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Medical Marijuana: Pharmacologic and Regulatory Considerations

That's the reefer man
I believe, he's losin' his mind
I think, he's lost his mind1

INTRODUCTION

In 1937, Harry Anslinger was the head of the Bureau of Narcotics and Dangerous Drugs; essentially, he was the first “drug czar” in the United States (U.S.). He 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 all the evil of Mr. Hyde. [Marijuana] is entirely the monster Hyde, the harmful effect of which cannot be measured.” Shortly after this testimony, 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; Colorado became the first state to permit recreational use of the notorious plant product a few years later.

Marijuana use generates strong emotions among advocates and opponents alike. Evidence, largely anecdotal or from small case reports, supports the use of constituents of marijuana 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 marijuana poses potential problems for pharmacists. Patients may be adding marijuana to their therapy without the pharmacist’s knowledge, raising the risk of interactions with or lack of adherence to conventional medications. Marijuana may also produce side effects that the counseling pharmacist may not be able to attribute to anything in the patient’s record. This manuscript will provide a brief overview of the pharmacology and therapeutics of marijuana and will describe the progress in developing new regulatory approaches promoting medical marijuana programs in some states and, potentially, at the national level.

TRADITIONAL USES OF MARIJUANA

Marijuana refers to preparations from the equatorial plant Cannabis sativa or from Cannabis indica, a shorter species indigenous to Asia. The active constituents found in the cannabis plant are obtained from the resin secreted by the flowering tops and leaves; much lower quantities of the active components are found in the stems and roots, and none is found in the in the seeds.4 The fibrous stalks of the plant can be used to manufacture rope and fabric (hemp). More than 400 chemicals can be found in the marijuana plant, including at least 100 cannabinoids (21-carbon, lipid-soluble terpenophenols). Many of the cannabinoids are metabolic precursors and degradation products of other cannabinoids.5 The cannabinoids and their relative abundances in a marijuana plant vary with growing conditions, including humidity, temperature, and soil nutrients.5

C. sativa was one 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.7 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.”7 Paradoxically, it was also prescribed for “absentmindedness,” although it is now suspected to cause short-term memory loss. References to the plant can also be found in Assyrian records, Egyptian hieroglyphics, and Greek and Roman medical treatises.6 Ancient Greek physicians Dioscorides and Galen found the juice from the seeds to be analgesic,6 an effect that is actively being reevaluated in this century. The popularity of cannabis as a medicinal product spread throughout Asia, the Middle East, and down the eastern coast of Africa and ultimately to Europe and the U.S.

Cannabis use continued throughout the world through the early 20th century. Popular medical uses included treatment of inflammation, cough, cramps, insomnia, arthritis, gout, epilepsy, and even venereal disease.8 Many cannabis-containing products were marketed in the U.S. 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.8

Cannabis also served as an important commercial source of fabric and paper in Europe and the U.S. and is believed to have first been cultivated in Virginia in 1611.8 George Washington and Thomas Jefferson cultivated cannabis, and Washington is said to have used marijuana to soothe his inflamed teeth and gums.8 It is estimated that at the time of the Revolutionary War, 90% of American clothing was made from cannabis hemp, and it is also believed that the first U.S. flags and the parchments for the Declaration of Independence and the Constitution may have been made from hemp.8

PHARMACOLOGY OF MARIJUANA

Cannabinoids are a diverse group of lipophillic compounds. More than 100 different cannabinoids have been identified, most of which are unique to species of Cannabis. The 2 most abundant and well known phytocannabinoids (cannabinoids that occur naturally in the cannabis plant) are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Delta-9-THC and the closely related but less potent delta-8-THC are believed to be the principal psychotomimetic compounds found in the plant.5 CBD is a non-psychotomimetic compound. THC and CBD are substances of great interest for their pharmacologic and therapeutic activities. A number of synthetic substances have been produced with cannabinomimetic activity, representing a variety of chemical classes.9 These drugs represent potentially novel therapeutic agents for the broad range of disease states for which marijuana has been proposed to have activity.

