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Report 10 of the Council on Scientific Affairs (I-97)
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Medical marijuana

Note: This report of the AMA Council on Scientific Affairs represents the medical/scientific literature on this subject as of December 1997. Also see the 2001 Report of the CSA on Medical Marijuana.

This report responds to Resolutions 407, 436, and 437 (I-97).

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This report summarizes federal and AMA responses to recent state initiatives designed to facilitate the medical use of marijuana. Additionally, the past and current status of marijuana, especially as related to federal regulations governing its medical use and the conduct of clinical research involving it, are explained. Finally, the pharmacology of marijuana and its major psychoactive ingredient, delta-9-tetrahydrocannabinol (THC), are reviewed, and the evidence for therapeutic benefits of these substances is evaluated.

Current AMA Policy concerning marijuana

The AMA has long supported the principle that Food and Drug Administration (FDA) approval of a new drug must be based on sound scientific and medical evidence derived from controlled trials and that social and economic concerns per se should not play a significant role in the FDA's decision-making process as it relates to either general or product-specific drug regulation (Policy H-100.992, reaffirmed in 1990,  AMA Policy Compendium). 

In policies reaffirmed in 1989, the AMA opposes legalization of the sale and possession of marijuana, and recommends that it be prohibited for public use (Policies H-95.997 and H-95.998) and also supports the modification of state laws to reduce the severity of penalties for possession of marijuana (Policy H-95.995). The AMA recommends that personal possession of insignificant amounts be considered a misdemeanor (Policy H-95.997) and advocates increased research into the effects of marijuana (Policies H-95.995, H-95.997, and H-95.998). 

Federal responses to state initiatives concerning medical marijuana

Recently, 1996 ballot initiatives in California (Proposition 215) and Arizona (Proposition 200), which were intended to facilitate the medical use of marijuana, sparked a national debate and prompted certain federal initiatives. In January 1997 the Office of National Drug Control Policy committed nearly $1 million to fund a comprehensive review by the Institute of Medicine of the National Academy of Sciences of the existing clinical, medical, and scientific knowledge of the health effects and potential medical uses of smoked marijuana. On Feb. 19-20, 1997, the National Institutes of Health (NIH) held a workshop on "The Medical Utility of Marijuana." The workshop was an open forum with the intent of gathering information to aid NIH in further informing the public and scientific community on this subject. A white paper summarizing the findings and recommendations of the NIH expert panel was released on Aug. 8, 1997 (see section entitled Debate on Marijuana as Medicine below).

On Dec. 30, 1996, Barry R. McCaffrey, Director of the Office of National Drug Control Policy; Attorney General Janet Reno; and Donna E. Shalala, Secretary of the Department of Health and Human Services announced the Administration's position on the passage of California Proposition 215 and Arizona Proposition 200. In commentary aimed at physicians who might wish to discuss or recommend the medical use of marijuana, the Administration warned of possible federal sanctions against those who invoked the new state medical marijuana laws. In its most direct action, the Administration warned that physicians who tried to make use of the state laws could: (1) lose their federal Drug Enforcement Administration (DEA) license for prescribing controlled substances; (2) be excluded from participation in the Medicare and Medicaid programs; and (3) be subject to criminal prosecution.

These pronouncements were widely interpreted as an attempt to intimidate and silence physicians who wished to discuss the possible risks and benefits of medical marijuana with their patients, and were seen by some as exerting a chilling effect on open discourse in the patient-physician relationship. This was soon followed by a federal class action suit,  Conant et al v. McCaffrey, filed by several California physicians and patients. The suit sought a preliminary and permanent injunction on First Amendment grounds against federal enforcement of (or threats to enforce) statutes or regulations that would punish or penalize physicians for communicating with patients about the risks and benefits of medical marijuana, including oral or written statements that indicate the physician believes that the potential benefits of medical marijuana outweigh its potential risks.

The Administration attempted to clarify its position on the two Propositions. A letter to medical organizations dated February 27, 1997, and signed by Jo Ivey Boufford, MD, Acting Assistant Secretary for Health, and Mark M. Richard, Esq, Acting Assistant Attorney General, states that nothing in federal law prevents a physician, in the context of a legitimate patient-physician relationship, from discussing with a patient the risks and alleged benefits of the use of marijuana to alleviate symptoms. Furthermore, the letter states that physicians are encouraged to talk with patients about their concerns and to answer inquiries about any treatment that may affect a patient's health. No "gag rule" stops physicians from engaging in these discussions. Physicians, however, cannot intentionally provide their patients with oral or written statements to enable them to obtain controlled substances in violation of federal law. 

AMA responses to federal actions

In a March 14, 1997, letter released jointly with the California Medical Association and delivered to the US Department of Justice, the AMA reiterated its support of "free and unfettered exchange of information" between patients and physicians. These principles of "free disclosure apply even if the effectiveness of a potential treatment or modality is not yet fully proven." In a March 24, 1997, letter, the AMA also urged the NIH to consider the institution of policies designed to facilitate well-designed clinical research into the medical utility of marijuana in patients who have serious conditions for which the bulk of anecdotal evidence suggests possible efficacy, such as acquired immunodeficiency syndrome (AIDS) wasting. 

Current status of the California and Arizona initiatives

Despite the federal pronouncements issued on Feb. 27, 1997, US District Judge Fern M. Smith issued a preliminary injunction in  Conant et al v. McCaffrey allowing physicians in California to recommend marijuana without fear of criminal prosecution in instances where there is a bona fide patient-physician relationship and action is not made to further an illegal objective. The order applies to California physicians who recommend marijuana for patients in California with human immunodeficiency virus (HIV) infection or AIDS, cancer, glaucoma, and seizures or muscle spasms associated with a chronic debilitating condition. Unless overturned by a higher court, the injunction remains in effect until the lawsuit goes to trial.

Meanwhile, the Arizona legislature passed a bill that was signed into law April 21, 1997, barring physicians from writing prescriptions for marijuana unless the US Congress or the FDA authorizes the medical use of marijuana and it is moved out of Schedule I. This action renders Proposition 200 moot.

In the aftermath of Propositions 200 and 215, at least 25 bills involving medical marijuana in 15 additional states have been introduced.1

Past and current status of medical marijuana

The marijuana, cannabis, or hemp plant is one of the oldest psychoactive plants known to humans.2 The chemical compounds responsible for the biological effects of  Cannabis sativa are contained in highest concentrations in the resin exuded from the flowers on the female plant. Cannabis was introduced into Western medicine in the 1840s following publication of a treatise by the Irish physician W.B. O'Shaughnessy.3 It was promoted for a variety of conditions based on its putative analgesic, sedative, anti-inflammatory, antispasmodic, antiasthmatic, and anticonvulsant properties.4,5 Interest in the medical use of marijuana waned in the late nineteenth and early twentieth centuries with the advent of opiates, barbiturates, chloral hydrate, and aspirin and the widespread availability of hypodermic syringes for injection of water-soluble compounds. 

