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Background
 
Methods

State initiatives concerning medical marijuana 
Federal Litigation Against State Initiatives

Current regulations and efforts to support research on medical marijuana 

Pharmacology of marijuana 
Constituents and Chemical Characteristics
Pharmacokinetics
Cannabinoid Receptors

Major proposed medical uses of marijuana 
HIV Wasting
Cancer Cachexia
Chemotherapy-Induced Nausea and Vomiting
Studies Involving THC
Studies Involving Smoked Marijuana
Glaucoma
Multiple Sclerosis, Spasticity, and Extrapyramidal Movement Disorders

Analgesic effects of THC and smoked marijuana 
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Adverse effects of marijuana

Progress on settling the debate on marijuana as medicine

Recommendation (Adopted AMA policy)

References

Appendix

NOTE: This report of the AMA Council on Scientific Affairs represents the medical/scientific literature on this subject as of June 2001; it was presented as CSA Report 6 at the 2001 AMA Annual Meeting.

Background. In adopting (as amended) the recommendations in Council on Scientific Affairs (CSA) Report 10 (I-97), Medical Marijuana, the American Medical Association (AMA) House of Delegates established new policy on the issue of medical marijuana.¹ At the time, this report represented the AMA?s contribution to the intensifying public debate on medical marijuana, which was fueled in part by ballot initiatives in California (Proposition 215) and Arizona (Proposition 200) that were intended to enhance access to marijuana for patients with selected medical conditions.^2,3

Subsequently, in 1999 the Institute of Medicine (IOM) published a comprehensive report commissioned by the Office of National Drug Control Policy, entitled "Marijuana and Medicine: Assessing the Science Base."⁴ The findings in this report generally agreed with the CSA?s assessment of the evidence on the potential medical utility of synthetic and plant-derived cannabinoids. The IOM report also concurred with the CSA that further research on the medical utility of marijuana and individual cannabinoids was warranted and that resources should be devoted to developing alternate, smoke-free delivery systems (see Appendix). In contrast to the CSA, the IOM report supported the availability of a compassionate-use protocol as an interim measure.

Since then, new findings have been reported on the function of endogenous cannabinoid systems, additional studies and clinical trials have been conducted on the medical utility of marijuana, and several more states have passed ballot or legislative initiatives intended to facilitate patient access to medical marijuana. This report examines these new developments, evaluates progress (or lack thereof) with respect to the Council?s previous recommendations, and summarizes the current science base on medical marijuana. For more detailed information on the history of medical marijuana, the Controlled Substances Act and efforts to remove marijuana from Schedule I, regulatory issues involved in research and treatment involving marijuana, and analysis of earlier clinical trials investigating the medical utility of marijuana, see CSA Report 10 (I-97).¹  Back to Top 

Methods

Literature searches were conducted in the MEDLINE, AIDSLINE, and Nexis databases for articles published between 1997 and April 2001 using the search terms cannabis, tetrahydrocannabinol, marijuana smoking, or cannabinoids. Secondary searches were conducted using the terms anadamide, antiemetic/therapy, and HIV wasting. Three hundred twenty-five articles were retrieved for analysis. Articles were selected based on provision of information on the function of endogenous cannabinoid systems or the clinical pharmacologic effects of cannbinoid agents. Additional references were culled from the bibliographies of these pertinent references. Back to top

State initiatives concerning medical marijuana

Between 1973 and the passage of Propositions 200 and 215 in 1996, 35 states and the District of Columbia enacted laws on medical marijuana. Thirteen states have either repealed or allowed their laws to "sunset," as most proved cumbersome to implement.⁵ Typically, these laws established therapeutic research programs; some 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 obtaining Food and Drug Administration (FDA) approval for an Investigational New Drug (IND) application. 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 was required to apply to the Drug Enforcement Administration (DEA) for a Schedule I license to receive and dispense the drug through a designated pharmacy. Some states had 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, although 14 technically remain in existence.⁶

However, in the aftermath of Propositions 200 and 215, several bills involving medical marijuana have been introduced.⁶ During the 2000 legislative session, 17 states considered various kinds of medical marijuana legislation. Advocates believe that effective laws are those that remove criminal penalties for the cultivation, possession, and use of medical marijuana. Eight states (Alaska, California, Colorado, Hawaii, Maine, Nevada, Oregon, and Washington) have enacted such measures via statute or constitutional amendment.⁶ In some cases, protection from prosecution requires registration with a state department or agency. For details on the types of physician documentation required, quantity limits, and caregiver provisions, see a recent summary on this subject.⁷ Other current state programs, including that established by Proposition 200 in Arizona, are largely symbolic in nature.