Mechanism of action

For many years, cannabinoids were believed to work by a nonspecific disruptive effect on the cell membrane related to their highly lipophilic nature, similar to the effect of general anesthetics.9 However, a selective binding site was identified more than 20 years ago, and it is now recognized that the active constituents of marijuana act primarily through a specific population of receptors termed the cannabinoid (CB) receptors.10  The CB receptors exist as at least 2 different subtypes, designated CB1 and CB2, and they are members of the large family of G protein-coupled receptors (GPRCs).11 The GPRC family is the target for a majority of the currently marketed pharmaceutical products. THC is a partial agonist for the CB receptors, while CBD appears to act as an antagonist.9

The CB1 receptor, which may also exist as multiple subtypes, is localized to brain regions critical for neurologic and psychological functions, including those concerned with memory and cognition, motor function, and pain.12 These functions represent potential targets for therapeutic uses of phytocannabinoids and synthetic cannabinoids. CB1 receptors have been identifiedon many different nerve terminals, and, when activated by agonists, they inhibit the release of transmitters, including serotonin, gamma-aminobutyric acid (GABA), dopamine, glutamate, norepinephrine, and acetylcholine.12

Less is known about the physiologic roles of CB2 receptors, but the receptor is found preferentially in the periphery, especially in the immune system, and it may be involved in the process of inflammation.11,12 Activation of CB2 receptors has been shown to have diverse anti-inflammatory effects, including regulating B and T cell differentiation, suppressing pro-inflammatory mediators, inhibiting phagocytosis, and suppressing neutrophil migration and differentiation.13

In addition to the CB receptors, many of the cannabinoids exert complex actions on other receptor families such as serotonin and, especially, the transient receptor potential (TRP) family of cation channel-activating receptors, including TRPV1, TRPV2, TRPV3, TRPV4, and TRPA1.14 Significantly, the TRP receptors are highly expressed on sensory neurons and may mediate some of the therapeutic activity of the cannabinoids.

In addition to the plant products, there are endogenous ligands for the CB receptors, termed endocannabinoids. The existence of endogenous ligands supports the concept that there is a physiologic role for cannabinoids and helps to clarify the pharmacologic and clinical activities of marijuana constituents. Endocannabinoids also present novel targets for potential therapeutic agents, since drugs can be designed to inhibit the metabolism or uptake of the endocannabinoids rather than acting as direct receptor agonists.15

Several endogenous substances are believed to bind to CB receptors, but the 2 best-characterized endocannabinoids are anandamide and 2-arachidonoylglycerol.14 These compounds are synthesized via separate pathways from different precursors and are synthesized “on demand” instead of being stored like traditional neuronal mediators. Calcium entry during depolarization activates their synthesis.16 Anandamide is subject to enzymatic degradation, largely through fatty acid amide hydrolase.14,16 Cyclooxygenase-2 and lipoxygenases may also break down anandamide; there is evidence suggesting that several nonsteroidal anti-inflammatory drugs may act, in part, through inhibition of cannabinoid metabolism.14 There is also a neuronal uptake mechanism for deactivating anandamide.

Pharmacokinetic properties

The onset of psychoactive and other pharmacologic effects of marijuana is rapid after smoking but much slower and variable after oral intake. When marijuana is smoked, THC is absorbed as an aerosol within seconds and delivered to the brain rapidly and efficiently, as would be expected of a very lipid-soluble drug. Peak blood levels appear 10 to 30 minutes after smoking, although the formation of active metabolites may prolong both the peak onset and duration of psychological effects.17

Plasma clearance of THC is quite high (at least 950 mL/min), but the rapid disappearance of THC from the blood is largely due to tissue redistribution or distribution into fat.17,18 Slow release of THC and other cannabinoids from tissues and subsequent metabolism creates a very long elimination half-time. The terminal half-life of THC is estimated to be as long as 10 to 13 days. Some inactive carboxy metabolites have terminal half-lives of 50 hours to 6 days or more and, thus, serve as long-persistence markers of prior marijuana use detected by urine tests.17 THC is retained in the brain and brain levels decrease more slowly than in the blood, so that low blood levels are not necessarily indicative of brain levels nor as an index of impairment.19 Much less is known about CBD pharmacokinetics, but is has demonstrated a half-life of 18 to 33 hours in humans following smoking and 2 to 5 days after oral administration.20

