Medical Marijuana Update #2

The use, abuse, and prescription of medical marijuana is, no doubt, an evolving landscape. I have a chapter on medical marijuana in my book, Alternative Medicine: The Christian Handbook (endorsed by the Christian Medical Association). Now, here’s an excellent update to that chapter by Matthew J. Seamon, PharmD, JD, which was published in MedScape:

Background

Marijuana has been used medically, recreationally, agriculturally, and industrially for millennia.[1] As a drug, marijuana was widely used by patients, under the direction and care of physicians and pharmacists, until the early part of the twentieth century, when the Marijuana Tax of 1937 essentially outlawed its use.

As a therapeutic mainstay, marijuana then underwent a draconian ban for almost 60 years until California passed Proposition 215 in 1996. Since then, marijuana has undergone an important resurrection and has increasingly gained popularity, acceptance, and momentum.[1]

What started in the West eventually sprouted to the East and is now encroaching on the Midwest. Moreover, Canada has a national program for medical marijuana, and Mexico has recently passed a personal use law, permitting individuals to possess small amounts of marijuana among other drugs.

Marijuana is used for a multitude of ailments; however, its primary utility is restricted to 5 general categories:

  • pain,
  • nausea and vomiting,
  • weight loss associated with debilitating disease,
  • neurologically induced spasticities, and
  • other uses such as glaucoma.[1]

Marijuana is a natural product derived from the Cannabis sativa plant. It has about 450 active constituents, including 60-plus compounds classified as cannabinoids.

The compound most often identified as the primary active constituent of marijuana is tetrahydrocannabinol (delta-9-THC, THC), although to a lesser extent, cannabidiol and cannabinol are also highly psychoactive and contribute significantly to marijuana’s medicinal effects.[1,2]

Nevertheless, marijuana is best understood not as a single uniform plant but as a sophisticated weed with hundreds of variants and a wide range of compositions and effects.[2]

The potency of THC varies from:

  • insignificant in hemp, the industrial fiber of the plant,
  • to 3%-6% typically found in smoked marijuana,
  • to > 6% widely found in hashish, a resinous and compressed paste obtained from the dried flowers of the plant.[2]

However, recent bioengineering of the plant has greatly impacted this yield for more potent and active products.

There are 2 cannabinoid subtype receptors, CB1 and CB2.[1-3] The CB1 receptor exists primarily in the brain and spinal cord and is involved with pleasure, memory, sensory and time perception, and coordinated movement, among other effects. The CB2 receptor is found mainly in the periphery and immune tissue and is involved with immunomodulation, inflammation, nociception, and gastrointestinal motility.[3]

In the United States there are 2 commercially available synthetic cannabinoids approved for marketing:

  • Marinol® (delta-9-THC; Solvay Pharmaceuticals, Inc., Marietta, Georgia) and
  • Cesamet® (nabilone; Valeant Pharmaceuticals International, Aliso Viejo, California).
  • Sativex® (delta-9-THC/cannabidiol; GW Pharmaceuticals, Wiltshire, United Kingdom) is a phytocannabinoid-based buccal product approved in Canada and in late-phase clinical testing in the United States.

Legal Risks

Marijuana is regulated as a Schedule I controlled substance in the United States, meaning the drug has a high potential for abuse, no currently accepted medical use in treatment, and a lack of accepted safety under medical supervision.

Thus, use and possession is a federal offense.

Meanwhile, since 1999, 14 states have passed laws supporting the use of medical marijuana. Suffice it to say, the legal landscape surrounding medical marijuana has been murky.

However, the waters are becoming increasingly clearer as the US Department of Justice issued an important memorandum on October 19, 2009.[4] The memo provides federal prosecutors with direction for enforcement discretion in their pursuit of violations of the Controlled Substance Act. It guides federal prosecutors to focus their investigations on major violations like trafficking and large-scale growing, and to leave alone individuals in clear, unambiguous compliance with state marijuana laws.[4]

The key to navigating the legal battleground of medical marijuana is the fact that about 99% of marijuana-related arrests are state and local.[1] Thus, if you are in compliance with your state and local laws, the risk for arrest is nonsignificant.

Local law enforcement is generally instructed to give deference to registered patients and caregivers. Also, state Boards of Health license physicians and other healthcare providers. Thus, in states with medical marijuana legislation, the risk for professional discipline is inconsequential if following the law.

Nevertheless, clinicians do face some degree of risk, especially under federal law. Physicians, pharmacies, and some midlevel practitioners are registered with the US Drug Enforcement Administration (DEA) to prescribe and dispense controlled substances.