Federal Litigation Against State Initiatives. After passage of Proposition 200, the Clinton Administration warned of possible federal sanctions against those who invoked the new state medical marijuana laws. 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 believed by some to exert a chilling effect on open discourse in the patient-physician relationship. In response, a federal class action suit, Conant et al v. McCaffrey (Case No. C 97-00139 WHA), was filed by several California physicians and patients. On April 30, 1997, the U.S. District Court 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 a bona fide patient-physician relationship exists 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. After the case was heard, the U.S. District Court ruled in September 2000 that the federal government cannot penalize California physicians who recommend medical marijuana under state law even if the physician anticipates that the recommendation will, in turn, be used by the patient to obtain marijuana in violation of federal law.

Still unresolved is the role of buyers? clubs or cooperatives that facilitate distribution of marijuana for medical use. In January 1998, the U.S Department of Justice filed a civil suit, United States of America v. Oakland Cannabis Buyers? Cooperative and Jeffrey Jones (Case No. 98-16950), to stop the operation of 6 distribution centers in northern California. A temporary injunction was issued to shut down distribution, which was appealed by the Oakland Cannabis Buyer?s Cooperative. In filing a supportive Amicus Curiae Brief, the California Medical Association noted the following:⁷

In September 1999, the Ninth U.S. Circuit Court of Appeals ruled that "medical necessity" is a valid defense against federal marijuana distribution charges, provided the distributor can prove that the patients it serves are seriously ill, face imminent harm without marijuana, and have no effective legal alternatives. The case was appealed to the U.S. Supreme Court, which granted the Justice Department?s request for a temporary injunction to prevent the Oakland Cooperative from distributing medical marijuana. The court heard the appeal of the Ninth Circuit Court?s decision in March 2001 and is expected to rule by June 2001. Back to top

Current Regulations and Efforts to Support Research on Medical Marijuana

Reorganization of NIDA under the National Institutes of Health (NIH) umbrella in 1992 prompted an internal review of policies and procedures that resulted in application of the peer-review process to projects involving the resources of NIDA. Although projects designed to study the effects of cannabis receive the requisite local institutional and FDA approvals, they still must achieve satisfactory competitive scores under the NIH review process.⁸ 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 NIH resources.

In May 1999, the Department of Health and Human Services announced a new guidance on procedures for the provision of marijuana for medical purposes on a cost-reimbursable basis.⁹ For protocols submitted by non-NIH funded sources, institutional peer review should precede the submission, after which the scientific merits of each protocol are evaluated through a Public Health Service interdisciplinary review process, with particular attention given to compliance with appropriate design elements outlined by a 1997 NIH Workshop.¹⁰ As before, researchers who propose to conduct investigations in humans must fulfill the FDA?s IND requirements and obtain a valid registration from the DEA for research with Schedule I drugs. This guidance creates an avenue for externally funded investigators to acquire marijuana for research purposes, but retains additional review and approval steps that are not required of other traditional IND-sponsors.

In another effort to promote research on medical marijuana, California?s State Assembly appropriated $3 million to establish a university-based Center for Medicinal Cannabis Research, to be administered jointly by the University of California?s San Diego and San Francisco campuses. The legislation calls for a 3-year program overseeing objective, high-quality medical research. Any research institution in California can apply for funds, to be awarded in support of studies that focus on the diseases and conditions previously identified by the NIH and IOM as warranting further study.^4,10 The cannabis to be used in such studies will be obtained from NIDA in accordance with the procedures outlined above.

In another government-funded initiative, Canada announced that it would make marijuana available on a compassionate-use basis for individual patients. Under the plan, which would go into effect July 31, 2001, terminally ill patients and people suffering from chronic illnesses could buy, cultivate, and use marijuana for medicinal purposes. Patients would require a physician?s recommendation, to be submitted by application to the government. Third parties would be able to grow marijuana for patients who cannot grow the plants themselves. Back to top

Pharmacology of Marijuana

Constituents and Chemical Characteristics. Marijuana contains more than 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 (hereafter referred to as 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 THC in marijuana plants usually ranges from 0.3% to 4% based on the climate, soil and growing conditions, and handling after harvest, but values as high as 20% 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% to 20%) 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, inhibiting adenylate cyclase in a pertussis-toxin sensitive manner, and activating protein kinase.^28,29 CB₁ receptors inhibit voltage-gated calcium channels and increase potassium conductance. Other effector systems for cannabinoid receptors also have been proposed.^29,30

Central nervous system (CNS) responses to cannabinoids are mediated by CB₁ receptors. Distribution within the CNS is heterogeneous, with the largest concentrations found in basal ganglia, cerebellum, hippocampus, cerebral cortex, and nucleus accumbens. Moderate concentrations are found in the hypothalamus, amygdala, spinal cord, brain stem, central gray, and nucleus of the solitary tract.^31-34 Cannabinoid receptors in the striatum are located on striatal projection neurons, and interneurons that enable functional interactions between striatal output patjways.^35,36 Most, but not all, CNS cellular responses mediated by CB₁ receptors are inhibitory. Lower concentrations of the CB₁ receptors are present in peripheral neural and non-neural tissue.

