Understanding Medical Marijuana

In 1996, California voters approved Proposition 215, making California the first state to legalize the use of marijuana for medical purposes. The trend spread rapidly. Most U.S. states now allow either marijuana or its derivatives to be prescribed and used for a variety of ailments, including cancer, anxiety disorders, chronic pain, multiple sclerosis, and epilepsy. This rapid expansion in the use of marijuana plus its ready availability suggests that there is a consensus among medical professionals about how well it works and how to use it. This article provides the data and offers advice that you may want to share with your patients who are asking about medical marijuana. Today there is growing evidence of the therapeutic benefits of cannabinoids found in the marijuana plant.(1) (And it is of interest that shrinking state budgets have caused legislatures to look for new sources of tax revenue.(2))

History of Medical Marijuana

Marijuana was described in 500 BCE as a botanical used as an herbal medicine. The ancient Greeks inhaled the smoke from cannabis seeds for its psychoactive effects. By 800 AD, Islam permitted the smoking of hashish, which is a purified form of cannabis. The early American colonists, including George Washington and Thomas Jefferson, grew hemp, which contains very low levels of tetrahydrocannabinol, for industrial purposes such as making textiles and rope. In the late 19th century, tetrahydrocannabinol was discovered to be a source of medicinal agents that could be used to treat gastrointestinal disorders. In 1985, the FDA approved the use of Marinol and Syndros, which are orally active synthetic cannabinoids, to treat nausea and as appetite stimulants. In 1970, President Nixon declared that marijuana was a Schedule I drug, along with heroin and cocaine. In 1996 California legalized marijuana for use in patients with chronic pain and some chronic illnesses. By 2016, 21 states had legalized marijuana for medicinal purposes. Today nearly 50 million Americans use marijuana for medicinal and recreational purposes.(3)

Marijuana Terms

Cannabis is the most commonly used word for the marijuana plant, which bears the scientific name Cannabis sativa. Cannabinoids are a large group of chemicals that are found in the cannabis plant. Although there are dozens of biologically active cannabinoids, the two found in the highest concentration are tetrahydrocannabinol (THC) and cannabidiol (CBD). THC is the major psychoactive compound. Whether smoked or eaten, THC gets users high. CBD, the other major cannabinoid, is purported to have medicinal properties to treat epilepsy, cancer, anxiety, posttraumatic stress disorder, and many other ailments. This article explores the peer-reviewed data that give clinicians the confidence, or skepticism, for or against the use and effect of cannabis in various clinical situations.

The use of cannabis for medicinal purposes is further complicated by the laws of individual states where it is legal.

The Institute of Medicine, now called the National Academy of Medicine, published on the beneficial health effects of cannabis and cannabinoids in 2017,(4) although the federal government, through the FDA and Drug Enforcement Administration (DEA), still considers marijuana to be a Schedule I substance under the Controlled Substance Act,(5) meaning that it has a high potential for abuse.

The use of cannabis for medicinal purposes is further complicated by the laws of individual states where it is legal. Every state specifies which diseases or symptoms can be legally treated with cannabis. A clinician must check with his or her state to be certain of the legality for using marijuana.(6)

How Does Cannabis Work?

Cannabis contains approximately 540 natural compounds. The predominant psychotropic component is THC, and the major non-psychoactive ingredient is CBD. These two compounds have been shown to be active at the cannabinoid receptors, CB1 and CB2. The therapeutic actions of THC and CBD include an ability to act as analgesics, antiemetics, antiinflammatory agents, and antiseizure compounds, and as protective agents in neurodegeneration. However, well-controlled, double-blind, randomized clinical trials to provide clarity on the efficacy of either THC or CBD as a therapeutic agent are still lacking.

Medicinal Uses for Cannabis

A plethora of medical conditions may be amenable to the use of medical marijuana. Hundreds of articles have made claims regarding the value of medical marijuana. The sidebar lists conditions where marijuana has been deemed effective, although peer-reviewed, evidence-based studies are lacking.

