Medical Marijuana: Therapeutic Uses and Legal Status

Release Date: October 1, 2010

Expiration Date: October 31, 2012

FACULTY:

Gerald Gianutsos, PhD, JD
Associate Professor of Pharmacology
University of Connecticut School of Pharmacy
Storrs, Connecticut

FACULTY DISCLOSURE STATEMENTS:

Dr. Gianutsos has no actual or potential conflict of interest in relation to this activity.

Postgraduate Healthcare Education, LLC does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.

ACCREDITATION STATEMENT:

Pharmacy
acpePostgraduate Healthcare Education, LLC is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.
UAN: 0430-0000-10-035-H03-P
Credits: 2.0 hours (0.20 ceu)
Type of Activity: Knowledge

TARGET AUDIENCE:

This accredited activity is targeted to pharmacists. Estimated time to complete this activity is 120 minutes.

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DISCLAIMER:

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

GOAL:

To provide an understanding of the pharmacology, effects, side effects, and potential clinical uses of marijuana and to provide a basis for appreciation of the controversy and legal issues surrounding state and federal programs that attempt to regulate the availability of marijuana for medical use.

OBJECTIVES:

After completing this activity, participants should be able to:

  1. List the potential therapeutic applications of marijuana.
  2. Describe the effects of marijuana on the central nervous system and other organ systems.
  3. Recognize the advantages and disadvantages of synthetic cannabinoids and smoked marijuana.
  4. Describe the different approaches states have taken to permit marijuana to be used for medical purposes.
  5. Analyze the controversy between state and federal law as it applies to marijuana and the historical context of regulation.

 


Few drugs elicit as divergent an emotional reaction as marijuana. In the classic 1936 film Reefer Madness, marijuana is described as “The Real Public Enemy Number One,” causing “the loss of all power to resist physical emotions leading finally to acts of shocking violence…ending often in incurable insanity.”1 The U.S. Drug Enforcement Administration (DEA) considers marijuana “an addictive drug with significant health consequences to its users and others,” concluding that “many harmful short-term and long-term problems have been documented with its use.”2 On the other hand, the National Organization for the Reform of Marijuana Laws (NORML) considers marijuana to be “far less dangerous than alcohol or tobacco,” and that it is “nontoxic and cannot cause death by overdose.”3

While this dispute is part of the give-and-take in formulating national drug policy for recreational use of marijuana, the debate has yet another component—its use as a therapeutic agent. Many states have enacted laws that permit marijuana to be used for medical purposes—a patchwork of policies that vary from state to state—but these policies conflict with federal regulations that categorize marijuana as a drug of abuse with no legitimate medical use. The two sides have battled over these conflicting viewpoints for more than four decades as evidence for clinical activity of marijuana mounts.

This lesson will review some of the pharmacologic and therapeutic properties of marijuana and will examine federal and state laws that regulate the use of marijuana for therapeutic purposes. It will also review recent Department of Justice actions, which further cloud the debate over marijuana’s place in health care.

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 are found in the stems and roots, and none in the seeds.4 The fibrous stalks of the plant can be used to manufacture rope and fabric (hemp).

Over 400 chemicals can be found in the marijuana plant, including more than 60 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 abundance 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 hempwoven 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.”8 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.9

Cannabis use continued in Europe and later in the U.S. through the early 20th century. Popular medical uses included treatment of inflammation, cough, cramps, insomnia, arthritis, gout, epilepsy, and even venereal disease.10 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 (NF).10

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 1611.10 George Washington and Thomas Jefferson cultivated cannabis, and Washington is said to have used marijuana to soothe his inflamed teeth and gums.10 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 were made from hemp.10

CANNABINOID COMPOUNDS

The primary ingredient in cannabis is delta-9-tetrahydrocannabinol (delta-9-THC) that, along with cannabidiol, is the most abundant cannabinoid in the plant.5 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. Delta-9-THC is stereoselective, with the (-) trans isomer showing greater activity.11 A nonpsychotomimetic naturally occurring compound (cannabidiol) has also been isolated.11

A number of synthetic substances have recently been synthesized with cannabinomimetic activity, representing a variety of chemical classes.12 These drugs represent potentially novel therapeutic agents for the broad range of disease states where marijuana has been proposed to have activity. Endogenous substances possessing marijuanalike properties have also been isolated from the brain and other tissues.