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.³⁷

Endogenous ligands for the cannabinoid receptors discovered to date are arachidonic acid derivatives (N-arachidonylethanolamide) termed anandamide, and arachidonyl glycerol (2-AG).^38,39 Most cannabinoid compounds (THC, Δ^{8THC, 11-OH-}Δ^9THC) bind with similar affinity to CB₁ and CB₂, except cannabidiol which has higher affinity for CB₂ receptors. Anadamide is less potent and shorter acting than THC and functions as a partial agonist in some test systems. Its distribution does not strictly parallel CB₁ receptor distribution in the CNS. Arachidonyl glycerol binds with low affinity but exhibits full efficacy.³⁹ In CB₂-containing cells, 2-AG is a full agonist; because it functions as a partial agonist, anadamide may attenuate the activity of 2-AG in some of these cells.⁴⁰

Specific cannabinoid receptor agonists and antagonists for CB₁ and CB₂ receptors are available to further enhance knowledge about the functional roles of endogenous cannabinoids.^41,42 Anandamide inhibits motor activity, prolactin release, and gastrointestinal motility; causes hypothermia, analgesia, hypotension, and bradycardia; interferes with learning and memory; activates the hypothalamic-pituitary-adrenal axis; decreases intraocular pressure; and modulates several immune parameters.⁴² Recently, it has been proposed that anandamide also activates the vanilloid receptor (VR1); VR1 is a ligand-gated ion channel that is activated by capsaicin, and plays an important role in modulating pain and inflammation.⁴³ Cannabinoids also may exert antioxidant and cytoprotective effects that are independent of receptor activity.⁴⁴  Back to top

Major Proposed Medical Uses of Marijuana

The following sections discuss the basic scientific rationale for several proposed therapeutic uses of marijuana and summarize the published evidence 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 hypotensive, 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 uses, human data are 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.

HIV-Wasting. Malnutrition is common is HIV infection, and attention has been given to the use of smoked marijuana by patients with HIV-wasting.⁴⁵ Previously, the AIDS-wasting syndrome was defined as involuntary weight loss of at least 10%, 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.⁴⁶ With improvements in treating/preventing opportunistic infections, the onset of wasting was the defining event for AIDS in 18% of the adult and 15% of the pediatric (<13 years of age) HIV-positive population in 1997.^47,48 With the change in AIDS case definition that occurred in 1997, wasting is no longer monitored as an AIDS indicator. Furthermore, the 1997 prevalence estimates were obtained before the widespread use of protease inhibitors in highly active antiretroviral therapy drug (HAART) cocktails. Because significant loss of body weight occurs earlier in the course of HIV illness, the term HIV-wasting will be applied.

HIV-wasting may be an episodic phenomenon associated with opportunistic infections or may be more gradual in onset in association with gastrointestinal problems.⁴⁹ Importantly, weight loss and decreases in body cell mass are independent predictors of (short-term) survival in AIDS patients.^50-53 Potential pathophysiologic mechanisms in HIV-wasting include inadequate oral intake and intestinal malabsorption or obstruction. Alterations in metabolism, endocrine dysfunction, and 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.⁵⁴ However, in HIV-infected men who suffer progressive decreases in fat and lean tissue, the composition of weight lost appears to depend on baseline fat content. This notion is contrary to the previous, widely held notion that HIV-wasting is characterized solely by preservation of fat at the expense of lean tissue.⁵⁵ In contrast, women exhibit a progressive and disproportionate decrease in body fat relative to lean body mass at all stages of wasting, consistent with gender-specific effects in body composition in HIV-wasting.⁵⁶

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.⁵⁷ During periods of rapid weight loss, total energy expenditure is decreased, once again pointing to reduced energy intake as a prime determinant of weight loss in HIV-wasting.⁵⁸

The effect of sustained viral suppression on HIV-wasting is not well established, but HAART is a potentially important treatment. Nevertheless, loss of body cell mass occurs in some patients who are receiving protease inhibitors. Additionally, resistant HIV strains emerge in some patients, and some are unable to tolerate or comply with therapy. HARRT also has been associated with weight gain and redistribution of fat with no change in lean body mass.⁵⁹ Therefore, recognition and appropriate management of HIV-wasting will likely continue to be clinically important.