Chronic Pain

One potential use for marijuana is the treatment of chronic pain. Currently, many traditional pain-treating medications are narcotics, derivatives of opium or morphine that can be addictive and can have some very serious side effects. Chronic pain is by far the most cited condition for medical marijuana use.(7)

It is estimated that 20.4% of U.S. adults, representing approximately 50 million Americans, had chronic pain, and 8% had high-impact chronic pain that restricted or hindered at least one major life activity such as walking, getting into and out of a chair, or participating in sexual intimacy. It is little wonder that 67% of those who use medical marijuana consume it for pain relief.(8)

Every state that has legalized medical marijuana lists chronic pain as an approved diagnosis for its use.

Research has concluded that medical marijuana can be beneficial in chronic pain and neuropathic pain.(9) However, the International Association for the Study of Pain recently has stated that there is insufficient evidence that marijuana relieves pain.(10) An important reason for their skepticism is the placebo effect, which can be as high as 30% to 40%. However, clinical trials have shown the benefit of marijuana on pain and the insomnia associated with chronic pain.(11)

Every state that has legalized medical marijuana lists chronic pain as an approved diagnosis for its use. The National Academy of Medicine has stated there is evidence for a benefit of marijuana for pain, and that no person has ever died of an overdose of marijuana(12) (https://www.healthline.com/health/can-you-overdose-on-marijuana ), in contradistinction to the 100,000 Americans who died of overdoses—76% from opioids—in 2021.(13)

An in-depth, comprehensive review of all available literature through 2016 done by the National Academy of Sciences found 30 randomized controlled trials using cannabis products to treat pain. One summary of plant-derived cannabinoids found an increase in improvement of 40% more than placebo.(14)

One study looked at smoked cannabis, in 50 patients with HIV-associated sensory neuropathy.(15) It documented somewhat better pain reduction than a placebo, but the confidence interval—that is, the statistical measurement of the range of likely effect sizes—was very large. The odds ratio was about 3.4, meaning people receiving cannabis were 3.4 times as likely to report a benefit as those given a placebo. Unfortunately, the study included only 50 subjects, and that was too small to obtain a more accurate estimate.

Studies like these—small studies with large confidence intervals—have their place, as pilot studies or as a starting point for larger investigations. However, it is difficult to draw broad conclusions about using marijuana to treat pain from the limited evidence available so far.

Epilepsy and Seizure Disorders

For most patients with epilepsy, most seizures can be prevented with medications. However, a few patients have intractable or difficult-to-control seizures. Epilepsy medications, like all medicines, can have side effects. Many people with epilepsy are looking for a safer or more effective alternative.

CBD was shown in early studies in the 1970s and 1980s to have antiseizure properties. Studies of seizure therapy in children report a 30% response rate. However, some of the studies that support FDA-approved seizure medications, such as Fintepla (fenfluramine), approved by the FDA in 2020, showed about a 30% response rate to placebos.(16) A large review from the Cochrane Collaboration published in 2016 concluded that the research on cannabis for epilepsy was inconclusive, finding no solid evidence to recommend it for treatment.(17)

A study published in 2017(18) used a randomized, controlled design to look at CBD for children with one specific kind of epilepsy, Dravet syndrome. In this study, adding CBD to the usual medical regimen was significantly more effective than placebo, providing the first solid evidence for CBD in seizure disorders. Still, this was used to treat only one very specific, uncommon type of epilepsy. It is not clear that these results apply to other kinds of seizure disorders in children or adults.

Alcohol Addiction and Drug Abuse

The use of marijuana to reduce addiction to alcohol or opioids is controversial, but has some public health evidence, especially among 21- to 40-year-olds.(19) The theory that marijuana is a gateway drug was debunked by the National Academy of Medicine 22 years ago. The potential substitution of marijuana in patients who are addicted to other drugs must be under very careful supervision by trained addiction specialists.

Insomnia

Insomnia has been an active area for research but yields inconclusive results.(20) A very recent study, published in 2021, showed that over a two-week period, cannabis can be effective.(21) In an Israeli study, marijuana had an overall positive effect on maintaining sleep throughout the night in patients with chronic pain, but tolerance may develop, in a type of tachyphylaxis phenomenon.(22)

Treatment of Posttraumatic Stress Disorder

Another common use of cannabis is in posttraumatic stress disorder (PTSD). Cannabis has been helpful to improve sleep for some patients with PTSD. However, in a peer-reviewed randomized placebo-controlled double-blind study, the researchers found that during three weeks of treatment, no active cannabis treatment statistically outperformed placebo. A Canadian study provides preliminary epidemiologic evidence that cannabis use may contribute to reducing the association between PTSD and severe depressive and suicidal states.(23)

In patients with PTSD, cannabis resulted in sleep improvement, likely due to the coping-oriented use.(24) Coping is defined broadly as an effort used to minimize distress associated with negative life experiences.

