Reviewed: Grotenhermen F, Müller-Vahl K. Medicinal uses of marijuana and cannabinoids. CRC Crit Rev Plant Sci. 2016;35(5-6):378-405. doi: 10.1080/07352689.2016.1265360.

In a special double issue on cannabis (Cannabis spp., Cannabaceae) in Critical Reviews in Plant Sciences, authors Franjo Grotenhermen, MD, and Kirsten Müller-Vahl, MD, review the evidence for the medicinal uses of cannabis- and cannabinoid-based medicines reported in clinical studies from 1975 to 2015.

History of Medicinal Cannabis

In the introduction, the authors note that cannabis has been used as a medicine for centuries in cultures around the world. The therapeutic use of cannabis was first well-described in Europe in 1830 by Theodor Friedrich Ludwig Nees von Esenbeck, a professor of botany and pharmacy at the University of Bonn in Germany. The better-known Sir William Brooke O’Shaughnessy, an Irish physician, described medicinal uses of cannabis in an account that appeared nine years later. Following those reports, cannabis tinctures became popular in the West and were manufactured by pharmaceutical companies in Germany, the United Kingdom, and the United States.

However, by the beginning of the 20th century, the medicinal use of cannabis preparations was in steep decline. Glossing over the United States’ prohibition of cannabis that began in the late 1930s, the authors suggest that cannabis’ simultaneous medicinal decline was a result of the late elucidation of its unique active constituents, the cannabinoids, which began to be understood only in the 1930s and 1940s. In contrast, the authors note, many other plant constituents had been identified by the late 1800s. The authors speculate that if cannabinoids been identified and separated earlier, then standardized preparations would have been available and, by the second half of the 20th century, synthesized for use in approved medicines.

Research and Regulation

Despite increasing evidence for therapeutic benefits of cannabis and cannabinoids in many conditions, “healthcare authorities in most countries handle cannabis and single cannabinoids as newly detected medicinal drugs,” each of which must “undergo rigid and expensive approval procedures comparable to entirely new molecules.” This “cannabis dilemma,” as the authors describe it, is compounded because many of these compounds have uniquely broad therapeutic applications, unlike most modern single-entity pharmaceutical agents.

Reliable evidence from large randomized controlled trials (RCTs) of cannabis preparations is available for only a few indications. Lawmakers and physicians increasingly acknowledge, however, that “seriously ill and otherwise treatment-resistant patients cannot be deprived from effective therapy,” even if such a therapy is not officially approved.

The discovery that the effects of tetrahydrocannabinol (THC), the principal psychoactive constituent of cannabis, are mediated by specific binding sites, including cannabinoid receptor type 1 (CB₁) and cannabinoid receptor type 2 (CB₂), was first demonstrated in 1988.¹ It is interesting to speculate how cannabis might have been regulated if the endocannabinoid system (ECS) and its endogenous cannabinoids (endocannabinoids) had been known in the 1940s or before. At the time of this report, more than 200 endocannabinoids and endocannabinoid-like substances have been identified, along with evidence of their widespread effects on many physiological systems.

In the cannabis plant, 120 cannabinoids have been identified. Most of cannabis’ known effects are based on THC’s agonistic actions at CB₁ and CB₂ sites; however, THC also acts on other receptor systems. After THC, cannabidiol (CBD) is the next most-studied cannabinoid, with antagonistic effects at CB₁, agonistic effects at vanilloid receptors type 1 (VR₁) and type 2 (VR₂), and binding at other receptor sites. 

Review of Controlled Clinical Trials

The article summarizes 140 controlled clinical studies (N = approx. 8,000) in tables organized by indication. The following cannabis preparations were used in these trials:

• Smoked or vaporized cannabis herbal material (“marijuana”);
• Sativex oromucosal spray (nabiximols; standardized extract of cannabis flower and leaf with a 1:1 ratio of THC and CBD; GW Pharmaceuticals; Cambridge, United Kingdom), approved in several countries to treat spasticity in multiple sclerosis (MS);
• Dronabinol (sold under various brand names, including Marinol; AbbVie Inc.; Chicago, Illinois), a form of synthetic THC that is licensed in the United States for cancer-related nausea and vomiting and HIV/AIDS-related loss of appetite;
• Nabilone (Cesamet; Valeant Pharmaceuticals; Costa Mesa, California), a synthetic cannabinoid similar to THC that is approved in the United Kingdom, United States, and Canada for side effects of cancer chemotherapy;
• CBD, approved in some US states for epilepsy and other indications.* For example, in Iowa, qualifying conditions for CBD use include HIV/AIDS; amyotrophic lateral sclerosis (ALS); cancer; cancer-related chronic pain, nausea, or cachexia (weakening or wasting of the body in chronic illness); Crohn’s disease; MS; Parkinson’s disease; intractable epilepsy; terminal illness; and untreatable pain; and
• A few other single cannabinoids.