Cannabinoids are extensively metabolized, with at least 80 metabolites formed primarily by cytochrome P450 (CYP) 2C9, 3A4, and C19.18,19 Most of the metabolites of THC appear to be biologically inactive, but some, such as 11-hydroxy-THC, are active. The glucuronide is excreted as the major urine metabolite along with approximately 18 non-conjugated metabolites.17 CBD undergoes significant first-pass metabolism with the primary metabolites being 7-hydroxy-CBD and CBD-7-oic acid.20 THC may induce CYP 1A2 activity,18 but CBD is a potent inhibitor of CYP enzymes, including CYP 1A2, CYP 2B6, CYP 2C9, CYP 2D6, and CYP 3A4 isoforms. Evidence also suggests that CBD may slightly reduce THC metabolism. Some animal studies have shown that CBD may alter the potency of certain anticonvulsant drugs, but a pharmacokinetic mechanism has not been established.20

Medical marijuana is available as cigarettes for smoking, but preparations of oral dosage forms are also available as beverages, lozenges, gums, tinctures, sublingual sprays, and baked goods. When cannabis is ingested, the onset of action is delayed and variable, with subjective effects lasting for 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.14,18 Oral bioavailability of THC, whether given in its pure form or as THC in marijuana, is low and extremely variable, ranging between 5% and 20%.17 Oral THC is subject to first-pass metabolism and erratic absorption from the stomach and bowel, which reduce its bioavailability. After oral doses, the formation of the active THC metabolite 11-hydroxy-THC may exceed that of delta-9-THC and, thus, contribute to the pharmacologic effects of oral THC and marijuana.17

The absorbed dose of THC from smoked marijuana varies greatly among individuals.19 Loss of the active ingredient in sidestream smoke, individual variation in puff rate and depth, pyrolysis, and metabolism in the lung all contribute to the variability. Experienced users are able to regulate the amount of THC delivered to the lung.18 This ability to self-titrate is a factor noted by advocates of medical marijuana, who endorse smoking as a superior delivery system compared to oral dosing with government-supplied synthetic THC, since the patient who smokes has better control over the dosing than the patient who ingests an oral dosage form. Advocates also note that a smoked form of delivery provides superiority over an oral dosage form when used to treat vomiting.

While smoked marijuana may provide improved control over bioavailability, smoke delivers a variable mixture of THC, other cannabinoids, and other biologically active and toxic substances to the lung.5 Other available dosage forms for medical marijuana include aerosols, patches, topical preparations, and suppositories.

THERAPEUTIC USES OF MARIJUANA

Marijuana has been touted as having clinically relevant effects in a large number of conditions, including emesis, pain, inflammation, multiple sclerosis (MS), anorexia, glaucoma, cardiovascular disorders, cancer, obesity, metabolic syndrome-related diseases, epilepsy and other seizure disorders, stroke, Parkinson's disease, Huntington's disease, Alzheimer's disease, Tourette's syndrome, schizophrenia, and post-traumatic stress disorder.16,21 The Institute of Medicine (IOM) released a detailed report in 1999 in response to a request by the White House Office of National Drug Control Policy “to conduct a review of the scientific evidence to assess the potential health benefits and risks of marijuana and its constituent cannabinoids.”5 The report concluded that marijuana offered potential therapeutic value for pain relief, control of nausea and vomiting, and appetite stimulation, noting that the effects are generally modest and that, in most cases, there were more effective medications available. The report also recognized that there are variations in patient responses to medication and that marijuana was moderately well-suited for certain conditions, such as chemotherapy-induced nausea and vomiting and AIDS wasting. However, the report also concluded that “the future of cannabinoid drugs lies not in smoked marijuana, but in chemically-defined drugs that act on the cannabinoid systems that are a natural component of human physiology.”5