Mechanism of Action

The mechanism of action of the cannabinoids was a subject of conjecture for many years. Originally, these substances were believed to work by a nonspecific disruptive effect on the cell membrane related to their highly lipophilic nature, similar to the effect of the general anesthetics.11 However, a selective binding site was identified more than 20 years ago, and it is now recognized that the active constituents of marijuana act through a specific population of receptors termed the cannabinoid or CB receptor.13

Cannabinoid Receptors: The CB receptor exists as at least two different subtypes, designated CB1 and CB2, and is a member of the large family of G-protein–coupled receptors.14 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.15 These functions represent potential targets for the medical uses of cannabinoids. The CB2 receptor is found preferentially in the periphery, especially in the immune system, and may be involved in the process of inflammation.14,15

CB1 receptors have been identified on many different nerve terminals, where they mediate inhibition of transmitter release when activated by agonists, including serotonin, gamma-aminobutyric acid (GABA), dopamine, glutamate, norepinephrine, and acetylcholine.15 Less is known about the physiologic roles of CB2 receptors, but most likely they include modulation of cytokine release from immune cells and immune cell migration.11,15

Endocannabinoids: Endogenous ligands to the CB receptors have been identified.14,15 These endogenous ligands, termed endocannabinoids, provide support for a physiologic role for cannabinoids and help to clarify the pharmacologic and clinical activity of marijuana. 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 receptor agonists.16

The first identified ligand is anandamide (arachidonylethanolamine), an unsaturated fatty acid derived from arachadonic acid, which is synthesized and secreted by nerve and immune cells. Anandamide has a slightly higher preference for CB1 receptors.15,16 Anandamide also binds to the vanilloid receptor (VR1 or TRPV1 receptor), a cation channel expressed by afferent nociceptive (painsensing) neurons that is also activated by capsaicin.16 Anandamide is found in high concentrations in regions of the brain regulating functions such as mood, behavior, cognition, movement, and pain, and is also found in the spleen and heart.5 Unlike traditional neurotransmitters, anandamide is not stored in cells but synthesized “on demand.”15 It is rapidly metabolized by the enzyme fatty acid amide hydrolase (FAAH). Cyclooxygenase-2 and lipoxygenases may also break down anandamide; there is evidence suggesting that the nonsteroidal anti-inflammatory drugs (NSAIDs) indomethacin and flurbiprofen may act, in part, through a cannabinoid mechanism.16 There is also a neuronal uptake mechanism for deactivating anandamide.

A second endocannabinoid, 2-arachidonoylglycerol (2-AG), has been isolated. 2-AG also acts on CB1 receptors and is more abundant in the central nervous system (CNS) than anandamide but is less potent.5 Like anandamide, 2-AG is inactivated by FAAH.

Another potential endogenous substance, palmitoylethanolamine (PEA), has also been investigated, but its role is less well established. PEA has been proposed as a possible selective CB2 agonist; however, it has also been reported to be an indirectly acting substance capable of inhibiting FAAH and/or enhancing the stimulation of vanilloid receptors by anandamide.17 Recently, a unique endocannabinoid, virodhamine, has been identified, which is a full agonist at the CB2 receptor and a partial agonist of CB1 receptors.18