Control of Nausea and Vomiting Associated With Chemotherapy

Although hundreds of articles tout the efficacy of cannabis in the treatment of cancer, none of these studies have been verified and accepted by the medical community. However, cannabis may help cancer patients manage the side effects of traditional cancer treatments such as chemotherapy. Those side effects include nausea, vomiting, appetite loss, and fatigue.(25)

Multiple Sclerosis

Treatment with medical cannabis has been demonstrated to be safe and well tolerated by patients with multiple sclerosis. The use of cannabis has been shown to reduce pain intensity, spasticity, and sleep disturbances in these patients. This suggests that medical cannabis oils can be used safely to treat symptoms related to multiple sclerosis, especially at relatively low doses and with slow titration, as an alternative when conventional therapy is inadequate.(26)

Caveats on Prescribing Cannabis

It is clear that in several conditions the use of medical marijuana is contraindicated. These include heart disease; pregnancy; chronic obstructive pulmonary disease; conditions in teenagers, whose brains are not yet completely developed; and illnesses in patients with a history of psychosis.

Any clinician who considers recommending medical cannabis for a patient must check with the state regulations to know whether the diagnosis that is being treated is a qualifying condition. In states that permit adult recreational usage, marijuana is readily available, which puts a greater responsibility on the clinician to educate the patient as to the benefits and risks.

Bottom Line: The current situation is that patients are embracing medical marijuana. Although we do not have rigorous studies and “gold standard” proof of the benefits and risks of medical marijuana, we need to learn about it, be open-minded, and above all, be nonjudgmental. Otherwise, our patients will seek out other, less reliable sources of information. They will continue to use marijuana but they just won’t tell us, and that will lead to that much less trust and strength in our doctor-patient relationship. The authors are in complete agreement that there is not adequate evidence to recommend medical marijuana, but there is even less scientific evidence for denying its application to managing several medical conditions.

References

1. Hill KP. Medical marijuana for treatment of chronic pain and other medical and psychiatric problems: a clinical review. JAMA. 2015;313(24):2474-2483.

2. Caulkins JP, Kilmer B, Kleiman M, et al. Considering Marijuana Legalization: Insights for Vermont and Other Jurisdictions. Rand Corporation; 2015..

3. Takakuwa KM. A history of the Society of Cannabis Clinicians and its contributions and impact on the US medical cannabis movement. Int J Drug Policy. 2020;79:102749. Online ahead of print. DOI: 10.1016/j.drugpo.2020.102749.

4. National Academies of Sciences, Engineering, and Medicine; Health and Medicine Division; Board on Population Health and Public Health Practice; Committee on the Health Effects of Marijuana. An Evidence Review and Research Agenda. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: National Academies Press; 2017.

5. Ortiz NR, Preuss CV. Controlled Substance Act. StatPearls [Internet]. 2021. www.ncbi.nlm.nih.gov/books/NBK574544/ .

6. ProCon.org . Legal medical and recreational marijuana states. https://medicalmarijuana.procon.org/legal-medical-marijuana-states-and-dc/

7. Terrie YC. Medical cannabis for chronic pain. US Pharm. 2020;44(3):​24-28.

8. Hill KP, Palastro MD, Johnson B, Ditre, JW. Cannabis and pain: a clinical review. Cannabis Cannabinoid Res. 2017;2(1):96-104. DOI:10.1089/can.2017.0017.

9. Hill KP. Medical marijuana for treatment of chronic pain and other medical and psychiatric problems: a clinical review. JAMA. 2015;313(24):2474-2483. DOI: 10.1001/jama.2015.6199. Erratum in: JAMA. 2016;316(9):995. PMID: 26103031.

10. Haroutounian S, Arendt-Nielsen L, Belton J, et al. International Association for the Study of Pain Presidential Task Force on Cannabis and Cannabinoid Analgesia: research agenda on the use of cannabinoids, cannabis, and cannabis-based medicines for pain management. Pain. 2021;162: S117-S124.