In the almost 2 decades since the IOM published their conclusions, there have been a limited, but growing, number of clinical studies published on marijuana; some studies have examined a single cannabinoid (e.g., THC/dronabinol) and others have investigated mixtures or smoked marijuana, which makes comparisons difficult. While there are numerous individual reports of the therapeutic uses of marijuana that are promising, 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 limited by short-term investigations, small sample sizes, and subjective effects.18,22 Another variable in interpreting the published studies is that, generally, marijuana preparations obtained from dispensaries are more potent than products used in clinical trials.18 The IOM’s recommendation remains compelling: “(r)esearch should continue into the physiological effects of synthetic and plant-derived cannabinoids and the natural function of cannabinoids found in the body. Because different cannabinoids appear to have different effects, cannabinoid research should include, but not be restricted to, effects attributable to THC alone.”5 Some of the more recent clinical and pre-clinical research findings will be briefly summarized below and the interested reader is directed to several reviews for more detail.22-26

A recent review by a medical researcher concluded that the therapeutic areas with the best potential for exploitation of Cannabis-related medicinal agents were pain, epilepsy, feeding disorders, MS, and glaucoma.14 Similarly, a review of the clinical literature concluded that the medical conditions with the current “best” clinical evidence supporting a benefit for cannabinoids are MS patient-reported symptoms of spasticity (nabiximols, nabilone, dronabinol, and oral cannabis extract), pain or painful spasms (nabiximols, nabilone, dronabinol, and oral cannabis extract), MS bladder frequency (nabiximols), and chronic cancer pain/neuropathic pain (nabiximols and smoked THC).23

The authors of another meta-analysis of clinical research concluded that the efficacy of cannabinoids is variable and that cannabinoids are 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 improved appetite and weight, decreased tic severity, and improved mood or sleep; and no benefit for anxiety or depression.24 Moderate-quality evidence supported the use of cannabinoids for the treatment of chronic pain and spasticity in another meta-analysis.25 Improvements in nausea and vomiting due to chemotherapy, weight gain in HIV infection, sleep disorders, and Tourette’s syndrome were also associated with cannabinoids, but the evidence was judged to be of low quality.25 These reviews illustrate that cannabinoid preparations have great potential, but that further research is necessary to provide 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 reduced expression of CB1 receptors in motor areas, and cannabinoid agonists show promising activity in animal models of stroke.14

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 in both preclinical and clinical studies.27 Clinical evidence, although limited and variable, suggests efficacy in refractory seizures in both children and adults with a favorable side effect profile. The mechanism of action of CBD is not established but would probably differ from THC. CBD shows in vitro and in vivo CB antagonist activity, which would account for the lack of psychoactivity.16

The reduced neuronal hyperexcitability produced by CBD is likely due to multiple actions and may be independent of effects mediated by the endocannabinoid system.27 CBD shares many properties with other anti-seizure compounds, including decreasing synaptic release of glutamate, stimulating α3 and α1 glycine receptors, activating 5-HT1a receptors, desensitizing several TRP receptors, and altering GABA, adenosine, and norepinephrine signaling, which may contribute to the anti-seizure activity.27

RISKS OF MARIJUANA

Like all pharmacologically active substances, cannabinoids produce adverse effects. An article published in the British journal Lancet compared the harms associated with 20 abused drugs on the basis of 16 criteria, including intrinsic harm, societal and health care costs, and risks to others.28 The authors concluded that alcohol, heroin, and crack cocaine posed the greatest risks of harm; Cannabis was ranked 8th.

Most analyses have found that acute effects of marijuana are consistent with its central nervous system (CNS) depressant activity and include dizziness, fatigue, somnolence, euphoria, disorientation, drowsiness, problems with balance, and dry mouth.24 In addition, deficits in memory, judgment, attention, coordination, and perception (such as time and color) have been reported along with anxiety, dysphoria, and psychosis.23 In addition to CNS effects, cardiovascular (tachycardia, palpitations, paroxysmal atrial fibrillation) and respiratory (cough, increased carboxyhemoglobin, bronchitis [when smoked]) effects have been described.23,24 A serious concern is the effect of marijuana on the ability to operate a motor vehicle. A dose-dependent increased risk of motor vehicle accidents has been reported.19,24 A THC blood level as low as 1 to 2 μg/L increases the risk of a motor vehicle accident 1.5- to 2.5- fold.19