MEDICAL USE OF MARIJUANA

Effects & Uses

Proponents for the use of medical marijuana have proposed that it benefits a broad range of CNS and other disorders. While the validity of these claims varies widely, the number of potential therapeutic uses for cannabinoid drugs is indeed large.14 Generally strong evidence supports the use of cannabinoid receptor agonists for treating the following disease states: chronic and neuropathic pain associated with multiple sclerosis (MS); spinal cord injury, cancer, and other painful states; tremors, spasms, and spasticity associated with spinal cord injury; nausea and vomiting induced by cancer chemotherapy; and loss of appetite in AIDS or cancer.14,19 Other potential, but less well characterized, uses for CB1 and CB2 agonists include anxiety disorders; agitation in patients with Alzheimer’s disease; amyotrophic lateral sclerosis (ALS); tics and behavioral problems in patients with Tourette’s syndrome; tardive dyskinesia induced by neuroleptic drugs; gastrointestinal (GI) disorders, including gastric ulcers, cholera-induced diarrhea, and inflammatory bowel disease; cardiovascular disorders, including hypertension, hemorrhagic and cardiogenic shock, and atherosclerosis; inhibition of angiogenesis and growth of tumors, including gliomas, lymphomas, and lung, breast, colorectal, thyroid, prostate, and skin cancer cells; and glaucoma.14,19

Few systematic controlled studies have been performed testing the efficacy of marijuana, especially long-term studies, due in part to its legal status. Controlled clinical trials suggesting that marijuana constituents may be useful in reducing the nausea in patients receiving cancer chemotherapy were first reported more than 30 years ago.20 One attempt at a meta-analysis of data from state-sponsored clinical trials reported that patients receiving smoked cannabis experienced a 70% to 100% improvement from nausea and vomiting compared with 76% to 88% relief reported by patients receiving oral THC.19

There is also evidence for the use of marijuana in pain. Cannabinoid drugs and anandamide are effective in animal models of pain.5 Endogenous cannabinoids and the CB1 receptor can be found at different levels of central pain pathways and may also modulate inflammation. CNS-mediated analgesia is likely due to stimulation of CB1 receptors, while CB2 (peripheral) receptors are likely responsible for the anti-inflammatory effects.5,14 CB2 receptors can also decrease platelet aggregation.4 A review of clinical trials on the use of cannabinoids in the management of pain concluded that cannabinoids were more effective than placebo and comparable to codeine.21

It should be noted that the DEA, using the Institute of Medicine’s seminal 1999 report as support, has concluded that smoking marijuana is not recommended for any disease state and that better alternatives are legally available.2

Pharmacokinetics

Cannabinoid metabolism is extensive, with at least 80 metabolites formed primarily by CYP450 2C9 and 3A4.22 Most of the metabolites appear to be biologically inactive, but some, like 11-hydroxy-THC, are active. The glucuronide is excreted as the major urine metabolite along with about 18 nonconjugated metabolites. Both frequent and infrequent marijuana users are similar in the way they metabolize THC.22

Plasma clearance of THC is quite high (~950 mL/min or greater); however, the rapid disappearance from blood is largely due to tissue redistribution or distribution into fat.22 Slow release of THC and other cannabinoids from tissues and subsequent metabolism makes for 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.22

The onset of psychoactive and other pharmacologic effects of marijuana is rapid after smoking but much slower after oral doses. 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.22

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.17 Oral bioavailability of THC, whether given in the pure form or as THC in marijuana, is low and extremely variable, ranging between 5% and 20%.2 Oral THC is subject to first-pass metabolism and erratic absorption from the stomach and bowel, which reduces 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 or marijuana.22 Relatively little 11-hydroxy-THC is formed after smoking.

The absorbed dose from smoked marijuana varies greatly among individuals.23 Among the factors accounting for the variability are loss of active ingredient in sidestream smoke, individual variation in puff rate and depth, pyrolysis, and metabolism in the lung. Experienced users are better able to regulate the amount of THC delivered to the lung.23 This 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. 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 possible dosage forms have been proposed, including aerosols, lozenges, patches, and suppositories.