Marihuana Tax Act: The Marihuana Tax Act of 1937 introduced the first federal restrictions on marijuana. This federal law required industrial or medical users to register and pay a tax of $1/ounce. Individuals using marijuana for recreational or other purposes were required to pay a tax of $100/ounce. The paperwork required of physicians who wished to use the drug in their practice and regulations later imposed by the Federal Bureau of Narcotics designed to prevent diversion dampened enthusiasm for pursuing medical applications. 

At the time, the AMA was virtually alone in opposing passage of this Act. The AMA believed that objective data were lacking on the harmful effects of marijuana, and that passage of the Act would impede future investigations into its potential medical uses.6   Furthermore, the AMA's Committee on Legislative Activities recommended that marijuana's status as a medicinal agent be maintained.7 Nevertheless, marijuana was removed from the US Pharmacopoeia in 1942, thus losing its remaining mantle of therapeutic legitimacy. 

Controlled Substances Act: As recreational drug use proliferated during the 1960s, legislative concern led to passage of the Comprehensive Drug Abuse Prevention and Control Act of 1970 (commonly referred to as the Controlled Substances Act). This Act classifies hazardous drugs into 5 categories, or schedules, that impose varying restrictions on access to the drugs under direction of the DEA.

A drug is placed in Schedule I if (1) it has a high potential for abuse; (2) it has no currently accepted medical use in treatment in the United States; and (3) there is a lack of accepted safety for use of the drug under medical supervision. In contrast, Schedule II criteria are that the drug (1) has a high potential for abuse; (2) has a currently accepted medical use in treatment in the United States or a currently accepted medical use with severe restrictions; and (3) abuse of the drug may lead to severe psychological or physical dependence. Marijuana is assigned by statute to Schedule I, along with many other drugs such as heroin, lysergic acid diethylamide (LSD), mescaline and other hallucinogenic amphetamine derivatives, methaqualone, and illicit fentanyl derivatives.

Efforts to remove marijuana from Schedule I: Advocates of decriminalizing marijuana have attempted to have it removed from Schedule I ever since it was placed there. A petition was first filed in 1972 by the National Organization for the Reform of Marijuana Laws (NORML) to the Bureau of Narcotics and Dangerous Drugs seeking to reschedule marijuana to Schedule II. After this petition was denied and public hearings were not conducted, NORML filed suit in 1974 against the Bureau and in 1975 against its successor, the DEA. After further legal maneuvering, the petition was eventually sent back to the DEA for consideration in 1980 by the US Court of Appeals for the District of Columbia. Eventually, public hearings were held over a 2-year period from 1986 to 1988, at which time the DEA Administrator once again rejected the position of NORML (now joined by the Alliance for Cannabis Therapeutics [ACT], the Drug Policy Foundation, and the Physician's Association for AIDS Care, among others) despite recommendations to the contrary by the administrative law judge in the case. The latter parties petitioned the District Court for review of this order; after once again remanding the case in 1991, the District Court denied the petition for review on February 18, 1994. 

Although the petition for review was denied, it led to a revised formulation for determining whether a drug has a "currently accepted medical use." The 5-part test for fulfilling this criteria of Schedule II is now comprised of the following:

• the drug's chemistry must be known and reproducible;
• there must be adequate safety studies;
• there must be adequate and well-controlled studies proving efficacy;
• the drug must be accepted by qualified experts; and
• the scientific evidence must be widely available.

Even if marijuana were rescheduled it could not be marketed or medically available for prescription use unless it was reviewed and approved by FDA under the Federal Food, Drug, and Cosmetic Act (FFDCA). Importantly, for a drug to obtain FDA approval under the FFDCA, the results of well-controlled studies must provide substantial evidence that the drug is effective for its intended use and appropriate tests must be conducted to show that is it safe.

Smoked marijuana has not been approved by the FDA to treat any disease or condition. Sufficient studies of smoked marijuana have not been submitted to permit the FDA to determine if the potential benefits of smoking marijuana for specific indications outweigh the known risks associated with the drug. By contrast, such studies have been completed and data submitted on Marinol, a drug product whose active ingredient is dronabinol or THC. FDA approved Marinol for the treatment of anorexia associated with weight loss in patients with AIDS and nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional treatment. Following approval under the FFDCA, Marinol was rescheduled from Schedule I to Schedule II. Therefore, this drug, which has been approved under the FFDCA and rescheduled under the Controlled Substances Act, may be legally prescribed by physicians.

Research and treatment involving marijuana

Despite being assigned to Schedule I, several avenues have been available that permitted limited access to marij uana for medical treatment or clinical research. 

State laws: Over the past 24 years, 36 states have enacted laws concerning medical marijuana; 13 of these states have either repealed or allowed their laws to "sunset."1 Most of these state laws were passed in the late 1970s and early 1980s but proved cumbersome to implement. They typically established therapeutic research programs, or sometimes provided protection for patients under the "medical necessity defense." 

For therapeutic research programs, states could dispense marijuana or other Schedule I drugs only by establishing formal research programs and getting FDA approval for an Investigational New Drug (IND) application. FDA's IND regulations require a sound scientific protocol, a qualified investigator, basic scientific data to suggest a reasonably safe and potentially efficacious use of a drug, a rational starting dose, and a drug supply that conforms to basic investigative manufacturing standards. In addition, any clinical trial must protect human test subjects by ensuring that they fully understand the risks of participating in the study and provide informed consent. In the case of INDs for marijuana, the marijuana was provided by the National Institute on Drug Abuse (NIDA), pursuant to its authority under the Public Health Service Act. Before NIDA could supply marijuana for research purposes, the investigator applied to the DEA for a Schedule I license in order to receive and dispense the drug through a designated pharmacy. This application included a copy of the IND and a statement of security precautions. Some states have their own registration requirements for Schedule I substances above and beyond the federal requirements.

As of 1991, all state-run therapeutic research programs on marijuana had expired or ceased to operate.1

Compassionate use treatment IND: In 1978, as a result of a settlement agreement in a lawsuit against the government, a procedure was devised to allow patients to receive marijuana cigarettes under the single-patient IND procedure at the FDA. In this case, an individual physician applied to the FDA for approval to receive and dispense marijuana for use in one specific patient. As above, the physician required special DEA approval to obtain and dispense the marijuana. When the DEA issued a registration for the physician to receive the marijuana, it provided the order form to submit to NIDA for shipment of the marijuana to a designated pharmacy. 