For chemotherapy-induced nausea and vomiting, 33 trials (including 30 RCTs) with a total of 1,525 patients reported that nausea and vomiting were reduced with THC preparations or Sativex; the latter added benefit to standard antiemetic therapy when used concurrently. For appetite loss and cachexia in patients with cancer or HIV/AIDS, 10 controlled studies (including seven RCTs) with a total of 973 patients reported significant benefits to taste and smell perception, appetite, caloric intake, quality of sleep, and quality of life with THC supplementation or smoked cannabis. In 35 controlled trials (including 18 RCTs) with a total of 2,046 patients with neuropathic or chronic pain, Sativex resulted in improvements in pain and sleep quality, and both low-THC and high-THC cannabis delivered by vaporizer effectively reduced central or peripheral neuropathy in patients resistant to other analgesics. The efficacy and safety of both Sativex and smoked cannabis for spasticity from MS have been well-demonstrated in 14 controlled trials with a total of 1,740 patients.

Not all results of studied cannabis medicines are positive. In 11 controlled studies (including seven RCTs) on experimental^2† or acute pain, with 377 total patients, neither THC, Cannador (a discontinued standardized extract in pill form with a 2:1 ratio of THC to CBD), nor nabilone showed significant benefits. However, one trial found a synergistic interaction between THC and morphine,³ and another RCT of intramuscular levonantradol (a synthetic analog of THC) showed pain-reduction benefits.⁴ In two of three studies of cannabis extract or smoked cannabis, reductions in pain were seen at low doses,^5,6 though high doses increased pain in one study.⁷

Other controlled studies of cannabinoids have been performed for conditions including tremor and bladder dysfunction in MS, spinal cord injury, Tourette’s syndrome, glaucoma, dystonia, irritable bowel syndrome, Crohn’s disease, pulmonary disease, schizophrenia, and Parkinson’s disease. For almost all, the limited evidence is favorable. Three studies using CBD^8-10 and one using nabilone¹¹ demonstrated improvements in patients with post-traumatic stress disorder and anxiety. Only one small RCT has investigated CBD in generalized epilepsy uncontrolled by standard medications.¹² Of eight patients receiving CBD for as long as four-and-a-half months, four were almost convulsion-free during the study and three more showed clinical improvements.

For most indications, only small, uncontrolled studies and/or case reports are available. Among these, notable benefits were seen in an open-label clinical study of women with trichotillomania (compulsive hair-pulling) treated with dronabinol.¹³ 

A few controlled studies have examined potential adverse effects of cannabinoids and their interactions with some drugs. THC is metabolized mainly in the liver by cytochrome P450 (CYP) isoenzymes (especially CYP2C), and it may interact with other substances metabolized by the same path. Smoking cannabis also can reduce plasma levels of some antipsychotic drugs. However, in studies of patients with cancer and HIV/AIDS, levels of cytostatic or antiretroviral drugs metabolized by CYP2C were not altered by concurrent THC treatment. The additive effect of THC taken with many analgesics and antiemetics is generally a desirable interaction. However, when taken with substances such as amphetamines that act on the cardiovascular system, the additive effects may increase tiredness. CBD helps to slow the degradation of some proton pump inhibitor drugs, as well as clobazam and risperidone (used for epilepsy and psychosis, respectively).

Many traditional and folk indications for cannabis have not been studied in controlled clinical trials. Uses for rheumatism, tetanus, rabies, and delirium tremens described by O’Shaughnessy, for example, have not been clinically investigated. Uses for joint inflammation, migraine, muscle cramps, and asthma, which were commonly treated by cannabis products in the 19th century and even after “marihuana” prohibition took effect in the 1930s, also have not been studied. Evidence from RCTs suggests that cannabis can improve sleep parameters in several conditions that may disrupt sleep, but its specific use in sleep disorders is unstudied. Other widespread but unstudied traditional uses for cannabis are for depression; alcohol, opioid, and/or nicotine withdrawal; premenstrual syndrome; women’s reproductive health; and childbirth.

The authors note that pharmaceutical companies are working to develop synthetic compounds that modulate the ECS. As laws that “inhibit access to potential natural remedies for serious diseases” are repealed, cannabinoids may help physicians and patients find new ways to manage disease.

* States with CBD-specific “medical marijuana” laws have not passed medical cannabis laws that would allow use of cannabis herbal material or any unapproved cannabinoids.

—Mariann Garner-Wizard

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