Approaches to HIV-wasting include nutritional supplements, appetite-stimulating drugs, testosterone, testosterone analogues, and other anabolic steroids, growth hormone, cytokine modulators, and institution of exercise training. ^60-66 Testosterone and like agents are indicated in men with wasting and hypogonadism.⁵⁹ Androgen deficiency also occurs in HIV-infected women; low-dose, transdermal application of testosterone may be beneficial.⁵⁹ Many patients with HIV-wasting are relatively resistant to growth hormone, but larger doses than those required for replacement therapy can be used in patients who do not respond adequately to other therapies.⁵⁹

The use of cannabinoids in patients with HIV-wasting is directed toward appetite stimulation. Appetite-stimulating drugs should generally be reserved for patients with weight loss and reduced food intake; however, such drugs tend to increase fat more than lean body mass.⁵⁹ Dronabinol (THC, Marinol? ) is FDA-approved for the treatment of anorexia associated with weight loss in patients with AIDS. In short-term trials, dronabinol stimulates appetite and decreases nausea, but its use is associated with only minimal weight gain.^23,67,68 However, a long-term open-label extension of the multicenter trial that served as the basis for FDA approval showed that patients achieved stable body weight for at least 7 months.⁶⁹ Dronabinol is less effective than megestrol (Megace? ) in promoting weight gain, and its effects are not additive when used in combination.⁷⁰ 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. Use of megestrol in male patients can lead to impotence, and it is an expensive drug.

Smoked marijuana stimulates appetite and increases caloric intake in normal subjects.^71-76 Because of the limitations associated with dronabinol and megestrol, the use of smoked marijuana to stimulate appetite has appealed to individual HIV-infected patients. In a prospective, randomized, placebo-controlled safety study reported recently, adult inpatients with a stable viral load on a stable antiviral regimen received marijuana cigarettes (3.95% THC), dronabinol (2.5 mg), or placebo 3 times daily for 3 weeks. All patients gained weight, with disproportionate increases in % body fat. Smoked marijuana had no deleterious effects on HIV RNA load or CD4+ cell counts, and caused clinically minor effects on the disposition kinetics of 1 of the protease inhibitors used (indinivar but not nelfinavir). Serum testosterone was slightly, but not significantly lower in marijuana or dronabinol recipients.^77-79

Information is lacking on the short- and long-term effects of marijuana in patients with HIV-wasting, particularly with respect to objective measures such as total energy intake, energy expenditure, body weight and composition, viral load, and other important immunologic markers. THC is only moderately effective in the treatment of HIV-wasting, and its long duration of action and intensity of side effects preclude routine use in some patients. 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 HIV-wasting syndrome. Preferably, trials should be conducted in concert with an anabolic agent. Preliminary findings in patients with stable viral loads point to the need for additional long-term data on safety and efficacy, as well as potential effects on the disposition of protease inhibitors.

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.^80,81 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.^82-84 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. ⁸⁵

Chemotherapy-Induced Nausea and Vomiting:   Cannabinoid receptors are relatively abundant in the solitary tract nucleus, a key relay center in the control of vomiting. Most reports on the antiemetic effects of marijuana or cannabinoids are based on chemotherapy-induced emesis. 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. Cisplatin is currently used as the benchmark for judging antiemetic efficacy. An important therapeutic agent, cisplatin is a major cause of emesis–virtually 100% of patients exposed to the standard dose will vomit. Efficacy against cisplatin usually means that the antiemetic will perform at least as well against other chemotherapeutic agents.

Many early studies involving THC relied on weaker criteria for assessing efficacy, such as evaluating whether nausea and vomiting was not as severe as during the previous cycle of chemotherapy, or whether the treatment was associated with at least a 50% 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. 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. The development of new, highly emetogenic drugs, and the intensification of chemotherapy regimens, including the use of combination therapies, exacerbated this situation.

Studies Involving THC: In several 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 in patients undergoing various chemotherapy protocols.^80,81,86-91 Most studies involved patients who were refractory to standard antiemetic regimens and who had already experienced vomiting in association with chemotherapy. Anticipatory emesis would be expected to reduce the efficacy of any agent tested in these patients. The combination of dronabinol and prochlorperazine was more effective than either drug alone in reducing nausea and vomiting, although more than one third of patients who received the combination still vomited.⁹² Oral THC is less effective than the use of high-dose, intravenous metoclopramide as an antiemetic, which itself is less effective than the 5-HT₃ antagonists.^80,93-95

Studies Involving Smoked Marijuana. In randomized, double-blind, crossover, placebo-controlled studies, oral and smoked THC reduced the number of retching and vomiting episodes, the degree and duration of nausea, and the volume of emesis in patients who were relatively young (median age = 24 years) and who had prior experience with smoked marijuana.⁸⁷ When directly compared, oral THC was preferred to smoked marijuana, but only 20% to 25% of patients receiving either drug achieved complete control of emesis.^96,97 Oral and smoked THC were ineffective in older patients (median age = 41 years) who were inexperienced in the use of smoked marijuana and were subjected to more highly emetogenic regimens.⁹⁸

Only a few other open studies have reported on the antiemetic efficacy of smoked marijuana. These involved research/treatment studies that 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.^97,99-103 Results of these studies generally were based on patients? and/or physicians? subjective ratings.