About 15 patients had received marijuana legally through this program through June 1991, when it was suspended after the number of applications surged in response to the AIDS epidemic. In March 1992, the Secretary of the Department of Health and Human Services decided that NIDA would not provide marijuana for single-patient INDs except to those patients who were receiving marijuana at the time. This decision was buttressed by a 1993 NIH review that concluded evidence was lacking to suggest that "that smoked marijuana might be superior to currently available therapies for glaucoma, weight loss associated with AIDS, nausea and vomiting associated with cancer chemotherapy, and muscle spasticity associated with multiple sclerosis or intractable pain."8 Additionally, there were concerns about the toxicity of a smoked product and doubts that the Treatment IND approach would produce useful information on safety and efficacy of smoked marijuana. When the program was terminated, 27 additional single-patient INDs that had received FDA approval were canceled and the patients were not supplied with marijuana.9

Non-IND research: The FDA also has ultimate authority to approve research protocols involving Schedule I substances for non-IND research under the Controlled Substances Act; however, the FDA must consult with the DEA concerning the adequacy of the applicant's diversion control procedures.

Current research on smoked marijuana: Federally funded clinical research on medical uses of smoked marijuana is not currently being conducted. Furthermore, reorganization of NIDA under the NIH umbrella in 1992 prompted an internal review of policies and procedures that resulted in the peer review process being applied to projects involving the resources of NIDA. 

This fundamental change has implications for clinicians wishing to pursue research into the medical uses of marijuana because NIDA is the only legal source of marijuana. For example, one pilot project designed to study the effects of smoked marijuana in AIDS wasting received the requisite local institutional and FDA approvals, only to be rejected by NIDA.10 Advocates of smoked marijuana view this additional oversight as a specific roadblock to the conduct of research on smoked marijuana, even though the same policy is applied to other internal and external projects involving the use of NIDA's resources.

Pharmacology of marijuana

Constituents and chemical characteristics: Marijuana contains over 400 chemical compounds.11 The main psychoactive substance is generally believed to be delta-9-tetrahydrocannabinol (THC), but at least 60 other cannabinoids (C21-containing compounds) have been identified in the pyrolysis products.12-14 Delta-8-THC is similar in potency to delta-9-THC, but is present in only small concentrations.15 Cannabinol and cannabadiol are the other major cannabinoids present. The former is slightly psychoactive, but not in the amounts delivered by smoking marijuana.15 The average content of delta-9-THC (hereafter referred to as THC) in marijuana plants usually ranges from 0.3 percent to 4 percent based on the climate, soil and growing conditions, and handling after harvest, but values as high as 20 percent have been achieved in some preparations.16 THC is a resinous weak acid, pKa = 10.6, with a very high lipid solubility and very low aqueous solubility.17 It binds to glass, diffuses into plastic, and is photolabile and susceptible to heat, acid, and oxidation.17,18 The (-) enantiomer is up to 100 times more potent than the (+) enantiomer depending on the pharmacological test.19 

Pharmacokinetics: Marinol capsules contain synthetic THC dissolved in sesame seed oil. Oral THC demonstrates low (6 percent to 20 percent) and variable bioavailability among test subjects. Gastric acidity causes some isomerization of THC to the delta-8-derivative and the drug is subject to a significant first pass effect. Peak plasma concentrations of THC are achieved within 1 to 6 hours, but may remain elevated for several hours.20-23 Initially, THC is oxidized in the liver to 11-hydroxy-THC, a potent psychoactive metabolite. Other minor hydroxylated metabolites also are formed. Major urinary metabolites are formed by further oxidation of 11-OH-THC and other hydroxylated metabolites to carboxylic acid derivatives and other polar acids, which are eliminated in the urine and feces as conjugated and unconjugated metabolites.20 

Although THC is cleared rapidly by the liver (hepatic clearance = 950 mL/min), it has a very large volume of distribution (10 L/kg).24 Thus, the terminal half-life of THC is on the order of 20 to 36 hours.20,23 With chronic use, the limiting step for elimination is redistribution from peripheral tissues.

Following inhalation, THC is rapidly absorbed into the blood stream and redistributed. Considerable amounts of the dose contained in one cigarette are lost in side stream smoke and destroyed by pyrolysis.20,25 Peak blood levels of THC are achieved at the end of smoking and then decline rapidly over the next 30 minutes.20 Smoked marijuana is associated with much larger peak plasma THC concentrations, but a shorter duration of effect than orally administered THC. The time course of plasma concentrations after smoking marijuana is similar to that obtained after intravenous administration.22 Considerably smaller amounts of 11-OH-THC are formed when THC is inhaled, as compared with the oral route.20

Cannabinoid receptors: Considerable progress has been made in understanding how cannabinoids exert their cellular effects. To date, 2 types of cannabinoid receptors (CB1 and CB2) have been identified.26,27 Cannabinoid receptors are coupled to G-proteins and inhibit adenylate cyclase in a pertussis-toxin sensitive manner.28 Central nervous system (CNS) responses to cannabinoids are believed to be mediated exclusively by the CB1 receptor. Distribution within the CNS is heterogeneous with the largest concentrations found in the basal ganglia (globus pallidus and substantia nigra pars reticulata) and cerebellum (dentate gyrus molecular layer). Moderate densities are located in the olfactory bulb, hippocampus, neocortex, amygdala, and striatum, with low densities in white matter and brainstem.28-32 Cannabinoid receptors in the striatum are located on striatal projection neurons.33 Only low concentrations of the CB1 receptor have been detected in peripheral organs.

Activation of the CB1 receptor has been noted to: ( 1) inhibit N-type voltage-gated calcium channels; (2) increase potassium conductance in hippocampal neurons; and (3) increase prostaglandin production.34 

The CB2 receptor is not expressed in the brain. It was originally detected in macrophages and in the marginal zone of the spleen and is particularly abundant in immune tissues.27 Among the formed elements of blood, the largest concentrations have been detected in B-cells and natural killer cells.35

One endogenous ligand for the CB1 receptor is an arachidonic acid derivative (N-arachidonylethanolamide) termed anandamide.36 The availability of a specific cannabinoid receptor antagonist for CB1 receptors (SR 141716A) has enhanced investigation into the functional roles of cannabinoids.37

Major proposed medical uses of marijuana

The following sections discuss the basic scientific rationale for several proposed therapeutic uses of marijuana and the evidence that has been published concerning the clinical efficacy of both marijuana and THC. While smoked marijuana can be viewed as an alternate delivery vehicle for THC, hundreds of other compounds are administered along with THC when marijuana is smoked, and the pattern of known active cannabinoid metabolites differs from those produced by oral THC. Most preclinical and human studies support the concept that THC accounts for the psychoactive effects ("high") of smoked marijuana; however, it is unclear whether THC is solely accountable for the putative appetite-stimulating, antiemetic, antispasmodic, ocular hypote nsive, and analgesic effects of smoked marijuana. Thus, when comparing responses between smoked marijuana and oral THC, both pharmacokinetic and pharmacodynamic differences based on different patterns of metabolites or interactions of additional cannabinoids and other compounds need to be considered. 