Tolerance & Dependence

Chronic administration of cannabinoids in animals results in tolerance to many of the acute effects of THC, including memory disruption, decreased locomotion, hypothermia, and analgesia. Tolerance also develops to the cardiovascular and psychological effects of THC and marijuana in humans.5 Tolerance to cannabinoids appears to result from both pharmacokinetic and pharmacodynamic changes. Chronic treatment with the cannabinoids increases the activity of the microsomal CYP450 oxidative system and produces changes in brain cannabinoidreceptor protein and mRNA concentrations.5

Symptoms of marijuana withdrawal include restlessness, irritability, mild agitation, insomnia, sleep disturbance, nausea, and cramping, although the changes are relatively mild.5 Withdrawal symptoms have been observed in carefully controlled laboratory studies of people after use of both oral THC and smoked marijuana. In one study, subjects were given very high doses of oral THC (180-210 mg/day for 10-20 days), roughly equivalent to smoking nine to ten 2% THC cigarettes per day.5 During the abstinence period, the subjects were irritable and showed insomnia, runny nose, sweating, and decreased appetite. The withdrawal symptoms, however, were short lived and abated after 4 days. There are reports that long-term marijuana use in heavy users may result in apathy, social isolation, irritability, paranoia, and impaired cognition and educational performance.5

Marijuana is the third most commonly abused substance, following alcohol and tobacco, with the first use of marijuana most commonly occurring during adolescence.5 Many marijuana users progress to the use of other drugs of abuse, and opponents of decriminalization of marijuana consider it to be a “gateway” drug. While many drug users have used marijuana as their first experience with an illegal drug, most drug users do not begin their drug use with marijuana but rather with alcohol and nicotine, usually when they are too young to do so legally.5

Toxicity

Adverse Effects: The most common adverse effect reported is dizziness, along with euphoria and irritability.24 Agitation and confusion progressing to sedation have been reported on overdose.19 Chronic use has been associated with memory loss and learning deficits, psychiatric disturbances, respiratory problems (when smoked), and male infertility, although the true incidence rate is difficult to determine.24 Cannabinoids can also produce tachycardia and hypotension.4 There has never been a death reported as a result of marijuana overdose.19

Immunosuppression may also result from marijuana use.5 Limited reports in humans suggest that marijuana may decrease the secretion of luteinizing hormone and could interfere with early pregnancy.5

Smoking marijuana potentially delivers numerous toxic substances to the lung, including many of the chemicals found in tobacco smoke. Given a cigarette of comparable weight, as much as four times the amount of tar can be deposited in the lungs of marijuana smokers as in the lungs of tobacco smokers.5 Heavy marijuana smokers have exhibited abnormalities of cells lining the respiratory tract and have an increased risk of lung cancer.5

Drug Interactions: Although there is little systematic, documented evidence on drug interactions, interactions between marijuana and other drugs would be expected due to either pharmacologic or pharmacokinetic factors.24 Likely candidates include opiates, barbiturates, and other CNS depressants, selective serotonin reuptake inhibitors and other antidepressants, lithium, neuroleptics, protease inhibitors, antimuscarinics, alpha-agonists, sympathomimetics, and theophylline.

Legally Available Products

Although cannabis and any products 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.

Dronabinol (Marinol): This synthetic form of delta-9-THC was approved by the FDA in 1985 and is available as an oral dosage form.23 The 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. The dose may be increased to a maximum of 20 mg/day. It is used to relieve the 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.8 It is currently classified as a Schedule III drug.

Clinical trials with dronabinol have reported an increase in appetite, but actual weight gain is less consistently reported and may be due to an increase in body water rather than lean body mass.23 Adverse CNS effects (i.e., feeling “stoned”) have been reported. Dronabinol has also been shown to be superior to placebo in controlling emesis associated with cancer chemotherapy.23 Comparisons with other known antiemetic agents have been mixed. The DEA claims that dronabinol is superior to smoked marijuana since it is a pure drug and does not deliver the variety of chemicals that would be found in marijuana smoke, including potential carcinogens.25

