially saying that the CSA did not apply to their circumstances. The Court decided that the application of the CSA in this situation was a proper use of governmental power and that no matter how valid a state’s law may be under state law, when it comes into conflict with federal law, the federal law prevails.

So, why hasn’t the DEA cracked down on the states? Fundamentally, it comes down to a Justice Department decision about how vigorously to enforce the CSA. In 2009, the U.S. Deputy Attorney General sent a memo to each of the U.S. attorneys announcing a policy that would deprioritize marijuana prosecutions of persons complying with existing state laws for the medical use of marijuana.⁴⁸

The memo went on to say that “(a)s a general matter, pursuit of these priorities should not focus federal resources in your States on individuals whose actions are in clear and unambiguous compliance with existing state laws providing for the medical use of marijuana. For example, prosecution of individuals with cancer or other serious illnesses who use marijuana as part of a recommended treatment regimen consistent with applicable state law, or those caregivers … who provide such individuals with marijuana, is unlikely to be an efficient use of limited federal resources.”⁴⁸

However, changes at the federal level may dampen the momentum for further loosening marijuana regulation. Attorney General Jeff Sessions has consistently taken a stand opposing legalization of marijuana and has criticized the Obama administration for its lax attitude towards marijuana prohibition. On January 4, 2018, Attorney General Sessions issued a memorandum to the U.S. Attorneys reminding them that the CSA and other statutes “reflect Congress's determination that marijuana is a dangerous drug and that marijuana activity is a serious crime.” It also indicates “previous nationwide guidance specific to marijuana enforcement is unnecessary and is rescinded, effective immediately.”⁴⁹ [Note: Sessions resigned as AG on November 7, 2018.]

CBD now belongs in a special category; FDA approval of Epidiolex required rescheduling. Since the U.S. is a signatory to the “Single Convention,” a 1961 international treaty designed to control trafficking in controlled substances, the Justice Department was required to place appropriate controls on CBD as a listed substance in the treaty. Previously, all forms of cannabidiol were C-I under the CSA. The DEA acknowledged that “Epidiolex no longer meets the criteria for placement in schedule I of the CSA” since it received FDA approval and can no longer be considered to have no medical use.⁵⁰ The DEA could have placed the drug in Schedule II, but elected, with advice from the FDA, to designate it as a Schedule V drug instead.⁵⁰

However, the DEA added a very important detail: “In taking this action, DEA decided to limit the rescheduling of CBD to a specific formulation of an FDA-approved drug product and re-emphasized that except for this specific formulation, CBD remains a Schedule I substance.”⁵⁰ The DEA further noted that it “remain[s] concerned about the proliferation and illegal marketing of unapproved CBD- containing products with unproven medical claims.”⁵⁰

While the DEA placed Epidiolex in Schedule V, pharmacists need to be aware of possible different classifications at the state level. For example, Connecticut considers the drug to be a Schedule II substance when sold in the state, pending further consideration.

CBD’s legal status is complex, controversial, and evolving.⁵¹ The status of cannabidiol remains clouded, despite the apparent ease with which it can purportedly be purchased off the Internet. As noted above, the DEA unequivocally recognizes all forms of CBD as Schedule I substances except for the recently FDA-approved Epidiolex. Some advocates claim that this opens the door to rescheduling of CBD, especially in light of the ambiguous nature of the recently passed 2018 Farm Bill which includes support for efforts to increase growth of hemp. To view more about the controversy, see references 51 and 52.

Several proposals in the U.S. Congress have sought to clarify CBD’s legal status, most recently a bill entitled “Charlotte's Web Medical Access Act” introduced in 2017.⁵³ If enacted in its current form, the bill would “amend the Controlled Substances Act to exclude cannabidiol and cannabidiol-rich plants from the definition of marihuana.” This would permit CBD to be marketed and sold but the status of non-FDA approved CBD if the law is eventually passed (e.g., Schedule II, Rx, OTC) remains uncertain.

SUMMARY AND FINAL COMMENTS

Cannabinoid compounds found in marijuana have been proposed to treat a wide variety of medical conditions. The use and acceptance of medical marijuana has proliferated over the past 2 decades (33 states currently have state sanctioned programs and 17 approve the non-psychoactive drug, cannabidiol). However, pharmacists should recognize that the clinical evidence for efficacy to date for many conditions is still relatively limited and inconsistent. With the growing approval of marijuana as a medicine and an intoxicant, pharmacists will see an increasing number of patients using marijuana. Since pharmacists play a direct role in medical marijuana in only a handful of states and no role in recreational marijuana distribution, it is incumbent to at least consider the possibility that a patient is a covert user and that there is a risk of interactions, unexpected adverse effects, and poor adherence to conventional therapies. A general rule of thumb for pharmacists would be to monitor for common CYP2C9, CYP2C19, and CYP3A4 inhibitors and substrates since cannabinoids could affect clinical activity.^23,25,26 Pharmacists should also inform patients that concomitant use may potentiate adverse effects. Moreover, different varieties of marijuana products sold differ in the amount and proportions of cannabinoids. Pharmacists should also be prepared for the development and approval of synthetic compounds affecting discrete pharmacodynamic targets within the endocannabinoid system, which will appear through normal FDA channels. The interested reader may view a case presentation on using marijuana to treat pain with opposing views presented.⁵⁴

Pharmacists and pharmacy technicians need to be aware of the lack of uniformity among state marijuana programs and that dispensaries in many states are poorly regulated. The state programs run contrary to federal law, which still treats marijuana as a C-I substance, although there has been some recent loosening of control of cannabidiol. Pharmacists need to stay abreast of regulatory changes in their states and at the national level affecting marijuana and advocate for a role in medical applications of cannabinoid products.

[1] DEA’s Full definition is: “The term ``marihuana'' means all parts of the plant Cannabis sativa L., whether growing or not; the seeds thereof; the resin extracted from any part of such plant; and every compound, manufacture, salt, derivative, mixture, or preparation of such plant, its seeds or resin. Such term does not include the mature stalks of such plant, fiber produced from such stalks, oil or cake made from the seeds of such plant, any other compound, manufacture, salt, derivative, mixture, or preparation of such mature stalks (except the resin extracted therefrom), fiber, oil, or cake, or the sterilized seed of such plant which is incapable of germination.” 21 USC 802(d) (16)⁴⁶

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