Delta-8-tetrahydrocannabinol, a cannabinoid with lower psychotropic potency than THC, was administered (18 mg/m² in edible oil, p.o.) to 8 children, aged 3 to 13 years with various hematologic cancers, treated with different antineoplastic drugs for up to 8 months. Treatment was administered 2 hours before each antineoplastic regimen and was continued every 6 hours for 24 hours. Vomiting was completely prevented and side effects were negligible.¹⁰⁴

At least 3 large surveys of clinical oncologists? antiemetic drug preferences have been conducted. Two were conducted in 1990 before the use of 5-HT₃ antagonists for emetic control was commonplace.^105,106 The most recent survey was mailed in mid-1994 to 1,500 oncologists in clinical practice; the response rate was 75%.¹⁰⁷ 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% 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. Based on clinical trials results, practice guidelines advocate the combined use of dexamethasone and a 5-HT₃ receptor antagonist to prevent acute vomiting in patients exposed to moderately and highly emetogenic agents.^95,108-110 Oral THC and smoked marijuana retain antiemetic efficacy but are clearly less effective than current standard therapies. In acute chemotherapy-induced emesis, especially in the high-risk setting, there is no group of patients for whom agents of lower therapeutic index (metoclopramide, phenothiazines, butyrophenones, and cannabinoids) are appropriate as first choice antiemetic drugs. These agents should be reserved for patients intolerant of or refractory to serotonin receptor antagonists and corticosteroids.¹¹⁰ Although there have been few formal studies of smoked marijuana, its reported efficacy 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. ¹¹¹ Furthermore, in some patients the efficacy of 5-HT₃ antagonists in controlling acute emesis may wane over repeated cycles of chemotherapy.¹¹² Also, delayed emesis continues to be a problem, particularly for patients receiving high-dose cisplatin.¹¹⁰ Drugs that are useful in alleviating acute emesis, including the 5-HT₃ antagonists, are considerably less effective in controlling delayed emesis.¹⁰⁶ Results of initial clinical trials with neurokinin NK₁ receptor antagonists demonstrate enhanced control of acute emesis with their addition to currently available agents and promising activity in controlling delayed emesis. 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.

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. Use of an inhaled substance has potential benefit in ambulatory patients who are experiencing the onset of nausea, which precludes administration of an oral dosage form.

Glaucoma: Recognized major risk factors for primary open-angle glaucoma (the most common form) include age, race, and elevated intraocular pressure (IOP); the presence of myopia, diabetes, hypertension and a positive family history also may contribute. This is a slowly progressive disorder that results in loss of retinal ganglion cells and degeneration of the optic nerve. 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 prostaglandin F_2a analogs. These agents 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.^100,113-115 Intravenous, but not topical THC also reduced IOP in normal volunteers.^116-119

Smoked or eaten marijuana and oral THC reduce IOP by approximately 25% in people with normal IOP who have visual field changes; results are similar in healthy adults and glaucoma patients.^{113,114,120-122} Peak effects were exerted within 90 minutes, with return of the IOP to pretreatment values within 3 to 4 hours. Intravenous administration of THC, D ⁸THC, or 11-OH-D ⁹THC in healthy adults also substantially decreased IOP.^117,118 Topical application of cannabis extract, but not THC, also decreased IOP.^122,123

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.¹²⁴ 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.^125-128

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 cardiovascular, pulmonary, and CNS effects of marijuana are of great concern given that glaucoma is a chronic illness and a large number of patients are elderly. Additionally, 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 federally administered compassionate-use program in 1988 when other agents were ineffective has apparently continued to benefit from the drug without systemic hypotensive complications.¹²⁹ Neither smoked marijuana nor THC is a viable approach 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.

Multiple Sclerosis, Spasticity, and Extrapyramidal Movement Disorders: The highest densities of CB₁ receptors are found in 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 receptors are also located in cortical areas, which project to alpha and gamma spinal motor neurons via the corticospinal tract.