Nabilone (Cesamet): This drug is a synthetic, substituted cannabinoid originally developed by Eli Lilly and approved by the FDA in 2006.26 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. Side effects include drowsiness, dizziness, vertigo, dry mouth, ataxia, euphoria, difficulty in concentration, and a decrease in blood pressure.26 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.27 It appears to be especially effective in children, who experience fewer side effects. Nabilone has also been studied in phase II trials as an agent for lowering intraocular pressure and as an antianxiety agent.26

Delta-9-THC/Cannabidiol (Sativex): Sativex was approved in Canada for treatment of neuropathic pain in patients with MS and as an adjunct for pain in cancer patients. It is currently undergoing clinical trials in the U.S. for cancer pain.28 Sativex is derived from an extract of specifically bred cannabis varieties and is a mixture of delta-9-THC and cannabidiol. 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.28

Synthetic Agonists: The search for synthetic cannabis drugs has been under way for more than 30 years.12 In the 1970s, Pfizer launched a cannabinoid research program that resulted in the development of a cannabinoid analogue, levonantradol, which was 1,000 times more potent than THC.29 Clinical trials showed that it was effective for postoperative pain and chemotherapy-associated nausea and vomiting; however, the company discontinued its development because the side effects (sleepiness, dysphoria, dizziness, thought disturbance, hypotension) were judged to be excessive.

The search for synthetic analogues was reinvigorated following the discovery of the selective cannabinoid binding sites, and a number of compounds are in development, although none were commercially available at the time this lesson was prepared. A wide variety of chemical classes are being investigated that include CB1 or CB2 selective agonists, as well as drugs that enhance the effects of endocannabinoids by inhibiting their degradation or uptake.12,29

Despite the availability of synthetic orally active products, proponents of medical herbal marijuana profess its superiority, since smoking allows patients to individually titrate their dose along with a more rapid onset of action. Moreover, they claim that the mix of different substances may produce a synergistic or qualitatively different effect than pure THC. In addition to smoking, medical marijuana may be administered by vaporization using commercially available devices. Marijuana vaporizes at a temperature of 284°F to 392°F, which is below the ignition point, so that the active constituents can allegedly be released into the air without burning plant products and producing potential carcinogens.8

Rimonabant (Acomplia): A unique compound, rimonabant differs from other cannabinoid-like drugs since it is not an agonist but a selective CB1 receptor antagonist or inverse agonist.30 Patients taking the drug exhibited weight loss, and clinical trials confirmed a loss of body weight in obese patients, consistent with a role for anandamide and CB1 receptors in appetite regulation. Several lines of evidence suggest that rimonabant may also be a novel therapeutic agent for treating the craving associated with a number of drugs of abuse, including alcohol and tobacco.30 However, FDA approval was denied and approval by the European Commission was withdrawn due to the emergence of side effects, including depression and suicidality.31

LEGAL STATUS OF MEDICAL MARIJUANA

Marijuana was not specifically covered by the original Harrison Narcotics Tax Act of 1914, which regulated the sale and importation of opiates and other abused drugs. The media in the 1920s reported on increased recreational use of marijuana and sensationalized stories of violent acts committed by marijuana users, and all states in the U.S. enacted laws criminalizing the sale and possession of marijuana by the late 1930s.32 Federal efforts to criminalize marijuana were spearheaded by Harry J. Anslinger, the commissioner of the Bureau of Narcotics and Dangerous Drugs, who testified that marijuana was addictive and led to violent crimes and mental deterioration, and that its users were more youthful than abusers of other drugs.8,33 In 1937, the federal Marihuana Tax Act was enacted, which made the nonmedical use of marijuana illegal. The drive for criminalization of marijuana is thought by some to have been promoted by commercial interests concerned with replacing hemp with other sources of paper and fabric. Only the birdseed industry was exempted, convincing Congress that hemp seeds gave birds’ feathers a particularly shiny gloss; to this day birdseed producers are allowed to use imported hemp seeds treated so that they do not sprout.9

While medical use of marijuana was permitted, the Act required physicians and pharmacists who prescribed or dispensed marijuana to register and pay a substantial tax; the administrative burden and increased costs led to a reduction in the prescribing of marijuana for therapeutic purposes.32,33 The Act was opposed by the American Medical Association.