For some proposed indications, much of the human data is derived principally from open, uncontrolled studies and case reports. Where available, the results from randomized controlled trials are emphasized. An effort was made to include results from all clinical reports in which smoked marijuana was utilized, regardless of their origin.

AIDS wasting syndrome: Malnutrition is common in HIV infection, and considerable attention has been given to the use of smoked marijuana by patients with the AIDS wasting syndrome.38 This syndrome is characterized by an involuntary weight loss of at least 10 percent with chronic diarrhea, weakness, or fever (intermittent or constant) for 30 days or more in the absence of other illnesses contributing to the weight loss.39 With improvements in treating/preventing opportunistic infections, the onset of wasting has been the defining event for AIDS in 18 percent to 31 percent of the HIV-positive population.40,41 However, these prevalence estimates were obtained before the availability and widespread use of protease inhibitors in highly active antiretroviral drug cocktails. The effect of sustained viral suppression on wasting is not well established. 

Wasting may be an episodic phenomenon associated with opportunistic infections or may be more gradual in onset in association with gastrointestinal problems.42 Importantly, weight loss is an independent predictor of (short-term) survival in AIDS patients.43,44 Weight loss of more than 5 percent over 4 months is associated with an increased risk of death and opportunistic infections even in those individuals with no prior history of an opportunistic infection, and body cell mass predicts patient survival independent of CD4+ lymphocyte counts.45,46 

Potential pathophysiologic mechanisms in AIDS wasting include inadequate oral intake, intestinal malabsorption or obstruction, alterations in metabolism, endocrine dysfunction, and cytokine effects.47 Factors reducing nutrient intake include oral lesions, taste aberrations, anorexia, and lethargy. Resting energy expenditure is increased in patients with AIDS; those with secondary infection are at particular risk of inadequate caloric intake to compensate for metabolic changes.48 During periods of rapid weight loss, total energy expenditure is decreased, once again pointing to reduced energy intake as the prime determinant of weight loss in HIV-associated wasting.49 Additionally, metabolic abnormalities induced by cytokines and endocrine dysfunction are believed to contribute to alterations in protein and lipid metabolism that favor lean body mass depletion and adipose tissue conservation.

 The effect of cannabinoids on AIDS wasting presumably involves appetite stimulation. There is a lack of published data on marijuana usage by patients with AIDS wasting; however, both survey50 and data derived from placebo-controlled single dose studies51,52 indicate that smoked marijuana stimulates appetite in normal subjects. The mechanism of this effect (enhanced sensory appeal, enhanced hunger, or collapse of satiety mechanisms) is unknown. Results of chronic dosing studies in normal volunteers in a residential setting indicate that smoked marijuana stimulates appetite and increases caloric intake.53-55 

Dronabinol (THC, Marinol) is FDA-approved for the treatment of anorexia associated with weight loss in patients with AIDS. In clinical trials most patients were treated with 5 mg daily in divided doses, although the dosages ranged from 2.5 to 20 mg daily.23 Dosage must be individualized. Dosage schedules may involve administration before lunch and supper, before supper only, or prior to bedtime in patients who have particular difficulty with CNS symptoms.23 In an open pilot study involving 12 patients with HIV-associated weight loss, dronabinol 2.5 mg twice daily to 5 mg 4 times daily (per patient preference) resulted in a median weight gain of 0.54 kg/month compared with a median monthly weight loss of 0.93 kg during the previous 3 months.56 In a small double-blind, randomized, placebo-controlled, crossover trial, HIV-infected patients who had lost at least 2.25 kg of body weight, experienced an increase in body fat, improved appetite, and a trend toward weight gain (0.5 kg) over a 5-week period.57 Although the increase in percent body fat was statistically significant, it was modest compared with increases in body fat that typically occur in megestrol recipients (see following). FDA approval of dronabinol was based on a multicenter, double-blind, parallel-group trial.58 One hundred thirty-nine patients with AIDS-related anorexia and 2.3 kg weight loss were treated with dronabinol 2.5 mg twice daily or placebo for 6 weeks. Dronabinol recipients reported increased appetite and decreased nausea. Weight was stable in dronabinol recipients (mean +0.1 kg), while placebo recipients experienced a mean change of -0.4 kg (p=0.14). 

In a recent comparative trial, dronabinol was less effective than megestrol (Megace) in promoting weight gain, and it did not add to the effects of megestrol when used in combination.59 These results suggest that combining appetite stimulants does not offer added benefit in patients with AIDS wasting. 

In addition to the use of appetite stimulants such as dronabinol and megestrol, other therapies used for AIDS wasting include anabolic agents (growth hormone, testosterone and derivatives) and enteral or parenteral nutrition.60-66 The use of dronabinol may be rejected by some patients because of the intensity of central effects, an inability to effectively titrate the dose, and its delayed onset and prolonged duration of action. The use of megestrol, while promoting weight gain, may do so primarily by increasing fat content with little or no increase in lean body mass. Furthermore, in male patients, its use can lead to impotence. The use of megestrol and growth hormone is further complicated by their considerable expense. 

Under these circumstances, the use of smoked marijuana to stimulate appetite has appealed to individual patients. However, controlled evidence on its efficacy and toxicity is lacking. Research about the potential value of smoked marijuana in patients with AIDS wasting could focus on objective measures such as total energy intake, energy expenditure, and body weight and composition, as well as quality of life benefits such as feeling of well being, appetite, and enjoyment of food. However, its use requires careful evaluation of side effects that could offset benefits, including a potential risk for increased pulmonary infections and uncertainties concerning the effects of marijuana on viral load and the immune system. Because social setting may influence the appetite-stimulating effects of marijuana, clinical trials of its potential benefit should incorporate a design that enables patients to use the drug in their normal environment.