Low doses of cannabinoid agonists increase motor activity, while larger doses induce catalepsy and also potentiate the cataleptic effects of dopamine receptor antagonists.¹³⁰ 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.¹³¹

Spasticity. Anecdotal, survey, and clinical trial data support the view that smoked marijuana and oral THC provide subjective relief of spasticity, pain, and tremor in some patients with multiple sclerosis (MS) or trauma^132-135 Posture and balance may be impaired in some of these patients who smoke marijuana. The overall value of these results is limited by the self-selected nature of the sample, but indicates that patients believe that smoked marijuana improves certain major disabling features of MS. In small controlled studies, selected MS patients had diminished tremor, reduced spasticity, and improved motor coordination in response to oral THC (5 to 15 mg).^136-138 In some studies, physician ratings of motor function, or the findings on standard clinical neurologic examination did not comport with the patient?s report.^138,139

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.¹⁴⁰ 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.¹⁴¹ 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.¹⁴²

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.^143,144 However, cannabadiol may exacerbate hypokinesia and resting tremor in patients with parkinsonism.¹⁴⁴ Smoked marijuana did not improve symptoms of tremor in 5 patients with idiopathic parkinsonism who smoked 1-g cigarettes containing 2.9% THC.¹⁴⁵ Cannabidiol was inactive in reducing chorea severity in neuroleptic-free patients with Huntington?s disease.¹⁴⁶

Only limited data exist on the effects of marijuana in patients with Tourette?s syndrome who respond inadequately to standard treatment, consisting of 4 case histories that report beneficial effects of smoked marijuana and 1 who reported substantial benefit from oral 9THC (10 mg). ^147-147

Epilepsy. A considerable body of preclinical evidence indicates that cannabinoids exert anticonvulsant effects against partial seizures and generalized tonic-clonic seizures.¹⁵⁰ 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.^151-153 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.¹⁵⁴ In another small placebo-controlled trial, cannabidiol 200 to 300 mg administered daily for more than 4 months significantly reduced seizure frequency in 7 of 8 patients with temporal lobe epilepsy.¹⁵⁵

In summary, limited controlled evidence supports the view that smoked marijuana and THC can provide symptomatic relief in patients with MS, spinal cord injury, and other causes of spasticity. Both subjective measures of patient satisfaction and, less commonly, objective measures of neurologic function may be improved. Neither has been compared with standard antispastic medications. 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. 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.  Back to top

Analgesic Effects of THC and Smoked Marijuana

Animal Studies. In rodents, cannabinoids provide analgesic responses against thermal, mechanical, and chemical stimuli.⁴ Intravenous THC exerts more potent antinociceptive effects than the subcutaneous route.^156-158 Endogenous cannabinoids (eg, anandamide) also cause a moderate antinociceptive state, and are released in response to noxious stimuli.^159,160

Multiple brain and spinal cord areas (periaqueductal gray, rostral vental medulla, thalamic nuclei, dorsal horn) as well as peripheral sensory nerves mediate the effects of cannabinoids on pain processing. These areas also participate in opioid analgesia. Like the latter, the endogenous cannabinoid system may be tonically active in regulating pain thresholds.¹⁶¹ Administration of cannabinoid antagonists increases the sensitivity of rodents to pain.

Cannabinoid-induced analgesia may 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 in mice.¹⁶² Kappa antagonists also block THC-induced spinal analgesia, and cannabinoid agonists and THC increase the spinal release of dynorphins.^163-165 Additionally, anandamide decreases naloxone-precipitated withdrawal symptoms.¹⁶⁶ In primates, however, THC and anandamide cause dose-dependent antinociception, but these effects are not blocked by antagonism of opioid receptors.¹⁶⁷ Interestingly, administration of high affinity cannabinoid agonists relieves pain behavior in a rat model of neuropathic pain and blocks the development of hyperalgesia produced by capsaicin in rodents.^168,169 Endogenous endocannabinoids protect against central hyperalgesia and allodynia that sometimes develops after skin or nerve injuries.^170,171 CB₁ and CB₂ agonists appear to potentiate one another in this regard.^172,173 Opioid analgesics are relatively ineffective in treating neuropathic and central pain syndromes.

Human Studies. The effects of smoked marijuana on pain responses in humans are variable. In some volunteer studies, marijuana increased the acute pain response to thermal, electrical, and ischemic stimuli.^174-176 In open studies involving acute pain, intravenous THC was not analgesic in patients with dental pain or experimental pain induced by electrical stimulation or noxious pressures.¹⁷⁷ However, in human volunteers, smoked marijuana produced dose-dependent analgesic effects; naltrexone did not block either the analgesic effects of smoked marijuana nor the subjective effects of oral THC.^178,179 Also, in patients with moderate-to-severe trauma or postoperative pain, intramuscular injection of a synthetic THC analogue was more effective than placebo.¹⁸⁰ These disparate effects may reflect the dual action of cannabinoids at the VR₁ receptor.