Adverse events associated with chronic use of marijuana include cognitive impairment, social dysfunction, and an increased risk of schizophrenia, especially in adolescents.24,26 The risk of immunosuppression in patients with compromised immune function has also been noted.24 It is important to remember that comparisons of research reports examining pure cannabinoids or mixtures and administration by different routes contributes to the lack of clarity in the analysis and interpretation of therapeutic activity and adverse events associated with marijuana.

LEGALLY AVAILABLE MARIJUANA PRODUCTS

Although Cannabis and any cannabinoids obtained from the plant are classified as Schedule I substances, some products derived from or related to marijuana can be legally obtained by prescription in the U.S. or Canada. These agents provide some support for potential uses of other marijuana preparations.

Dronabinol (Marinol)

Dronabinol is a synthetic form of delta-9-THC that was approved by the U.S. Food and Drug Administration (FDA) in 1985. It is available as an oral dosage form.29 The drug 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 dinner. The dose 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.29 It is currently classified as a Schedule III drug.

Clinical trials with dronabinol have reported increased appetite related to its use, but actual weight gain is not consistently reported.Adverse CNS effects (i.e., feeling “stoned”) have been reported with dronabinol. Comparisons with other known antiemetic agents have provided inconsistent results. The Drug Enforcement Administration (DEA) claims that dronabinol is superior to smoked marijuana since it is a pure drug and does not deliver the variety of chemicals that is found in marijuana smoke, including potential carcinogens.26

Nabilone (Cesamet)

Nabilone is a synthetic, substituted cannabinoid originally developed by Eli Lilly and approved by the FDA as a Schedule II drug in 2006.30 Nabilone is used to treat nausea and vomiting related to cancer chemotherapy; the usual dose is 1 to 2 mg twice daily. It has a duration of action of 8 to 12 hours. Side effects include drowsiness, dizziness, vertigo, dry mouth, ataxia, euphoria, difficulty in concentration, and decreased blood pressure.30 In some studies, cannabinoids such as nabilone and dronabinol were at least as effective as standard antiemetic agents (e.g., metoclopramide, prochlorperazine) and offered good patient acceptance.30 Nabilone appears to be especially effective in children, who experience fewer side effects than adults. Nabilone has also been studied in Phase II trials as an agent for lowering intraocular pressure and as an antianxiety agent.30

Delta-9-THC/Cannabidiol (Sativex)

Sativex contains a synthesized cannabis extract known as nabiximols, which contains a combination of delta-9-THC and CBD. Nabiximols 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. Sativex differs from other marijuana products in that it is an oral/mucosal spray that allows more flexible dosing than other marijuana products; each spray delivers a fixed dose of 2.7 mg THC and 2.5 mg CBD. It is approved in Canada for the treatment of neuropathic pain in patients with MS and as an adjunct for pain in cancer patients; in New Zealand, Israel, and 11 European countries, it is approved for MS-associated spasticity.22

Sativex recently completed Phase III clinical trials for cancer pain31 and, significantly, was given “fast track” (expedited review) status by the FDA. The drug did not achieve statistically significant pain improvement overall, but analysis of the results appeared to show some improvement in U.S. patients whom the manufacturer characterized as “less frail.” Relief of pain and improved sleep were reported in a study of 300 opioid-refractory cancer patients using a low (1-4 sprays/day) or moderate (6-10 sprays/day) dose of the drug.32 The approval of Sativex for the U.S. market remains uncertain.