Cancer cachexia: Smoked marijuana has not been studied in patients with cancer cachexia. In studies involving investigation of THC's antiemetic effects, beneficial effects on appetite and food intake were reported by some patients on the day of chemotherapy.67,68 In open label dose-ranging studies, dronabinol 2.5 mg 2 to 3 times daily for 4 to 6 weeks improved baseline measures of mood and appetite in patients with unresectable or advanced cancer. 69-71 Weight gain was achieved in only a few patients; the usual pattern was stabilization or a decrease in the rate of weight loss. Larger doses (0.1 mg/kg) administered 3 times daily were associated with modest weight gain, but at the expense of dizziness and somnolence.72

Chemotherapy-induced nausea and vomiting: The ideal antiemetic agent would completely prevent nausea and vomiting without significant side effects, and would be easy and convenient to use at low cost. Objective methods of assessment currently used in evaluating antiemetic efficacy are the number of emetic episodes and the volume and duration of emesis. Subjective assessments include the presence or absence of nausea (visual analog scale) and patient preference. Many early studies involving THC relied on weaker criteria for assessing efficacy, such as evaluating whether the treatment was better than the prior cycle and whether the treatment was associated with at least a 50 percent decrease in emetic episodes. Evaluation of the former is complicated by the natural variation in emetic patterns and achievement of the latter does not indicate adequate control by contemporary standards.

Cisplatin is currently used as the benchmark for judging antiemetic efficacy. It is an important therapeutic agent and is a major cause of emesisvirtually 100 percent of patients exposed to the standard dose of cisplatin will vomit. Efficacy against cisplatin usually means that the antiemetic will perform at least as well against other chemotherapeutic agents. 

Studies involving THC: Interest in marijuana and THC during the 1970s and early 1980s was prompted by anecdotal patient reports of smoked marijuana's efficacy, and the fact that available agents were inadequate for control of emesis. This situation was exacerbated by the development of new, highly emetogenic drugs, and the intensification of chemotherapy regimens, including the use of combination therapies.

Several studies conducted during this period assessed the antiemetic efficacy of THC. These trials typically employed THC doses of 10 mg/m2 administered 1 to 2 hours before chemotherapy and then every 3 to 4 hours for variable periods of time afterwards. In open and randomized, double-blind crossover trials, oral THC was more effective than placebo and equivalent or superior to prochlorperazine in controlling nausea and vomiting.67,68,73-78 Except for 3 studies that used methotrexate, 5-fluoruracil + semustine, or the MOPP regimen, the chemotherapy protocols used in these studies were uncontrolled. Most studies involved patients who were refractory to standard antiemetic regimens and who had already experienced vomiting in association with chemotherapy. 

Only recently has the combination of dronabinol and prochlorperazine been evaluated. This combination was significantly more effective than either drug alone in reducing nausea and vomiting, although more than one third of patients who received the combination still vomited.79

In 2 randomized, double-blind, crossover, placebo-controlled studies, Chang et al74,80 evaluated the effectiveness of oral and smoked THC. If the patient vomited after oral dosing, smoked THC was provided for subsequent doses. The THC-containing cigarettes were prepared by injecting THC (17.4 mg) into ethanol-extracted marijuana cigarettes. In the first study, THC 10 mg/m2 was administered 2 hours prior to high-dose methotrexate chemotherapy and then every 3 hours for a total of 5 doses. THC reduced the number of retching and vomiting episodes, the degree and duration of nausea, and the volume of emesis. Clinical responses appeared to correlate with plasma THC values. Smoked THC yielded plasma concentrations more than 5 ng/mL on 70 percent of occasions compared with 44 percent of the time with oral THC. These patients were relatively young (median age = 24 years) and most had prior experience with smoked marijuana. 

In contrast, oral and smoked THC were ineffective in a small follow-up study of older patients (median age = 41 years) receiving adjuvant therapy with doxorubicin (Adriamycin) and cyclophosphamide (Cytoxan).80 Seven of the 8 patients were inexperienced in the use of smoked marijuana. Plasma concentrations of THC achieved with smoked marijuana were considerably lower than those of the previous study, perhaps because the patients were unable to effectively use the inhaled route.

Oral THC was comparable or superior to metoclopramide in 2 early studies that employed what are now recognized as subtherapeutic doses of metoclopramide.67,81 With the advent of high-dose intravenous metoclopramide, it was clear that THC is less effective than metoclopramide as an antiemetic, which itself is less effective than the 5-HT3 antagonists, ondansetron (Zofran) or granisetron (Kytril).82,83 

The product labeling for Marinol indicates that most patients respond to 5 mg administered 3 or 4 times daily. Dosage may be escalated during a chemotherapy cycle or at subsequent cycles. 

Studies involving smoked marijuana: Few published studies have reported on the antiemetic efficacy of smoked marijuana.

In a preliminary report of one randomized, double-blind study of 20 patients with various malignancies undergoing chemotherapy, pure THC was more effective for nausea than smoked marijuana in 35 percent of patients; 45 percent expressed no preference.84 There was a trend toward increased plasma concentrations with oral THC.

Several research/treatment studies were conducted by state departments of health during the late 1970s and early to mid-1980s under protocols approved by the FDA. These open label studies involved patients who had responded inadequately to other antiemetics. Smoked marijuana was comparable to or more effective than oral THC, and considerably more effective than prochlorperazine or other previous antiemetics in reducing nausea and emesis.85-88 Results of these studies generally were based on patients' and/or physicians' subjective ratings. 

The Michigan research program compared smoked marijuana with thiethylperazine (Torecan).89 During the patient's initial chemotherapy session, both interventions were comparable in their effects on vomiting. Both drugs afforded complete protection to approximately 20 percent of patients. When patients who vomited 1 to 3 times within 24 hours were included as responders, the response rate in marijuana recipients was slightly higher than in thiethylperazine recipients (45 percent versus 35 percent).

Results of the New York program have been published.90 Seventy-four patients refractory to conventional antiemetics agreed to smoke marijuana cigarettes containing approximately 10.8 mg of THC starting 6 to 8 hours prior to chemotherapy and continuing every 4 to 6 hours for a total of 4 cigarettes on the day of chemotherapy. Fifty-six patients were evaluable for efficacy. Reasons for 18 patients not participating in the study were not provided. Thirty-four percent of patients rated the marijuana as very effective, and an additional 44 percent rated the drug as moderately effective. The lack of a control group limits conclusions about the relative value of smoked marijuana in this population.

At least 3 large surveys of clinical oncologists' antiemetic drug preferences have been conducted. Two were conducted in 1990 before the use 5-HT3 antagonists for emetic control was commonplace.91,92 The most recent survey was mailed in mid-1994 to 1,500 oncologists in clinical practice; the response rate was 75 percent.93 As expected, the prescription of 5-HT3 antagonists was almost universal. Twelve percent of respondents had recommended marijuana cigarettes at least once to their patients. Twenty-eight percent favored the rescheduling of marijuana, and 30 percent indicated they might prescribe marijuana cigarettes for selected patients if the drug was rescheduled. 