Later, marijuana was included in the Comprehensive Drug Abuse Prevention and Control Act of 1970 (Controlled Substances Act; CSA) where it was placed in Schedule I.34 Drugs are placed in Schedule I if they have a high potential for abuse, lack any accepted medical use in the U.S., and do not have any accepted safety for use in medically supervised treatment.34 This decision meant that in the eyes of Congress there is no medical basis for prescribing marijuana. Congress placed marijuana in this schedule temporarily pending a report of a national commission, which subsequently recommended decriminalization, a recommendation that was not accepted by President Richard Nixon,35 and the drug remains in Schedule I to this day.

In 1972, a petition was filed with the Bureau of Narcotics and Dangerous Drugs (now the DEA) to reclassify marijuana as a Schedule II drug so that physicians could prescribe it. A series of court battles ensued until the U.S. Court of Appeals (DC Circuit) in 1994 upheld the decision of the DEA to maintain marijuana as a Schedule I drug.32

In 1976, a patient (Robert Randall) petitioned the FDA and later successfully sued the government to permit use of marijuana to treat his glaucoma, using the argument of medical necessity. Following the successful suit, the U.S. established the Compassionate Investigational New Drug (IND) program.32 The program permitted physicians to prescribe marijuana to patients enrolled in the federal program following strict scientific protocols, and the marijuana had to be obtained directly from a federal source to prevent individual cultivation.32 The only approved source of marijuana was grown on a National Institute on Drug Abuse (NIDA)–operated farm at the University of Mississippi School of Pharmacy. The product was shipped to North Carolina, where it was rolled into cigarettes containing a standardized concentration of THC that was said to be equivalent to street marijuana—2% then and 3.5% today.8 However, the patient approval process took 4 to 8 months, and the burdens placed on enrollment were such that few patients participated in the program.8

In response, 31 states established their own programs by 1982.32 Twenty-two states developed marijuana therapeutic research programs (TRPs) that were patterned after the federal program, establishing clinical trials in which qualified patients could enroll and receive marijuana from participating physicians. The drug could still only be obtained from the NIDA, but selection criteria were less restrictive than those of the federal program. However, the protocols for establishing a TRP were strict and required federal oversight, so that only 8 of the 22 state programs became operable.32 New Mexico, the first state to establish a program in 1978, encountered difficulty in implementing its program because of the insistence by the FDA that it establish placebo-controlled trials rather than simply providing marijuana to ill patients.8

State Programs

After the Compassionate IND program was suspended in 1992, all legal sources of marijuana for medical purposes disappeared (except for 13 patients who were grandfathered in).8 As a result, several states took a more direct approach to decriminalizing medical marijuana.

As of 2010, 14 states (Alaska, California, Colorado, Hawaii, Maine, Michigan, Montana, Nevada, New Jersey, New Mexico, Oregon, Rhode Island, Vermont, and Washington) had enacted laws that permitted patients to use and possess marijuana for personal medical purposes with a physician’s approval, and most permit patients or caregivers to grow marijuana for medical use (FIGURE 1).36,37 A 15th state, Maryland, establishes an affirmative defense for possession (but not cultivation) that protects patients from jail sentences but permits fines to be levied.36

fig1

Eight additional states have laws that permit the possession of marijuana if obtained through a physician’s prescription.36 However, since there is no legitimate source to fill the prescription, these laws are largely symbolic. Four additional states place marijuana into a schedule that would permit prescribing under state law, but these measures are merely symbolic since prescribing it violates federal law. A total of 31 states plus the District of Columbia have laws that recognize marijuana’s therapeutic value, although this recognition does not permit patients to use it.36

Nine of the 14 states that enacted laws did so through a ballot initiative, while others were enacted by legislative action (Rhode Island’s law was enacted after the legislature overrode the governor’s veto).36 In 2000, Hawaii became the first state to pass a medical marijuana law by action of the state legislature rather than by a ballot initiative.37 Estimates from the limited data available suggest that approximately 0.17% of the population uses marijuana for medical purposes in states where it has been legalized.36