REGULATION OF MARIJUANA

Marijuana has been listed in the USP for almost 100 years and it has an even longer history of medical use. However, federal and state restrictions on marijuana began in the early 1900s3 and its use is now tightly controlled. The Harrison Act, the precursor to the current Controlled Substances Act (CSA), was enacted in 1914 and placed restrictions on the sale of opiate products. Early drafts of the legislation also listed marijuana, but marijuana was not included in the final version of the law, possibly due to opposition by the pharmaceutical industry.3 In the 1920s, concerns about marijuana contributing to crime, drug abuse, degenerate behavior, and sexual depravity began to spread in certain parts of the U.S. The concerns were related particularly to its use by immigrant Mexican laborers and African-American musicians and the concerns became more widespread at the time of the Great Depression, likely fueled by economic concerns.3

Fears and associated political pressures about the use of marijuana resulted in the passage of the Marijuana Tax Act in 1937. The act was passed with little debate or public attention, despite the opposition by the American Medical Association. (Its spokesperson is quoted as saying: “The American Medical Association knows of no evidence that marijuana is a dangerous drug.”33) The provisions of the act resembled the Harrison Act and required registration and payment of a fee (tax) for all sellers and buyers of marijuana.33

Marijuana was placed in Schedule I as a temporary measure when the CSA was passed in 1970, but it continues to reside in this schedule more than 4 decades later. A drug is classified as Schedule I if the DEA concludes that it does not have a recognized medical use and cannot be safely prescribed by a health care practitioner nor possessed in any amount.

A report by the National Commission on Marijuana and Drug Abuse in 1972 intended to provide Congress and then President Richard Nixon with an “independent, nonpartisan appraisal of the nature of [marijuana] and the consequences of its use” concluded that “(t)he existing social and legal policy is out of proportion to the individual and social harm engendered by the use of the drug.”34 Essentially, the report recommended decriminalization of marijuana. The recommendation was not supported by the President and Congress and the drug remains classified in Schedule I.

State initiatives to regulate marijuana

Although still illegal under the Federal CSA, some states, beginning with California in 1996, have enacted laws that permit the sale, use, possession and, in some cases, cultivation, of marijuana for medical purposes. In June 2016, Ohio became the 25th state (plus the District of Columbia) to enact a medical marijuana law.35 States with an approved medical marijuana program are listed in Table 1.

Table 1: States with marijuana regulations*35
States with medical marijuana programs
Alaska
Arizona   
California
Colorado 
Connecticut
Delaware
Hawaii
Illinois
Maine
Maryland
Massachusetts
Michigan
Minnesota
Montana		 Nevada
New Hampshire
New Jersey
New Mexico
New York
Ohio
Oregon
Pennsylvania
Rhode Island
Vermont
Washington
   (District of Columbia)
States with cannabidiol regulations
Alabama
Delaware
Florida   
Georgia 
Iowa  
Kentucky
Mississippi
Missouri		 North Carolina
Oklahoma
South Carolina
Tennessee
Texas
Utah
Virginia
Wisconsin
States permitting recreational marijuana use
Alaska
Colorado
Oregon
Washington
   (District of Columbia)		  
*As of June 2016

The Marijuana Policy Project, an organization committed to ending marijuana prohibition, estimates that there are almost 1.5 million registered medical marijuana patients in the U.S. as of April 2016.36 Data from 2 states with medical marijuana programs (Colorado and Arizona) reveal that the most common indications for registered users are severe or chronic pain (Colorado: 94%; Arizona: 89%) and muscle spasticity (Colorado: 17%, Arizona: 14%).26

Legislation is pending in several other states and the number of states permitting medical use of marijuana will likely increase after the November 2016 election cycle. Some states have regulations that permit someone who is arrested for marijuana possession to mention medical use as a possible affirmative defense, and other states have measures that are largely symbolic. For example, in 2015, Louisiana passed a law permitting physicians to “prescribe” marijuana but, since this is prohibited by Federal law, the state law has no significance. Most states use terms such as a physician “recommends” or “affirms.”