11. Ware MA, Wang T, Shapiro S, et al. Smoked cannabis for chronic neuropathic pain: a randomized controlled trial. CMAJ. 2010;182(14):​E694-701. Epub 2010 Aug 30. DOI:10.1503/cmaj.091414.

12. Martínez-Alés G, Jiang T, Keyes KM, Gradus JL. The recent rise of suicide mortality in the United States. Annu Rev Public Health. 2021;43:99-116.

13. Irvine MA, Oller D, Boggis J, et al. Estimating naloxone need in the USA across fentanyl, heroin, and prescription opioid epidemics: a modelling study. The Lancet Public Health; 20207(3):e210-e218.

14. Meng H, Dai T, Hanlon JG, Downar J, Alibhai SM, Clarke H. Cannabis and cannabinoids in cancer pain management. Curr Opin Support Palliat Care. 2020;14(2):87-93.

15. Eibach L, Scheffel S, Cardebring M, et al. Cannabidivarin for HIV‐associated neuropathic pain: a randomized, blinded, controlled clinical trial. Clin Pharmacol Ther. 2021;109:1055-1062.

16. Nabbout R, Mistry A, Zuberi S, et al. Fenfluramine for treatment-resistant seizures in patients with Dravet syndrome receiving stiripentol-inclusive regimens: a randomized clinical trial. JAMA Neurol. 2020;77:300-308.

17. Paolino MC, Ferretti A, Papetti L, Villa MP, Parisi P. Cannabidiol as potential treatment in refractory pediatric epilepsy. Expert Rev Neurother. 2016;16(1):17-21.

18. Devinsky O, Cross JH, Laux L, et al. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med. 2017;376(21)​2011-2020.

19. Subbaraman MS. Can cannabis be considered a substitute medication for alcohol? Alcohol Alcohol. 2014;49:292-298.

20. Gates PJ, Albertella L, Copeland J. The effects of cannabinoid administration on sleep: a systematic review of human studies. Sleep medicine reviews. 2014;18:477-487.

21. Walsh JH, Maddison KJ, Rankin T, et al. Treating insomnia symptoms with medicinal cannabis: a randomized, cross-over trial of the efficacy of a cannabinoid medicine compared with placebo. Sleep. 2021;44(11):zsab149. DOI: 10.1093/sleep/zsab149.

22. Sznitman SR, Vulfsons S, Meiri D, Weinstein G. Medical cannabis and insomnia in older adults with chronic pain: a cross-sectional study. BMJ Support Palliat Care. 2020;10:415-420.

23. Lake S, Kerr T, Buxton J, et al. Does cannabis use modify the effect of post-traumatic stress disorder on severe depression and suicidal ideation? Evidence from a population-based cross-sectional study of Canadians. J Psychopharmacol. 2020;34:181-188.

24. Bonn-Miller MO, Babson KA, Vandrey R. Using cannabis to help you sleep: heightened frequency of medical cannabis use among those with PTSD. Drug Alcohol Depend. 2014;136:162-165.

25. Braun IM, Abrams DI, Blansky SE, Pergam SA. Cannabis and the cancer patient. J Natl Cancer Inst Monogr. 2021(58):68-77.

26. Gustavsen S, Søndergaard HB, Linnet K, et al. Safety and efficacy of low-dose medical cannabis oils in multiple sclerosis. Mult Scler Relat Disord. 2021;48:102708. DOI: 10.1016/j.msard.2020.102708. Epub 2020 Dec 30.

Conditions That Have Been Treated by Cannabis

• Anorexia and wasting associated with chronic illness

• Anxiety

• Cancer pain

• Chemotherapy-induced nausea and vomiting*

• Chronic infection

• Chronic pain*

• Depression

• Dystonia

• Epilepsy*

• Fibromyalgia

• Migraines

• Neuropathic pain

• Neuropathies

• Opioid dependence

• Parkinson disease

• Polymyalgia rheumatica

• Post-cerebrovascular accident neuropathy

• Posttraumatic stress disorder

• Radiculopathies

• Polymyalgia rheumatica

• Rheumatoid arthritis

• Spasticity from neurologic conditions*

• Tremors

*Scientifically proven benefits