Medical cannabis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [14]; Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [15]

Overview

With recent legalization of medical and recreational marijuana in many states in the US, physicians are often facing questions from their patients regarding the potential harmful effects of this drug on their body. Once known as an illegal substance, marijuana is now legalized for medicinal purposes in many states and for recreational use in Alaska, Washington and Colorado.

Marijuana is made from drying and shredding the leaves and flowers of the plant Cannabis sativa. Tetrahydrocannabinol is the active component which primarily acts on the cannabinoid receptors I and II in the central nervous system and the periphery, respectively. In the United States, it is mostly used in its inhalational form via smoking and is the most commonly used illicit drug.

Medical marijuana plays a crucial role in the management of chronic pain syndromes, glaucoma, multiple sclerosis, HIV especially AIDS associated anorexia and wasting syndrome and epilepsy. With clinical evidence backing the use of marijuana in population with chronic, debilitating conditions, the widespread legalization raises concerns over its safety.

History

Cannabis has been used for medicinal purposes for over 4,800 years[1]. The documentation of marijuana goes back to the ancient Chinese civilizations, Indian literature and Egyptian pharaohs. Cannabis as a medicine was common throughout most of the world in the 1800s. It was used as the primary pain reliever until the invention of aspirinref>http://news.bbc.co.uk/1/hi/programmes/panorama/1632726.stm</ref>. Modern medical and scientific inquiry began with doctors like O'Shaughnessy and Moreau de Tours, who used it to treat melancholia, migraines, and as a sleeping aid, analgesic and anticonvulsant.

By the time the United States banned cannabis (the third country to do so) with the 1937 Marijuana Tax Act, the plant was no longer extremely popular. Skepticism about marijuana arose in response to the bill. One of the main opponents to the bill was the representative of the American Medical Association.[2]

Later in the century, researchers investigating methods of detecting cannabis intoxication discovered that smoking the drug reduced intraocular pressure.[3] High intraocular pressure causes blindness in glaucoma patients, so many believed that using the drug could prevent blindness in patients. Many Vietnam War veterans also believed that the drug prevented muscle spasms caused by battle-induced spinal injuries. Later medical use has focused primarily on its role in preventing the wasting syndromes and chronic loss of appetite associated with chemotherapy and AIDS, along with a variety of rare muscular and skeletal disorders. Less commonly, cannabis has been used in the treatment of alcoholism and addiction to other drugs such as heroin and the prevention of migraines. In recent years, studies have shown or researchers have speculated that the main chemical in the drug, THC, might help prevent atherosclerosis.

In 1972 Tod H. Mikuriya, M.D. reignited the debate concerning marijuana as medicine when he published "Marijuana Medical Papers 1839-1972".

Later, in the 1970s, a synthetic version of THC, the primary active ingredient in cannabis, was synthesized to make the drug Marinol. Users reported several problems with Marinol, however, that led many to abandon the pill and resume smoking the plant. Patients complained that the violent nausea associated with chemotherapy made swallowing pills difficult. The effects of smoked cannabis are felt almost immediately, and is therefore easily dosed.[4] Marinol (Dronabinol), like ingested cannabis, is very psychoactive, and is harder to titrate than smoked cannabis.[5] Marinol has also consistently been more expensive than herbal cannabis.[6] Some studies have indicated that other chemicals in the plant may have a synergistic effect with THC.[7]

In addition, during the 1970s and 1980s, six US states' health departments performed studies on the use of medical marijuana. These are widely considered some of the most useful and pioneering studies on the subject.Template:Fix/category[citation needed]

In May 2001, "The Chronic Cannabis Use in the Compassionate Investigational New Drug Program: An Examination of Benefits and Adverse Effects of Legal Clinical Cannabis" (Russo, Mathre, Byrne et al) was completed. This three-day examination of major body functions of four of the five living US federal cannabis patients found "mild pulmonary changes" in two patients.[8]

Clinical pharmacology of medical cannabis

Marijuana is classified as a schedule I substance by the FDA. As mentioned above, tetrahydrocannabinol (THC) is the principal compound found in the cannabis plant that is responsible for its psychoactive effects.

Pharmacodynamics

  • Marijuana acts on the cannabonoid receptors CB-1 and CB-2. The CB-1 receptors are found primarily in the central nervous system. They are found in high density in the basal ganglia, hippocampus, cerebellum, hypothalamus, limbic cortex and the neocortex. The CB-2 receptors are found peripherally in the immune cells and tissues.
  • CB-2 receptors are also found on the microglia. These receptors are thus studied as targets in the treatment of Alzheimer's dememtia.