While the number of states permitting medical marijuana has grown since 1996, opposition to legalization of marijuana remains. Efforts to institute medical marijuana programs have failed in the past 2 years in as many as 9 states, including Florida, Utah, Wisconsin, and others. It is important that pharmacists and patients appreciate the lack of uniformity among the different states with medical marijuana programs.36,37 Differences include factors such as medical conditions that qualify for medical marijuana; the amount of marijuana that can be purchased or possessed; the requirement for registration by the patient; whether the patient can grow their own marijuana; residency requirements; and the role of caregivers.36,37

Some of these differences may or may not be meaningful. For example, states limit the amount of marijuana that a patient or his or her caregiver can possess, but these limits are often not based on clinical protocols nor do they vary on the basis of medical conditions.37 Alaska and Montana permit 1 oz of “usable” marijuana but also permit possession of whole plants. Massachusetts and Washington permit possession of a 60-day supply of marijuana, estimated as 24 oz or 15 plants in Washington and 10 oz in Massachussetts. In New Jersey, a 30-day supply is only 2 oz, but California permits 8 oz and up to 18 (mature and immature) plants for a 30-day supply.

States usually require that the patient who uses marijuana be diagnosed with a “debilitating medical condition” but conditions that qualify as such vary. Some states, such as California, negate this listing by permitting 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." Connecticut offers more strict regulation on marijuana use as part of its program. A patient may only register for a marijuana-use identification card if his or her physician initiates the registration process; a patient may not self-register. More significantly, Connecticut requires a permit to operate a marijuana dispensary and recently increased the number of permits to 9 for the entire state. Together, these dispensaries currently serve more than 12,000 patients. All registered dispensaries must be owned and operated by a licensed pharmacist who is required to document all orders in the state’s prescription management program database. The dispensary must be a separate facility from the main pharmacy. In contrast, the City of Los Angeles alone has 935 dispensaries, and the entire state of California has more than 2500. California dispensaries are unregulated, but a recent law will require them to obtain state and local permits to continue to operate after 2018.38

Cannabidiol. Sixteen states that do not permit general medical marijuana use do, however, have regulations addressing the non-psychoactive cannabinoid, CBD. In most cases, the regulations permit the use of an extract of certain strains of Cannabis containing CBD with low concentrations of THC. The regulations are typically designed to permit treatment of epilepsy or seizures, especially in seriously ill children. Similar to the regulations surrounding medical marijuana, laws covering CBD vary significantly from state to state.

Florida permits patients with cancer, epilepsy, or severe and persistent muscle spasms to access preparations containing at least 10% CBD and no more than 0.8% THC. In order to qualify for these preparations, a patient is added to a compassionate use registry by a physician who has completed an 8-hour training course and has registered with the State Department of Health; the physician must repeat the training course each time his or her medical license is renewed. If the patient is younger than 18 years old, a second physician must concur with the registration. Iowa restricts CBD use to patients with epilepsy and only if recommended by a neurologist. The preparation may not contain more than 3% THC. As of 2015, Oklahoma permits CBD liquid with less than 0.3% THC to be used in peer-reviewed clinical trials for minors suffering from a severe seizure disorder (e.g., Lennox-Gastaut Syndrome or Dravet Syndrome). The law, however, does not permit growing plants anywhere in the state and specifies that the substance may be shipped into the state, which is illegal under federal law.

Some of the legal ambiguity may be corrected by a bill introduced in Congress in 2015: the Charlotte’s Web Medical Access Act.39 If passed, the Act would exclude CBD and CBD-rich plants (less than 0.3% THC) from the CSA, effectively making it legal to use CBD nationwide. There appears to be a softening in the regulation of CBD, but some medical marijuana advocates maintain that allowing CBD while continuing restrictions on THC is ill-advised. Advocates argue that THC has its own unique medical properties, that CBD and THC may be synergistic, and that “euphoria” may be therapeutically beneficial.