In summary, substantial progress has been made in controlling chemotherapy-induced nausea and vomiting. The combination of dexamethasone and a 5-HT3 receptor antagonist prevents acute vomiting in more than 75 percent of patients exposed to cisplatin and in at least 90 percent of patients receiving moderately emetogenic regimens.83,94,95 Oral THC and smoked marijuana retain antiemetic efficacy but they are clearly less effective than current standard therapies. Although there have been few formal studies of smoked marijuana, the reported efficacy of smoked marijuana for complete prevention of acute emesis is less than what normally would be considered sufficient to warrant a formal trial given the efficacy of available agents. 

Nevertheless, acute emesis is still a problem in some patients receiving either high-dose cisplatin or the intensive chemotherapy regimens used for bone marrow or stem cell transplantation. Also, delayed emesis continues to be a problem, particularly for patients receiving high-dose cisplatin.96 Drugs that are useful in alleviating acute emesis, including the 5-HT3 antagonists, are considerably less effective in controlling delayed emesis.92 Furthermore, in some patients the efficacy of 5-HT3 antagonists in controlling acute emesis may wane over repeated cycles of chemotherapy.97 Neither smoked marijuana nor oral THC have been investigated in combination with 5-HT3 antagonists in the treatment of acute emesis, nor in the treatment of delayed nausea and vomiting. 

Glaucoma: Recognized risk factors for primary open angle glaucoma include age, race, myopia, diabetes, family history, hypertension, and elevated intraocular pressure (IOP), although some patients with normal IOP also develop glaucoma. Current therapies are directed at reducing IOP. It is anticipated that future therapies will target retinal cell death as well.

A variety of medications are available to treat glaucoma including beta adrenergic agonists, cholinergic agonists, alpha receptor agonists, beta receptor antagonists, carbonic anhydrase inhibitors, and a prostaglandin analog. These agents either enhance hydraulic conductivity, contract the ciliary body, inhibit aqueous humor formation, or enhance fluid outflow. Additionally, surgical treatments such as laser trabeculopathy, trabeculotomy/sclerostomy, drainage implants, and cytodestruction of fluid-forming tissues are used in some patients to slow progression of glaucoma. 

Ocular effects of marijuana include decreased IOP, pupil constriction, and conjunctival hyperemia. The mechanism of marijuana's ocular hypotensive effect is unknown. In normal volunteers, smoked marijuana can reduce IOP by one third, but this beneficial effect persists for only a few hours. The maximum fall in IOP occurs in a similar time frame as the hyperemic and euphoric responses.98-100 Intravenous, but not topical THC also reduced IOP in normal volunteers.101-104 

Intraocular pressure also was reduced approximately one third in a small number of patients with primary open angle or heterogeneous glaucoma who smoked marijuana containing 2 percent to 2.8 percent THC.99,105,106 In some studies, the decrease in intraocular pressure tended to parallel the decrease in systemic blood pressure. Peak effects were exerted within 90 minutes with return of the IOP to pretreatment values within 3 to 4 hours. In a randomized, double-blind study, topical administration of 0.05 percent to 0.1 percent THC did not reduce IOP in 6 patients with primary open-angle glaucoma.107 However, in another study, cannabis 5 percent extract drops decreased IOP.108

Ancillary issues pertaining to the long-term clinical use of marijuana in glaucoma patients are a theoretical concern about the potential for marijuana to reduce blood flow to the optic nerve because of its systemic hypotensive effects and its potential for interaction with other antiglaucoma drugs. Also of interest are reports that nonpsychotropic cannabinoids exert independent neuroprotective effects that might be important in delaying retinal cell death.109 Also, analogs of THC and other cannabinoids that are largely devoid of CNS effects exert ocular hypotensive effects in animals and humans who have elevated IOP but normally appearing optic tissues.110-113 

Although smoked marijuana reduces intraocular pressure, its clinical utility in glaucoma is compromised by its short duration of action and accompanying central side effects. Furthermore, the ability of marijuana or THC to protect the optic nerve has not been studied. However, at least one patient who acquired marijuana from the compassionate use program in 1988 when other agents were ineffective, has apparently continued to benefit from the drug without systemic hypotensive complications.114 The role of other cannabinoids in glaucoma should be further investigated for the development of new agents with novel or additive effects in patients who do not respond adequately to available medications.

Multiple sclerosis, spasticity, and extrapyramidal movement disorders: Cannabinoid receptors are localized to the extrapyramidal motor tracts and cerebellum. Receptor binding is most dense in outflow nuclei of the basal ganglia (substantia nigra pars reticulata and globus pallidus on projection neurons) and in the cerebellar molecular layer. CB1 agonists induce catalepsy and also potentiate the cataleptic effects of dopamine receptor antagonists.115 THC inhibits polysynaptic reflexes and potentiates hypokinesia. These properties suggest that cannabinoids possess antispasmodic and antidystonic properties. Interestingly, preclinical studies indicate that oral but not parenteral delta-8 THC suppresses the development of experimental autoimmune encephalitis in mice, which is a laboratory model for multiple sclerosis.116 

Spasticity: Anecdotal, survey, and clinical trial data support the view that smoked marijuana and oral THC provide symptomatic relief in some patients with spasticity associated with multiple sclerosis (MS) or trauma.117-119 The most recent survey targeted MS patients (n=112) who smoke marijuana to relieve their symptoms. More than 70 percent of survey respondents reported that smoked marijuana reduced spasticity, chronic pain of the extremities, paresthesias, numbness, and trigeminal neuralgia, tremor, and reactive depression and anxiety.120 The value of these results is limited by the self-selected nature of the sample, but indicates that patients believe that smoked marijuana improves major disabling features of MS.