There is little uniformity among the laws in the different states that have approved medical marijuana use (TABLE 1). For example, the diseases for which marijuana use is permitted vary. All states where there is statutory language permit marijuana to be used by cancer patients and patients with HIV/AIDS; all but one permit use for glaucoma, but only California specifies migraine and only Michigan designates ALS.37 Of the 14 states, 11 have a registry and/or ID program, with two more expected to add this feature, but the nature of the registry programs differs between the states. Most states protect registered patients from arrest and prosecution.37

tbl1

Limits on the amount that can be possessed also differ, ranging from 1 oz and no more than 3 mature plants in Nevada and Alaska to 24 oz and 15 plants in Washington.37 California makes a distinction between registered and nonregistered users. Registered users can possess up to 8 oz and 6 mature or 12 immature plants; for nonregistered users, it is a “quantity…reasonably related to patient’s needs.”37 New Jersey requires physicians to provide written instructions specifying the amount to be dispensed by legally sanctioned alternative treatment centers; a 60-day supply is limited to only 4 oz.37 No state requires a disclosure by physicians regarding risks and benefits (some require such information for minors), although Canada has such a requirement.37

Model Program: California became the first state to independently legalize the use of marijuana for medical reasons with the passage of the Compassionate Use Act in 1996. The purpose of the California law is: “To ensure that seriously ill Californians have the right to obtain and use marijuana for medical purposes where that medical use is deemed appropriate and has been recommended by a physician who has determined that the person’s health would benefit from the use of marijuana in the treatment of cancer, anorexia, AIDS, chronic pain, spasticity, glaucoma, arthritis, migraine, or any other illness for which marijuana provides relief.”38 Thus, California takes a very liberal approach to the therapeutic use of marijuana, permitting it to be used for a broad range of disease states and not requiring documented evidence of efficacy.

The California program has some other notable characteristics. Upon obtaining a recommendation from their physician for use of medicinal marijuana, patients may apply for and be issued a Medical Marijuana Identification Card that authorizes the possession, cultivation, transportation, and use of marijuana for medical purposes. Registrants also appear on a Web-based registry that permits verification of their registration. Although the ID card program is voluntary, more than 40,000 ID cards have been distributed as of 2010.38

The physician recommending marijuana must possess an allopathic or osteopathic medical license in the state. Before recommending marijuana for their patients, physicians are expected to perform a medical examination and, as a result of the examination, to document in the patient’s medical record that the patient has a serious medical condition and that the medical use of marijuana is appropriate. The patient using the marijuana must be a California resident. The patient may also apply for a registration card for a primary caregiver (the caregiver may not apply directly). The caregiver must be “a person who consistently assumes the responsibility for the housing, health or safety of the applicant (patient).” The caregiver may be an individual or may operate or be employed by a clinic, hospice, or home health care agency.38

The legalization of marijuana in California has spawned a new commercial enterprise. Dispensaries openly sell marijuana to the public and some have physicians on hand to make the appropriate recommendation to obtain an ID card. It is estimated that there are close to 1,000 dispensaries in Los Angeles alone, and in some neighborhoods they are said to outnumber Starbucks.39

Opponents to the California initiative note that patients do not necessarily need to be evaluated or diagnosed to receive marijuana, and that once it is recommended, the patient does not need to be reevaluated to assess its effectiveness. They also suggest that marijuana cooperatives are operating as a facade to supply the drug to any user regardless of medical use, pointing out that undercover agents have shut down clubs selling to minors, while one user even claimed it helped with an ingrown toenail problem.40

A new ballot initiative, The Regulate, Control and Tax Cannabis Act of 2010 (Proposition 19), was introduced in California that would further expand access to marijuana beyond its medical applications. This initiative would permit the possession and transportation of not more than 1 oz of cannabis for personal use by a person 21 years or older and would permit cultivation of cannabis in an area not to exceed 25 square feet. It would also permit taxing the sale of cannabis, and it cites, by analogy, the control of ethanol.41 The vote is scheduled for November 2010.