Pharmacokinetics

  • THC is a strong lipophilic compound. Its distribution phase half life is 0.5 hours, whereas its termination phase half life is variable with mean being around 30 hours owing to its lipophilic properties.
  • Smoking marijuana has a bioavailability of 10 to 25% whereas orally consumed THC was found to have a bioavailability of 5 to 20% in clinical studies. Presence of acids in the stomach and first pass elimination in the liver influences bioavailability of ingested THC.
  • Peak concentrations of the oral THC is achieved in 1 to 3 hours. This variability is attributed to incomplete and delayed absorption in subjects.

Early studies on efficacy

New Mexico

Approved by the Food and Drug Administration, the study included 250 patients and compared smoked cannabis to oral THC. All participants were referred by a medical doctor and had failed to control vomiting using at least three alternative antiemetics. Patients chose smoking cannabis or taking the THC pill. Multiple objective and subjective standards were used to determine the effectiveness.

  • Conclusion: cannabis is far superior to the best available drug at the time of testing, Compazine, and smoked cannabis is clearly superior to oral THC. "More than ninety percent of the patients who received cannabis ... reported significant or total relief from nausea and vomiting." No major side effects were reported, though three patients reported adverse reactions that did not involve cannabis alone. The report can be read here.

Tennessee

27 patients had failed on other antiemetics therapies, including oral THC.

  • Conclusion: 90.4% success for smoked cannabis; 66.7% for oral THC. "We found both marijuana smoking and THC capsules to be effective antiemetics. We found an approximate 23% higher success rate among those patients administered smoked marijuana. We found no significant differences in success rates by age group. The major reason for THC capsule failure was nausea and vomiting so severe that the patient could not retain the capsule."

California

A series of studies throughout the 1980s involved 90–100 patients a year. The study was designed to make it easier for patients to enter the oral THC part of the study. Patients who wanted to smoke cannabis had to be over 15 years old (oral THC patients had to be over 5) and use the drug only in the hospital and not at home. Smoked cannabis patients also had to be receiving rare and painful forms of chemotherapy to qualify.

  • Conclusion: Despite the bias towards oral THC, the California study concluded that smoked cannabis was more effective and established a safe dosage regimen that minimized adverse side effects. The full text of the study can be seen here.
File:Vaporong 001.jpg
A Vapor-Bong for use with medicinal herbs prescribed by a physician.

Georgia

119 patients that had failed using other antiemetics were randomly assigned to oral THC pills and either standardized or patient-controlled smoking of cannabis.

  • Conclusion: All three categories were successful — patient controlled smokers at 72.2%; standardized smokers at 65.4%; oral THC at 76%. Failure of oral THC patients was due to adverse reaction (6 out of 18) or failure to improve (9 out of 18); failure of smoking cannabis was due to intolerance for smoking (6 out of 14) or failure to improve (3 out of 14).

Meta-analysis

Dronabinol, in a single study, may be worse than placebo for neuropathic pain associated with spinal cord injury.[9]

Adverse effects

With increasing use of marijuana as a recreational substance in adolescents and recent legalization of its medical use, the concerns over detrimental effects of cannabinoids is a stormy debate. In this article, we will focus on the neuropsychiatric, cognitive, cardiovascular, cerebrovascular and peripheral vascular adverse effects of cannabinoids.

Cardiovascular effects of marijuana

Cerebrovascular effects of marijuana

  • Risk of stroke has been clearly documented in case reports. Mouzak et al.[18] reported transient ischemic attacks (TIA) in marijuana users, suggesting either reversible spasm of cerebral vessels or transient increase in blood pressures.

Peripheral vascular effects of marijuana

  • Cannabis arteritis was first described in 1960. Case reports describe proximal arteriopathy of lower limbs leading to tissue necrosis in long standing cannabis users[19].
  • Favorable outcomes on the peripheral vasculopathy after cessation of cannabis in some patients suggest reversible endothelial dysfunction from its use. It is considered to be a form of Buerger's disease.