Because marijuana is a Schedule I controlled substance, the DEA theoretically can revoke these licenses, and federal law enforcement officials (DEA, US Marshalls, Federal Bureau of Investigation) maintain the legal authority to act.

Obviously, patients driving under the influence, using marijuana in plain sight, in excess possession, and flaunting law enforcement officials increase their risk for arrest.

Interestingly enough, state laws do not provide a basis for buying or selling marijuana, so there remains a legal vacuum whereby the law remains unsettled.

Additionally, employees who test positive for marijuana, despite the recommendation of a physician and in full compliance with state law, are often defenseless against termination, as the growing body of case law holds this permissible.[5]

Clinical Limitations and Safety Concerns

As marijuana is regulated as a Schedule I controlled substance, the body of sound clinical data is limited. There are a number of regulatory and legal obstacles involved with studying marijuana, including ethical, social, political, and administrative challenges that have hindered the scientific process.

Accordingly, there are surprisingly few double-blind, randomized, controlled trials investigating marijuana. Most of the published studies look at synthetic cannabinoids or Sativex®, and the practitioner is hard pressed to find a reliable clinical study of direct relevance to an individual patient.[6]

Furthermore, much of the available data is marginal, with mixed results.[6]

Thus, much of the “effectiveness” of medical marijuana is anecdotal.

This is not to say that marijuana is ineffective or the data are strictly lacking; but a comprehensive and systematic review of the literature reveals gaps, especially when one considers the wide range of diseases potentially treated with marijuana.

The best available data are for pain management.[7]

Because of this dearth of clinical data, many professional associations have been hesitant to endorse the widespread use of marijuana.

  • For example, the American Cancer Society acknowledges that the research results are mixed, although they support the rights of individuals to decide treatment.
  • The National Multiple Sclerosis Society identifies a clear potential role but does not support widespread availability, based on the available data and known risks.
  • The American Medical Association supports the current DEA schedule of marijuana, although they identify a need for further research.

Marijuana is regarded by many as remarkably safe.[8,9]

No median lethal dose in humans has been established, and the risk for serious adverse effects is rather low, especially compared with prescription drugs.

However, evaluating the available safety data is complicated. Marijuana is an illicit substance under federal law; thus, long-term safety data are difficult to find and interpret based on a number of confounding variables, including other illicit drug use, concomitant diseases, lack of patient follow-up, and poor overall healthcare in many of these patients.

Nevertheless, marijuana is associated with a number of safety concerns.[1,2,8,9]

Most of the risks associated with medical marijuana are mild and involve central nervous system (CNS) and gastrointestinal effects. Dizziness is often reported as the most common adverse effect, with nausea, feelings of euphoria, and irritability also reported.

The drug is also associated with memory and learning defects, psychiatric disturbances, respiratory problems, cancer, cardiovascular complications, male infertility, periodontal disease, bone loss, sleep disturbance, aluminum and other heavy metal accumulation, addiction, dependence, and withdrawal, although the true incidence and risk are difficult to ascertain.[1,2,8,9]

As with all drugs, marijuana has a number of potential interactions.[1,10] The drug undergoes extensive hepatic metabolism and may be involved with a number of pharmacokinetic drug interactions.

Marijuana is believed to inhibit CYP3A4 and possibly induce CYP1A2.

Marijuana can interact with warfarin to increase the international normalized ratio and bleeding risk.[10]

Nevertheless, one study showed no effect of marijuana on indinavir or nelfinavir, and another study showed no interaction with docetaxel or irinotecan.

Marijuana may further interact with drugs through a pharmacodynamic process. It may potentiate the effects of opioids and CNS depressants like benzodiazepines, muscle relaxants, and alcohol. Marijuana also reportedly interacts with a number of antidepressants and neuroleptics.[1]

Marijuana exerts myriad clinical effects and has the potential for a number of disease interactions.[1]

  • Patients with a history of addiction should best avoid marijuana, as should patients with a history of psychiatric disturbances.
  • Immunosuppressed patients such as transplant patients and those with AIDS also should avoid marijuana as there is a risk for opportunistic infections including aspergillosis and pneumonia.
  • Patients with respiratory disease should avoid smoking marijuana, especially because it is often done without a filter and because marijuana smokers generally inhale deeper and hold their breath longer than cigarette smokers.
  • Patients with vertigo should avoid marijuana as proper diagnosis and treatment is confounded with the use of medical marijuana.
  • The risk for heart disease among medical marijuana users is considered low, especially among otherwise young and healthy individuals, although elderly patients and those with moderate to severe heart disease should avoid use.[1,2]

Practical Challenges

Medical marijuana is administered primarily through smoking and eating.[1,2] The drug is often smoked as joints, rolled in blunts, or used in a water pipe (ie, bong) or vaporizer. The use of a vaporizer is considered the safest and most effective route of administration.