[Editor’s Note: Proposition 19 did not pass in California.]

Federal Issues

While several states have established access to medical marijuana, these laws are at variance with the federal CSA, which continues to classify marijuana as a Schedule I drug. This clash has spawned a number of lawsuits that culminated in an important Supreme Court decision in 2005.

In 2002, federal DEA agents and local law enforcement personnel raided the home of Angel Raich and seized and destroyed marijuana she was cultivating under California’s Compassionate Use Act.35 She and others brought suit against the government to prevent the enforcement of the CSA, alleging several constitutional claims and invoking the doctrine of medical necessity. Ms. Raich was suffering from an inoperable brain tumor, seizures, and wasting syndrome and claimed that she was taking the drug under a physician’s recommendation. Her physician testified that she did not respond to conventional medicine and that forgoing cannabis would cause Ms. Raich excruciating pain and could prove fatal. Although she lost her suit at the trial level, the U.S. Court of Appeals ruled that federal power to regulate commerce did not apply to state-authorized medical drug use and noted that the case presented activities that were “different in kind from drug trafficking because interposing a physician’s recommendation raises different health and safety concerns.”42 However, the U.S. Supreme Court reversed the judgment by a vote of 6-3, finding that “the CSA is a valid exercise of federal power, even as applied to the troubling facts of this case.”43 The Court’s action effectively invalidated all state marijuana laws. It should be noted that in his opinion, Justice John Paul Stevens stated the risk, shared by some opponents to a medical exception, that “no small number of unscrupulous people will make use of the California exemptions to serve their commercial ends whenever it is feasible to do so.”43 Thus, the battle between providing relief to patients and the desire to minimize abuse of psychoactive substances continues.

Recent Department of Justice Actions

In October 2009, the Department of Justice issued a memorandum attempting to provide “clarification and guidance to federal prosecutors in states that have enacted laws authorizing the medical use of marijuana.”44 The memorandum emphasized that the prosecution of traffickers in illegal drugs, including marijuana, continues to be a “core priority” of the department’s efforts. However, the memorandum stated that the priority should not focus federal resources on those individuals in “clear and unambiguous compliance” with state laws providing for the medical use of marijuana. The guidelines were not intended to provide a legal defense to a violation of federal law but to serve as a “guide to the exercise of investigative and prosecutorial discretion.”44 In effect, the Department of Justice has stated that it will not enforce federal laws in jurisdictions where medical marijuana laws protect patients.

SUMMARY & CONCLUSIONS

Although the use of marijuana for medical purposes can be traced back many millennia, the 20th century was characterized by a demonization of the drug and its banishment from the medical arsenal. The last few decades have seen a revival of interest in medical marijuana, and currently 14 states have enacted laws permitting the use and (generally) the cultivation of marijuana for personal medical use. Most other states recognize the therapeutic value of marijuana, but these are largely symbolic measures since it is not available for dispensing from pharmacies. However, all these laws run afoul of federal law that still classifies marijuana as a drug of abuse with no redeeming value.

Pharmacists need to stay abreast of several emerging trends: evolving state laws, the changing political climate in Washington exemplified by the recent guidance document from the Department of Justice, and the development of synthetic cannabinoid analogues by the pharmaceutical industry. Interested pharmacists may also be effective advocates for easing of sanctions on medical marijuana by following the example of U.S. Pharmacist Editor-in-Chief Harold Cohen. He has proposed classifying marijuana as a Schedule II drug, adding that the FDA should “allow pharmaceutical companies to carry out controlled clinical trials to see if medical marijuana lives up to the hype being promulgated in the literature. If the results are positive, the FDA should then give its stamp of approval as it would for any drug.…Pharmacists should endorse this course of action because, if it is approved, they are the ones who will ultimately be responsible for dispensing medical marijuana, not some storefront retailer or street-corner drug dealer.”45

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