Case reports suggest that smoked marijuana may benefit selected patients suffering from headache, menstrual cramps, or abdominal pain related to tubal ligation, and may decrease opioid requirements.^181,182 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.¹⁸³ 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.¹⁸⁴ Oral THC 10 mg was less effective than 20 mg, and it was comparable to codeine 60 mg. Similar results were obtained in a study involving a THC analogue in patients with cancer pain.¹⁸⁵ No information from controlled trials is available concerning the clinical utility of chronic dosing with smoked marijuana or oral THC for pain relief.

Controlled evidence does not support the view that THC or smoked marijuana offers clinically effective analgesia without causing significant adverse events when used alone. There is a small margin between clinical benefit and unacceptable adverse events. However, smoked marijuana may benefit individual patients suffering from intermittent or chronic pain. 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. Back to top

Adverse Effects of Marijuana

Nonmedical use of marijuana continues to be problematic in society. Approximately one third of all Americans over 12 years of age have tried marijuana, usually experimenting first during adolescence.⁴ However, the age distribution of those who use marijuana among the general population declines sharply after age 34, while most medical marijuana users are more than 35 years of age.⁴ Since 1997, an increasing percentage of young adults aged 18 to 25 years (up from 12.8% to 16.4%) and a decreasing percentage of youths aged 12 to 17 years (down from 9.4% to 7%) perceive smoking marijuana once or twice a week as presenting great risk of harm.¹⁸⁶ It is not clear whether these trends have been influenced by the medical marijuana debate.

Most research on the harmful consequences of marijuana use has been conducted in simulated laboratory environments and in individuals who use cannabis for nonmedical purposes. Some of marijuana?s adverse effects differ in experienced versus inexperienced users, and it is not clear to what extent the adverse effects reported in recreational users are applicable to those who use medical marijuana.

Acutely, marijuana increases heart rate, and blood pressure may decrease on standing. Intoxication is associated with impairment of short-term memory, attention, motor skills, reaction time, and the organization and integration of complex information.^187,188 Although dependent on the setting, marijuana can cause relaxation and enhance mood. Ordinary sensory experiences may be intensified, with increased talkativeness, perceptual alterations, and distortion in time sense followed by drowsiness and lethargy. These effects appear to be mediated by CB₁ receptors because they are diminished by selective antagonism of the CB₁ receptor.¹⁸⁹ However, some individuals experience acute anxiety or panic reactions, confusion, dysphoria, paranoia, and psychotic symptoms (eg, delusions, hallucinations).¹⁸⁸

Heavy users may experience apathy, lowered motivation, and impaired cognitive performance.¹⁸⁸ Chronic marijuana use is associated with development of tolerance to some effects and the appearance of withdrawal symptoms (restlessness, irritability, mild agitation, insomnia, sleep disturbances, nausea, cramping) with the onset of abstinence. Depending on the measures and age group studied, 4% to 9% of marijuana users fulfill diagnostic criteria for substance dependence. Although some marijuana users develop dependence, they appear to be less likely to do so than users of alcohol and nicotine, and the abstinence syndrome is less severe.^4,188,190 Like other drugs, dependence is more likely to occur in individuals with co-morbid psychiatric conditions.

Data on drug use progression and the view that marijuana is a "gateway" drug pertain to nonmedical use. However, "present data on drug use progression neither support nor refute the suggestions that medical availability [of marijuana] would increase drug abuse."⁴ Of comparable or greater concern, are potential adverse effects of cannabinoids and marijuana smoke on the immune, respiratory, cardiovascular, and reproductive systems, and the potential for enhancing carcinogenesis."⁴

In addition to effects attributable to THC, the chronic effects of marijuana smoke are of perhaps greater concern than marijuana?s acute safety profile. Like tobacco, chronic marijuana smoking is associated with lung damage, increased symptoms of chronic bronchitis, and possibly increased risk of lung cancer.

Cannabinoids impair cell-mediated and humoral immunity in rodents and decrease resistance to infection; however, there is no conclusive evidence that consumption of cannabinoids impairs human immune function, and some evidence suggests that cannabinoids exert anti-tumor effects in human cancer cell lines.^191,192 Cannabinoids and cannabinoid receptor agonists exert both inflammatory and anti-inflammatory effects and also appear to modulate hematopoiesis and possibly tumor growth.¹⁹³ Clearly, cannabinoids are immune modulators, but how they regulate various elements of the human immune response is unclear.¹⁹⁴ The initial safety trials in HIV-positive patients are encouraging regarding a lack of apparent marijuana-induced immunosuppression, but these were short-term trials.
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Progress on Settling the Debate on Marijuana as Medicine

Four main issues comprise the debate on medical marijuana: (1) its role as a significant drug of abuse and the reluctance of policy makers to dissociate the potential harmful effects of recreational marijuana use from its potential therapeutic effects; (2) the wisdom of burning and inhaling the combustion products of a dried plant product as a valid therapeutic agent; (3) the view that smoked marijuana is not a unique therapeutic substance but rather represents an alternate, but more toxic, delivery vehicle for delta-9-tetrahydrocannabinol (THC; Dronabinol?); and (4) the value of analyzing smoked marijuana?s potential medical use in the traditional manner of risk versus benefit in individual patients.