Harm reduction

Many medical cannabis opponents note that smoked cannabis is harmful to the respiratory system. However, this harm can be minimalized or eliminated by the use of a vaporizer or ingesting the drug in an edible form or other non-smoking modes of delivery like tinctures. Vaporizers are devices that vaporize the active constituents (cannabinoids) and the fragrant aromatic substances in the preparation without combusting the plant material and thus preventing the formation of toxic substances. Studies have shown that vaporizers can dramatically reduce[20] or even eliminate[21] the release of irritants and toxic compounds.

Indications

According to a survey on the recommendation of cannabis in California[22], cannabis is indicated for over 250 conditions. Cannabis is most importantly indicated as an antiemetic for the treatment of nausea and anorexia associated with treatments for cancer, AIDS, and hepatitis. Cannabis also acts as an antispasmodic and anticonvulsant and is indicated for neurological conditions such as epilepsy, multiple sclerosis, and spasms. As an analgesic and an immunomodulator it is indicated for conditions such as migraine, arthritis, spinal and skeletal disorders. As a bronchodilator it is beneficial for asthma. It also reduces the intraocular pressure and is indicated for glaucoma. Cannabis is also used to treat some mood disorders such as post traumatic stress disorder, clinical depression, obsessive-compulsive disorder, panic disorder, and bipolar disorder. It is also indicated for premenstrual syndrome, hypertension, and insomnia.

In the United States, the Federal Food, Drug, and Cosmetic Act makes the Food and Drug Administration (FDA) the sole government entity responsible for ensuring the safety and efficacy of new prescription and over-the-counter drugs, overseeing the labeling and marketing of drugs, and regulating the manufacturing and packaging of drugs.[23] The FDA defines a drug as safe and effective for a specific indication if the clinical benefits to the patient are felt to outweigh any health risks the drug might pose. FDA and comparable authorities in Western Europe in including the Netherlands, have not approved smoked marijuana for any condition or disease. [24] [25] Cannabis remains illegal throughout the United States and is not approved for prescription as medicine, although 12 states - Alaska, California, Colorado, Hawaii, Maine, Montana, Nevada, New Mexico, Oregon, Rhode Island, Vermont and Washington - approve and regulate its medical use. (The federal government continues to enforce its prohibition in these states.) However, there are also 2 states, Arizona and Maryland, whose drug laws are favourable towards the medicinal use of marijuana,Template:Huh but which still explicitly ban it.

Notable pro- and anti-medical cannabis individuals

Proponents

  • Mary Lynn Mathre, RN, MSN, CARN. President, Patients Out of Time; Cannabis spokesperson for the Virginia Nurses Association. Editor, "Cannabis in Medical Practice: A Legal, Historical and Pharmacological Overview of the Therapeutic Use of Marijuana."
File:Willie Nelson.jpg
Willie Nelson performing at the Chumash Casino Resort in Santa Ynez, California.

Emerging Medical Consensus

Dozens of medical organizations have endorsed allowing patients access to medical marijuana with their physicians' approval. These include, but are not limited to, the following:

Opponents

[35]

Pharmacologic THC and THC derivatives

In the USA, the FDA has approved two cannabinoids for use as medical therapies: dronabinol and nabilone. It is important to note that these medicines are not smoked. Dronabinol is a synthetic THC medication[36], while nabilone is a synthetic cannabinoid, never marketed in the U.S.[37]

Medication Year approved Licensed indications
Nabilone 1985 Nausea of cancer chemotherapy that has failed to respond adequately to other antiemetics
Marinol 1992 Nausea of cancer chemotherapy that has failed to respond adequately to other antiemetics, AIDS wasting

These medications are usually used when first line treatments for nausea fail to work. In extremely high doses and in rare cases there is a possibility of "psychotomimetic" side effects. The other commonly-used antiemetic drugs are not associated with these side effects.

The prescription drug Sativex, an extract of cannabis administered as a sublingual spray, has been approved in Canada for the treatment of multiple sclerosis;[38] this medication may now be legally imported into the United Kingdom and Spain on prescription.[39] Dr. William Notcutt is one of the chief researchers that has developed Sativex, he has been working with GW and founder Geoffrey Guy since the company's inception in 1998. Notcutt states that the use of MS as the disease to study "had everything to do with politics."[40]

Criticism

See also: Health issues and the effects of cannabis

On 4-20-2006, The United States Food and Drug Administration (FDA) issued an advisory against medical marijuana stating that, "marijuana has a high potential for abuse, has no currently accepted medical use in treatment in the United States, and has a lack of accepted safety for use under medical supervision. Furthermore, there is currently sound evidence that smoked marijuana is harmful." [17]. Some prominent American societies have been reluctant to endorse medicinal cannabis. For example: [18], the National Multiple Sclerosis Society [19] , the American Academy of Ophthalmology [20] and the American Cancer Society [21]. (Federal Register, 1992).