In one small controlled study, 2 of 8 patients with multiple sclerosis who were seriously disabled with tremor and ataxia had diminished tremor and improved motor coordination in response to oral THC (5 or 15 mg) that was not duplicated with placebo substitution.121 In a double-blind placebo controlled study, 4 of 9 patients with multiple sclerosis experienced substantial benefit from oral THC (5 to 10 mg) in reducing leg spasticity, as did 3 of 8 patients with spasticity caused by other CNS lesions.122 In a double-blind, placebo-controlled, dose-escalation crossover trial involving 13 patients, oral doses of THC 7.5 mg were required for most patients to rate their spasticity as improved over a 24-hour period; 9 of these patients had previously used marijuana to treat their symptoms.123 Physician ratings of motor function, however, did not detect any significant differences between placebo and oral THC 7.5 mg. Larger doses were precluded by side effects in some patients. In a double-blind, randomized, placebo-controlled study in 10 adult patients with multiple sclerosis and spasticity, smoked marijuana (one cigarette containing 1.54 percent THC) impaired posture and balance as measured by dynamic posturography. Findings on the standard clinical neurologic examination were unaffected.124

Single oral doses of THC 5 mg exerted both analgesic and antispastic effects in a patient with spinal cord injury, who also received codeine and placebo in a double-blind, randomized and balanced order.125 The patient also was being treated with baclofen and clonazepam. In 2 patients with organically caused spasticity, oral (10 to 15 mg) and rectally administered THC (2.5 to 5 mg) improved measures of spasticity, rigidity, and pain. Bioavailabilty of THC from the rectal route was approximately twice that of the oral route.126 In a placebo-controlled, double-blind, randomized crossover pilot study, 2 of 5 patients with traumatic paraplegia treated with oral THC 35 mg experienced improvements in stretch resistance and reflex activity.127 

Other Extrapyramidal Movement Disorders: Anecdotal and open-label studies suggest that adjunctive use of smoked marijuana and cannabadiol improve symptoms in patients with various forms of dystonia.128,129 However, cannabadiol may exacerbate hypokinesia and resting tremor in patients with parkinsonism.129 Smoked marijuana did not improve symptoms of tremor in 5 patients with idiopathic parkinsonism who smoked 1-g cigarettes containing 2.9 percent THC.130 Cannabidiol was inactive in reducing chorea severity in neuroleptic-free patients with Huntington disease.131 

Only limited data exist on the effects of marijuana in patients with Tourette's syndrome who respond inadequately to standard treatment.132 Further studies are required.

Epilepsy: A considerable body of preclinical evidence indicates that cannabinoids exert anticonvulsant effects against partial seizures and generalized tonic-clonic seizures.133  Results of limited human experimentation have been mixed. One case report suggests that smoked marijuana may exacerbate epilepsy, whereas others suggest that it improves seizure control.134-136 In one small parallel group placebo-controlled trial, cannabinol 200 to 300 mg daily did not exert anticonvulsant effects over a 4-week period in mentally retarded patients with multiple seizures.137 In another small placebo-controlled trial, cannabidiol 200 mg to 300 mg administered daily for more than 4 months significantly reduced seizure frequency in 7 of 8 patients with temporal lobe epilepsy.138

In summary, limited data support the view that smoked marijuana and THC are beneficial in some patients with spasticity, improving both subjective measures of patient satisfaction and objective measures of neurologic function. Neither has been compared with standard antispastic medications. However, a clinical trial may be justified in patients who do not respond adequately to standard oral medications, or when the side effects of oral medication are intolerable, and prior to operative procedures in patients who may be candidates for intrathecal baclofen or neuroablation. Oral THC has not been tested in epilepsy, and data on smoked marijuana are too sparse to draw any conclusions.

Analgesic effects of THC and smoked marijuana: The results of one preclinical study suggest that intravenous THC exerts potent antinociceptive effects. Both supraspinal and spinal components are involved.139,140 Results of other studies that used the subcutaneous route found that THC exerted only relatively weak antinociceptive activity in standard rodent or murine models.141

Endogenous cannabinoids (ie, anandamide) cause a moderate antinociceptive state.142 This system may be tonically active in regulating pain thresholds.143 Cannabinoid-induced analgesia appears to be linked to the opioid system because intrathecal THC potentiates morphine-induced analgesia, an effect that is blocked by opioid kappa and delta receptor antagonists.144 Kappa antagonists also block THC-induced analgesia, and cannabinoid agonists increase the spinal release of dynorphin B.145,146 Additionally, anandamide decreases naloxone-precipitated withdrawal symptoms.147 One recent preclinical report of significant interest indicates that administration of a high affinity cannabinoid agonist is highly effective in relieving pain behavior in a rat model of neuropathic pain.148 Opioid analgesics are relatively ineffective in treating neuropathic pain.

Case reports suggest that smoked marijuana may benefit selected patients suffering from headache, menstrual cramps, or abdominal pain related to tubal ligation.149 In a placebo-controlled dose-ranging pilot study involving 10 cancer patients, single oral doses of THC 15 mg and 20 mg exerted significant analgesic effects in association with sedation and mental clouding.150 In a follow-up comparative study also involving cancer patients (median age = 51 years), oral THC 20 mg was comparable to codeine 120 mg in relieving pain, but caused alarming psychological effects (eg, depersonalization, loss of control) in addition to somnolence, dizziness, ataxia, and blurred vision.151 Oral THC 10 mg was less effective than 20 mg and it was comparable to codeine 60 mg. No information from controlled trials is available concerning the clinical utility of chronic dosing with smoked marijuana or oral THC for pain relief.

In summary, although oral THC produces analgesia, there is a small margin between clinical benefit and unacceptable adverse events. Smoked marijuana may benefit individual patients suffering from intermittent or chronic pain. Individuals with chronic pain who do not experience adequate relief from traditional therapies could be candidates for marijuana treatment under a compassionate use Treatment IND if it were available. The use of marijuana and/or oral THC in the treatment of neuropathic pain should be further investigated.

Debate on marijuana as medicine

Four main issues comprise the debate on medical marijuana. First, its role as a significant drug of abuse with dependence liability understandably creates reluctance among policy makers to distinguish between therapeutic uses that may help individual patients and broader patterns of abuse that irreparably damage lives and increase societal costs. This viewpoint asserts that smoked marijuana is a trivial therapeutic agent and that any stamp of medical legitimacy conveys the wrong message to the nation's youth that experimenting with marijuana is not dangerous. 

Second, the concept of burning and inhaling the combustion products of a dried plant product containing dozens of toxic and carcinogenic chemicals11 as a therapeutic agent represents a significant departure from the standard drug approval process. According to this viewpoint, legitimate therapeutic agents are comprised of a purified substance(s) that can be manufactured and tested in a reproducible manner. In recent memory, crude plant products or extracts such as rauwolfia alkaloids, digitalis leaf, and belladonna extract have been used therapeutically, albeit not by burning and inhaling, except for the use of stramonium in asthma. The use of these agents was based on clinical need and a therapeutic niche. They have since been replaced by agents that are more effective and/or easier to use because the principal ingredient has been isolated and offered in a pure dosage form. A similar situation existed from the mid-1970s to the late 1980s concerning the use of antiemetics in cancer chemotherapy. Existing treatments were inadequate, and THC as well as smoked marijuana offered significant clinical benefit to individual patients. The advent of intravenous metoclopramide, dexamethasone, and the 5-HT3 antagonists caused most clinicians to lose interest in the cannabinoids. 