Federal laws regulating marijuana

Despite the existence of state medical marijuana programs, it is important to remember that under the Federal CSA, marijuana is classified as a Schedule I drug. Attempts to reschedule marijuana have been made, typically citing the need for an exception on the basis of medical necessity, but the DEA has denied these petitions on at least 3 occasions (in 2001, 2006, and 2011) by asserting, among other criteria, that individuals are using marijuana “in amounts sufficient to create a hazard to their health or to the safety of other individuals or to the community.” Some of the decisions have been appealed as far as the U.S. Supreme Court, but the Court has consistently ruled in favor of the DEA.40

In 2011, the DEA received a petition from the then governors of Washington and Rhode Island (states with medical marijuana programs) arguing that federal law makes it impossible for state governments to ensure a safe supply of marijuana for serious medical conditions without putting its employees at risk of prosecution. The petition further stated that “it is clear that the long-standing classification of medical use of cannabis in the United States as an illegal Schedule I substance is fundamentally wrong and should be changed” (written communication, November 30, 2011). The DEA has traditionally taken a different view. In a lengthy report published in 2013, the DEA stated its position on marijuana: “(m)arijuana is properly categorized under Schedule I of the Controlled Substances Act...The clear weight of the currently available evidence supports this classification, including evidence that smoked marijuana has a high potential for abuse, has no accepted medicinal value in treatment in the United States, and evidence that there is a general lack of accepted safety for its use even under medical supervision.”41 Moreover, the DEA maintains that “(t)he proposition that smoked marijuana is ‘medicine’ is, in sum, false-trickery used by those promoting wholesale legalization.”41

Clearly, state medical marijuana programs are at odds with federal law and the DEA. However, the possibility that marijuana will be rescheduled remains viable. In a letter to Congress in late 2015, the DEA stated that it received a scientific and medical evaluation of marijuana from the Department of Health and Human Services (HHS) and a recommendation from HHS for scheduling, which is required before rescheduling can take place.42 In August 2016, the DEA announced its conclusion, stating “there is no substantial evidence that marijuana should be removed from Schedule I.” This decision was based on the standards established by the Controlled Substances Act, which maintain that there is no accepted medical use of marijuana in any treatment and that the “known risks of marijuana use have not been shown to be outweighed by specific benefits in well-controlled clinical trials that scientifically evaluate safety and efficacy.”43 The DEA did note that its conclusions could change if scientific understanding about marijuana changes. There is also an ongoing DEA evaluation of CBD, but this may be rendered unnecessary by pending Congressional action.

Recreational marijuana

In 2012, Colorado and Washington became the first states to legalize the recreational sale and use of marijuana for adults 21 years of age and older. As of 2016, 4 states (Colorado, Oregon, Alaska, and Washington) plus the District of Columbia permit marijuana use for recreational purposes. Several other states have also decriminalized possession of small amounts of marijuana, typically replacing prosecution and incarceration with a civil fine.44

SUMMARY AND CONCLUSIONS

Cannabinoid compounds found in marijuana have been recommended to treat a variety of medical conditions. However, the pharmacist should recognize that the clinical evidence for efficacy to date is still relatively scant and inconsistent. The use of medical marijuana has proliferated over the past 2 decades, and 25 states currently have state-sanctioned programs with an additional 16 approving the non-psychoactive drug, CBD. Still, these programs contradict federal law, which recognizes marijuana as a Schedule I controlled substance. Pharmacists should be aware of the lack of uniformity of these programs among the states. Patients using marijuana for medical purposes present challenges for the counseling pharmacist (see Table 2), whether the pharmacist is directly involved in dispensing (as in Connecticut) or the patient is receiving the drug from poorly regulated dispensaries. With increasing attention to the pharmacologically active ingredients in and medical uses of marijuana, synthetic compounds affecting discrete pharmacodynamic targets within the endocannabinoid system will likely be developed and approved in the future under traditional drug-development channels.

Table 2: Counseling considerations for patients receiving medical marijuana22
Pharmacokinetics: Oral absorption is delayed and erratic compared with smoking

Metabolism: CYP450 2C9, 3A4, and C19

Adverse effects:
  • CNS depression (drowsiness, dizziness, vertigo, ataxia, difficulty in concentration, euphoria)
    • Impaired driving likely
  • Cardiovascular effects (tachycardia, decreased blood pressure)
  • Dry mouth
  • Cough and bronchitis, if smoked
  • Immunosuppression possible
  • Alterations in blood glucose and increased risk of bleeding have been reported
Drug interactions: CNS depressants, anticoagulants, antihypertensives, antimuscarinics 
Abbreviations: CNS, central nervous system

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