On June 6, 2005, the U.S. Supreme Court handed down a decision which approved the Federal Government's position that federal law permits the prosecution of persons possessing cannabis regardless of the defense that they are medicinal cannabis patients, even in states that exempt its prohibition for medicinal purposes.. [22]

The Institute of Medicine, run by the United States National Academy of Sciences and funded by the United States federal government, conducted a comprehensive study in 1999 to assess the potential health benefits of cannabis and its constituent cannabinoids. The study concluded that smoking cannabis is not recommended for the treatment of any disease condition, but did conclude that nausea, appetite loss, pain and anxiety can all be mitigated by marijuana. While the study expressed reservations about smoked marijuana due to the health risks associated with smoking, the study team concluded that until another mode of ingestion was perfected that could provide the same relief as smoked marijuana, there was no alternative. In addition, the study pointed out the inherent difficulty in marketing a non patentable herb. Pharmaceutical companies will not substantially profit unless there is a patent. For those reasons, the Institute of Medicine concluded that there is little future in smoked cannabis as a medically approved medication. The report also concluded for certain patients, such as the terminally ill or those with debilitating symptoms, the long-term risks are not of great concern.[41]

In an unpublished 2001 study by the Mayo Clinic, Marinol was shown to be less effective than megestrol acetate in helping cancer patients regain lost appetites.[42]

In 2003, the American Academy of Ophthalmology released a position statement asserting that "no scientific evidence has been found that demonstrates increased benefits and/or diminished risks of marijuana use to treat glaucoma compared with the wide variety of pharmaceutical agents now available." [43]

Legal and medical status of cannabis

File:World-cannabis-laws.png
World laws on cannabis possession (small amount). Data is from multiple sources detailed on the full source list
File:European-cannabis-laws.png
European laws on cannabis possession (small amount). Data is from multiple sources detailed on the full source list

Cannabis is in Schedule IV of the Single Convention on Narcotic Drugs, making it subject to special restrictions. Article 2 provides for the following, in reference to Schedule IV drugs:

A Party shall, if in its opinion the prevailing conditions in its country render it the most appropriate means of protecting the public health and welfare, prohibit the production, manufacture, export and import of, trade in, possession or use of any such drug except for amounts which may be necessary for medical and scientific research only, including clinical trials therewith to be conducted under or subject to the direct supervision and control of the Party.

This provision, while apparently providing for the limitation of cannabis to research purposes only, also seems to allow some latitude for nations to make their own judgments. The official Commentary on the Single Convention indicates that Parties are expected to make that judgment in good faith.