Since CSA Report 10 (I-97) was written, substantial progress has occurred in further elucidating the role of endogenous cannabinoid systems, but this has not been matched by high-quality clinical research into the potential medical utility of marijuana or its constituents. The lack of this evidence base continues to hamper development of rational public policy. 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 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 respiratory and cardiovascular system. A smoke-free inhaled or sublingual delivery system for whole marijuana extract or isolated cannabinoids would be preferred, and some progress has been made in this effort by the pharmaceutical industry.

Based on the current science base, the following conditions continue to merit further study on the potential medical utility of marijuana. In some cases, advantage may be taken of multiple pharmacologic effects of cannabinoids. Conditions for which continued research into the potential therapeutic effects include:

• HIV-infected patients with cachexia, neuropathy, or chronic pain, or who are suffering adverse effects from medication, such as nausea, vomiting, and peripheral neuropathy, that impede compliance with antiretroviral therapy;
• Patients undergoing chemotherapy, especially those being treated for mucositis, nausea, and anorexia, and those patients who do not obtain adequate relief from either acute or delayed emetic episodes from standard therapy;
• To potentiate the analgesic effects of opioids and to reduce their emetic effects in the treatment of postoperative, traumatic, or cancer pain;
• Patients suffering from spasticity or pain due to spinal cord injury, or neuropathic or central pain syndromes; and
• Patients with chronic pain and insomnia.

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RECOMMENDATION

The following statement, recommended by the Council on Scientific Affairs, was adopted as AMA policy by the AMA House of Delegates at the 2001 AMA Annual Meeting:

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.

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A ppendix. Institute of Medicine: Marijuana and Medicine:
 Assessing the Science Base

RECOMMENDATION 1: Research should continue into the physiological effects of synthetic and plant-derived cannabinoids and the natural function of cannabinoids found in the body. Because different cannabinoids appear to have different effects, cannabinoids research should include, but not be restricted to, effects attributable to THC alone.

 Scientific data indicate the potential therapeutic value of cannabinoid drugs for pain relief, control of nausea and vomiting, and appetite stimulation. This value would be enhanced by a rapid onset of drug effect.

RECOMMENDATION 2: Clinical trials of cannabinoid drugs for symptom management should be conducted with the goal of developing rapid-onset, reliable, and safe delivery systems.

The psychological effects of cannabinoids are probably important determinants of their potential therapeutic value. They can influence symptoms indirectly which could create false impressions of the drug effect or be beneficial as a form of adjunctive therapy.

RECOMMENDATION 3: Psychological effects of cannabinoids such as anxiety reduction and sedation, which can influence medical benefits, should be evaluated in clinical trials.

Numerous studies suggest that marijuana smoke is an important risk factor in the development of respiratory diseases, but the data that could conclusively establish or refute this suspected link have not been collected.

RECOMMENDATION 4: Studies to define the individual health risks of smoking marijuana should be conducted, particularly among populations in which marijuana use is prevalent.

Because marijuana is a crude THC delivery system that also delivers harmful substances, smoked marijuana should generally not be recommended for medical use. Nonetheless, marijuana is widely used by certain patient groups, which raises both safety and efficacy issues.

RECOMMENDATION 5: Clinical trials of marijuana use for medical purposes should be conducted under the following limited circumstances: trials should involve only short-term marijuana use (less than six months), should be conducted in patients with conditions for which there is reasonable expectation of efficacy, should be approved by institutional review boards, and should collect data about efficacy.

If there is any future for marijuana as a medicine, it lies in its isolated components, the cannabinoids and their synthetic derivatives. Isolated cannabinoids will provide more reliable effects than crude plant mixtures. Therefore, the purpose of clinical trials of smoked marijuana would not be to develop marijuana as a licensed drug but rather to serve as a first step toward the development of nonsmoked rapid-onset cannabinoid delivery systems.

RECOMMENDATION 6: Short-term use of smoked marijuana (less than six months) for patients with debilitating symptoms (such as intractable pain or vomiting) must meet the following conditions:

•   failure of all approved medications to provide relief has been documented,
• the symptoms can reasonably be expected to be relieved by rapid-onset cannabinoid drugs,
• such treatment is administered under medical supervision in a manner that allows for assessment of treatment effectiveness, and
• involves an oversight strategy comparable to an institutional review board process that could provide guidance within 24 house of a submission by a physician to provide marijuana to a patient for a specified use.

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