Third, it is often asserted that smoked marijuana is not a unique therapeutic substance but should be viewed simply as an alternate, but toxic delivery vehicle for THC. This viewpoint  a priori rejects interest in investigating the potential therapeutic use of smoked marijuana because smoked marijuana provides at best the same therapeutic response, but at the cost of pulmonary toxicity with frequent use.152-154 However, smoked marijuana may allow individual patients to self-titrate their dosage to the point of therapeutic benefit, while minimizing undesirable psychoactive effects. It also provides a method with a more rapid onset and offset than oral THC. This may be of benefit, for example, in patients seeking appetite stimulation. 

Fourth, some believe that smoked marijuana's medical use should be framed in the traditional manner of analyzing the risks versus benefits in individual patients. Previously, the compassionate use Treatment IND program provided such an avenue. However, given the current publicity and fervor concerning medical marijuana, reinstitution of this program would not be feasible without creating a large bureaucracy. The main reason for marijuana remaining in Schedule I is the lack of adequate controlled studies demonstrating efficacy. However, clinical trials involving smoked marijuana generally should involve the treatment of conditions characterized by significant morbidity (including quality of life impairments) or mortality, or conditions for which current therapies are inadequate, not widely available, or intolerable for some patients. For acute conditions, the pulmonary and possible immunotoxicity16,155 of smoked marijuana is of less concern than it would be for patients contemplating long-term therapy. 

Conclusions

Some of the apparently disparate findings on the medical utility of smoked marijuana may be explained by the use of crude plants of variable potency and the inclusion of both experienced and naive smokers in the study. The latter feature affects the smoking behavior and efficiency of drug delivery by inhalation. Depending on the condition, research questions to be addressed on smoked marijuana include determining (1) whether it is efficacious; (2) how it compares with Dronabinol; (3) whether it is beneficial when used in combination with standard therapies or in patients refractory to standard medications; and (4) whether it has benefit primarily in marijuana-experienced smokers. Additional concerns in conducting research on smoked marijuana are the lack of data on its safety in older patients and in those with serious diseases, especially involving the cardiovascular system. A smoke-free inhaled delivery system for marijuana or THC would be preferred.

THC is moderately effective in the treatment of AIDS wasting, but its long duration of action and intensity of side effects preclude routine use. The ability of patients who smoke marijuana to titrate their dosage according to need and the lack of highly effective, inexpensive options to treat this debilitating disease create the conditions warranting a formal clinical trial of smoked marijuana as an appetite stimulant in patients with AIDS wasting syndrome.

THC and smoked marijuana are considerably less effective than currently available therapies to treat acute nausea and vomiting caused by chemotherapy, although certain patients still do not respond adequately to conventional therapy. Research involving these substances should focus on their possible use in treating delayed nausea and vomiting, and their adjunctive use in patients who respond inadequately to 5-HT3 antagonists. The use of an inhaled substance has the potential for benefit in ambulatory patients who are experiencing the onset of nausea, which precludes administration of an oral dosage form.

Very limited controlled evidence suggests cannabinoids can modify the symptoms of individual patients with spasticity or dystonia. Considerably more research is required to identify patients who may benefit from THC or smoked marijuana, and to establish whether responses are primarily subjective in nature. A therapeutic trial of smoked marijuana or THC may be warranted in patients with spasticity who do not derive adequate benefit from available oral medications, prior to their considering intrathecal baclofen therapy or neuroablative procedures.

Controlled evidence does not support the view that THC or smoked marijuana offer clinically effective analgesia without causing significant adverse events when used alone. Preclinical evidence suggests that cannabinoids can potentiate opioid analgesia and that cannabinoids may be effective in animal models of neuropathic pain. Further research into the use of cannabinoids in neuropathic pain is warranted. 

Neither smoked marijuana nor THC are viable approaches in the treatment of glaucoma, but research on their mechanism of action may be important in developing new agents that act in an additive or synergistic manner with currently available therapies.

Recommendations

Note: AMA Policy on medical marijuna was amended in June 2001 (AMA Annual Meeting) to read:

(1) The AMA calls for further adequate and well-controlled studies of marijuana and related cannabinoids in patients who have serious conditions for which preclinical, anecdotal, or controlled evidence suggests possible efficacy and the application of such results to the understanding and treatment of disease. (2) the AMA recommends that marijuana be retained in Schedule I of the Controlled Substances Act pending the outcome of such studies. (3) The AMA urges the National Institutes of Health (NIH) to implement administrative procedures to facilitate grant applications and the conduct of well-designed clinical research into the medical utility of marijuana. This effort should include: a) disseminating specific information for researchers on the development of safeguards for marijuana clinical research protocols and the development of a model informed consent on marijuana for institutional review board evaluation; b) sufficient funding to support such clinical research and access for qualified investigators to adequate supplies of marijuana for clinical research purposes; c) confirming that marijuana of various and consistent strengths and/or placebo will be supplied by the National Institute on Drug Abuse to investigators registered with the Drug Enforcement Agency who are conducting bona fide clinical research studies that receive Food and Drug Administration approval, regardless of whether or not the NIH is the primary source of grant support. (4) The AMA believes that the NIH should use its resources and influence to support the development of a smoke-free inhaled delivery system for marijuana or delta-9-tetrahydrocannabinol (THC) to reduce the health hazards associated with the combustion and inhalation of marijuana. (5) The AMA believes that effective patient care requires the free and unfettered exchange of information on treatment alternatives and that discussion of these alternatives between physicians and patients should not subject either party to criminal sanctions.

Reports by topic

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Resolutions

Resolution 407, introduced by the New York delegation; Resolution 436, introduced by the Florida delegation; and Resolution 437, introduced by the Arizona delegation, were referred to the Board of Trustees at the 1997 American Medical Association (AMA) Annual Meeting.

Resolution 407 asked:

That the AMA study and update its positions on marijuana, including whether to advocate the transfer of marijuana from Schedule I to Schedule II, and comment on the penalties for possession and prescription of marijuana proposed by the Attorney General's Office.

Resolution 436 asked:

That the AMA urge state and federal governments and the U.S. Public Health Service to open limited access to medicinal marijuana by reopening the investigational new drug program to new applicants, and

That the AMA urge Congress, the Food and Drug Administration, National Institute of Drug Abuse, Drug Enforcement Agency and all other relevant governmental agencies to expedite unimpeded research into the therapeutic potential of smokeable marijuana.

Resolution 437 asked:

That the AMA seek, in appropriate fashion, the transfer of marijuana out of Schedule I without specifying the schedule under which it belongs.
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