Further reading

See also

References

Notes

  1. http://www.zauberpilz.com/golden/g31-40.htm
  2. http://www.marijuanalibrary.org/AMA_opposes_1937.html
  3. http://www.zauberpilz.com/golden/g31-40.htm
  4. http://www.lycos.com/info/cannabis--effects.html
  5. http://www.ardpark.org/reference/synmjcompare.htm
  6. http://www.medicalmarijuanaprocon.org/pop/cost.htm
  7. http://www.cannabis-med.org/membersonly/mo.php?aid=2001-03-04&fid=2001-03-04-7&mode=a&sid=
  8. http://www.medicalcannabis.com/PDF/Chronic_Cannabis.pdf
  9. Snedecor SJ, Sudharshan L, Cappelleri JC, Sadosky A, Desai P, Jalundhwala YJ; et al. (2013). "Systematic review and comparison of pharmacologic therapies for neuropathic pain associated with spinal cord injury.". J Pain Res. 6: 539–47. PMC 3712802Freely accessible. PMID 23874121. doi:10.2147/JPR.S45966. 
  10. Thomas G, Kloner RA, Rezkalla S (2014). "Adverse cardiovascular, cerebrovascular, and peripheral vascular effects of marijuana inhalation: what cardiologists need to know.". Am J Cardiol. 113 (1): 187–90. PMID 24176069. doi:10.1016/j.amjcard.2013.09.042. 
  11. Arora S, Goyal H, Aggarwal P, Kukar A (2012). "ST-segment elevation myocardial infarction in a 37-year-old man with normal coronaries--it is not always cocaine!". Am J Emerg Med. 30 (9): 2091.e3–5. PMID 22306387. doi:10.1016/j.ajem.2011.12.033. 
  12. Caldicott DG, Holmes J, Roberts-Thomson KC, Mahar L (2005). "Keep off the grass: marijuana use and acute cardiovascular events.". Eur J Emerg Med. 12 (5): 236–44. PMID 16175062. 
  13. Montisci M, Thiene G, Ferrara SD, Basso C (2008). "Cannabis and cocaine: a lethal cocktail triggering coronary sudden death.". Cardiovasc Pathol. 17 (5): 344–6. PMID 18402793. doi:10.1016/j.carpath.2007.05.005. 
  14. Ting JY (2007). "Reversible cardiomyopathy associated with acute inhaled marijuana use in a young adult.". Clin Toxicol (Phila). 45 (4): 432–4. PMID 17486490. doi:10.1080/15563650601073587. 
  15. Rezkalla SH, Sharma P, Kloner RA (2003). "Coronary no-flow and ventricular tachycardia associated with habitual marijuana use.". Ann Emerg Med. 42 (3): 365–9. PMID 12944889. doi:10.1067/mem.2003.297. 
  16. Gaziano JM (2008). "Marijuana use among those at risk for cardiovascular events.". Am Heart J. 155 (3): 395–6. PMID 18294471. doi:10.1016/j.ahj.2007.12.016. 
  17. Mukamal KJ, Maclure M, Muller JE, Mittleman MA (2008). "An exploratory prospective study of marijuana use and mortality following acute myocardial infarction.". Am Heart J. 155 (3): 465–70. PMC 2276621Freely accessible. PMID 18294478. doi:10.1016/j.ahj.2007.10.049. 
  18. Mouzak A, Agathos P, Kerezoudi E, Mantas A, Vourdeli-Yiannakoura E (2000). "Transient ischemic attack in heavy cannabis smokers--how 'safe' is it?". Eur Neurol. 44 (1): 42–4. PMID 10894994. doi:8191 . 
  19. Combemale P, Consort T, Denis-Thelis L, Estival JL, Dupin M, Kanitakis J (2005). "Cannabis arteritis.". Br J Dermatol. 152 (1): 166–9. PMID 15656820. doi:10.1111/j.1365-2133.2005.06340.x. 
  20. Cannabis Vaporizer Combines Efficient Delivery of THC with Effective Suppression of Pyrolytic Compounds By D. Gieringer et.al. Journal of Cannabis Therapeutics, Vol. 4(1) 2004, [1]
  21. Evaluation of a Vaporizing Device (Volcano) for the Pulmonary Administration of Tetrahydrocannabinol. By A. HAZEKAMP, R. RUHAAK, et.al. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 95, NO. 6, JUNE 2006 abstract
  22. Dale Gieringer, "Medical Use of Cannabis in California," in Franjo Grotenhermen, M.D. & Ethan Russo, M.D., ed., Cannabis and Cannabinoids: Pharmacology, Toxicology and Therapeutic Potential, Haworth Press, 2002 [2]
  23. [3]
  24. Meyer, Robert J. "Testimony before the Subcommittee on Criminal Justice, Drug Policy, and Human Resources, Committee on Government Reform". U.S. Food and Drug Administration. Retrieved 2007-09-15. 
  25. [4]
  26. [5]
  27. [6]
  28. [7]
  29. [8]
  30. [9]
  31. [10]
  32. [11]
  33. [12]
  34. [13]
  35. "Romney Confronted" (html). CNN Video - Breaking News. CNN. 2007-10-08. Retrieved 2007-10-08. 
  36. FDA Press Release
  37. Congressional Testimony of Robert J. Meyer, M.D., April 1, 2004
  38. Koch, W. 23 Jun 2005. Spray alternative to pot on the market in Canada. USA Today (online). Retrieved on 27 Feb 2007
  39. "Europe: Sativex Coming to England, Spain". Retrieved 2006-03-25. 
  40. Greenberg, Gary (2005-11-01). "Respectable Reefer". Mother Jones. Retrieved 2007-04-03. 
  41. Cannabis and Medicine: Assessing the Science Base," Institute of Medicine, 1999.
  42. Cannabis Appetite Boost Lacking in Cancer Study" The New York Times, May 13, 2001.
  43. American Academy of Ophthalmology. Complementary Therapy Assessment: Marijuana in the Treatment of Glaucoma. Retrieved August 2, 2006.

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