Based on its volatility, marijuana vaporizes at a much lower temperature than it combusts, allowing inhalation with minimal generation of and ingestion of harmful byproducts.[11]

Additionally, hashish is used to create oil and (bud) butter and is often baked in a variety of products such as brownies and cakes.

Dosing is an important consideration with medical marijuana. Although general guidelines are available, the lack of standardization and potency among available products makes any real attempts at consistency or generalizability nearly impossible.[12]

Moreover, smoking marijuana is a highly unpredictable route of administration, depending on the user, the route, the method used to inhale, and the time to exhale.[2]

As physicians are registered with the DEA, they cannot legally “prescribe” marijuana but instead may provide a recommendation and certification to the state. Pharmacies do not stock medical marijuana as it remains outlawed under federal law. Thus, patients are left looking for a source of product and are left unprotected.

Business owners have been quick to fill the niche. A number of dispensaries operate with colorful names and wide product selection. Thus, although access to information, seeds, seedlings, and marijuana is not difficult, the patient is outside the realm of a traditional healthcare environment and is exposed to some degree of uncertainty and lack of regulation.

Conclusions

Based on the legal and clinical risks associated with medical marijuana, practitioners should be well versed in these challenges and should stay abreast of the latest breakthroughs and advances to best serve their patients. In the interim, the political landscape of medical marijuana continues to evolve.

Hopefully, this will ease some of the regulatory obstacles to proper research and better patient care. With increasing data, marijuana may be proven or disproven to be an important and affordable therapeutic option in the practitioner’s armamentarium.

The bottom line is that properly registered patients and practitioners who follow the law are at essentially no legal risk and can safely integrate medical marijuana into their disease management program. The caveat, of course, is that you must be in one of the states that has legalized the medical use of marijuana.

References

  1. Seamon MJ, Fass JA, Maniscalco-Feichtl M, et al. Medical marijuana and the developing role of the pharmacist. Am J Health-Syst Pharm. 2007;64:1037-1044.
  2. Department of Justice, Drug Enforcement Agency, Denial of Petition; Notice. Federal Register 2001 (20038-20076).
  3. Onaivi ES. Cannabinoid receptors in brain: pharmacogenetics, neuropharmacology, neurotoxicology, and potential therapeutic applications. Int Rev Neurobiol. 2009;88:335-369. Abstract http://www.medscape.com/medline/abstract/19897083
  4. United States Department of Justice. Memorandum for Selected United States Attorneys. Available at: http://www.justice.gov/opa/pr/2009/October/09-ag-1119.html Accessed November 11, 2009.
  5. Supreme Court of California. Ross v. Ragingwire (S138130). Available at: http://www.courtinfo.ca.gov/opinions/archive/S138130.PDF Accessed November 11, 2009.
  6. Zajicek J, Fox P, Sanders H, et al. Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre, randomized, placebo-controlled trial. Lancet. 2003;362:1517-1526. Abstract http://www.medscape.com/medline/abstract/14615106
  7. Wilsey B, Marcotte T, Tsodikov A, et al. A randomized, placebo-controlled, crossover trial of cannabis cigarettes in neuropathic pain. J Pain. 2008;9:506-521. Abstract http://www.medscape.com/medline/abstract/18403272
  8. Tongtong W, Collet JP, Shapito S, et al. Adverse effects of medical cannabinoids: a systematic review. CMJ. 2008;178:1669-1678.
  9. Reece AS. Chronic toxicology of cannabis. Clin Toxicol. 2009;47:517-524.
  10. 10. Yamreudeewong W, Wong HK, Brausch LM, et al. Probable interaction between warfarin and marijuana smoking. Ann Pharmacother. 2009;43:1347-1353. Abstract http://www.medscape.com/medline/abstract/19531696
  11. 11. Dosing Medical Marijuana: Rational Guidelines on Trial in Washington State: Deriving Dosing Guidelines for Medical Marijuana: Clearing the Smoke. Available at: /viewarticle/562451_3547  Accessed November 11, 2009.
  12. 12. Hazekamp A, Ruhaak R, Zuurman L, et al. Evaluation of a vaporizing device (Volcano) for the pulmonary administration of tetrahydrocannabinol. J Pharm Sci. 2006;95:1308-1317. Abstract http://www.medscape.com/medline/abstract/16637053

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