Over the past decade, marijuana has had quite a run. Seventeen US states and the District of Columbia now allow recreational use of marijuana; only 13 states have not yet legalized it for either medical or recreational purposes. But what do we really know about the relative benefits and risks of the popular and remarkably complex cannabis plant?
Researchers have long asserted that the science has badly trailed the claims and counterclaims of supporters and detractors. Over the past 5 years, however, high-quality trials and reviews have begun to close the gap. Of the cannabis plant's roughly 140 unique chemical constituents, or phytocannabinoids, 2 of the best studied are Δ-9-tetrahydrocannabinol (THC), the plant's main psychoactive ingredient, and cannabidiol (CBD).
In an April 2021 telebriefing on cannabis and health sponsored by the nonprofit journalism service SciLine, experts noted that CBD is gaining prominence mainly because of its significant differences with THC. “What is unique about CBD is that although it is psychoactive—so we think that it is helpful for some indications for the central nervous system and in the brain, like anxiety, and perhaps pain—it is not intoxicating,” says Ziva Cooper, PhD, director of the University of California, Los Angeles Cannabis Research Initiative. Some scientists believe that other phytocannabinoids and hundreds of separate chemicals called terpenes might likewise have therapeutic effects, although Dr. Cooper cautions that most research on these chemicals has so far been limited to animal studies.
Conclusive or Substantial Evidence for Some Effects
Despite the unknown effects, evidence is steadily mounting that at least some cannabis health claims are backed by science. In 2017, the National Academies of Sciences, Engineering, and Medicine released The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research, a report by an expert committee that reviewed the available evidence for 20 indications.1 As expected, the committee found conclusive evidence that oral cannabinoids were effective in preventing and treating chemotherapy-induced nausea and vomiting. The committee also found substantial evidence that cannabis or cannabinoid compounds were likely to significantly reduce the symptoms of patients with chronic pain and that the short-term use of some oral cannabinoid medications improved the self-reported symptoms of adults with multiple sclerosis–related muscle spasms.
The committee found moderate evidence that cannabis or cannabinoids could improve the symptoms of fibromyalgia and, at least in the short term, improve sleep disturbances associated with obstructive sleep apnea syndrome. The report cited limited evidence of effectiveness for increasing appetite and decreasing weight loss associated with HIV and AIDS, for improving the symptoms of Tourette syndrome and posttraumatic stress disorder, and for aiding the public speaking ability of patients with social anxiety disorders. Dr. Cooper, a member of the review committee, emphasizes that most of the assessed studies did not use the cannabis plant itself, and none used medical dispensary products. “So, we have very little knowledge about the whole cannabis plant and what people are using,” she says.
Since the report's release, other studies have offered compelling evidence that a purified extract of CBD called Epidiolex is effective in alleviating epileptic seizures associated with 2 rare but severe conditions: Lennox-Gastaut syndrome and Dravet syndrome.2 On the basis of that evidence, in fact, the Food and Drug Administration (FDA) approved Epidiolex in 2018, and this made it “the first FDA-approved drug that contains a purified drug substance derived from marijuana” according to the agency.
Igor Grant, MD, director of the Center for Medicinal Cannabis Research at the University of California, San Diego, says that the National Academies report agreed with his group's longstanding conclusions about the usefulness of cannabis for managing pain, particularly neuropathic pain. “I think what is not known is how enduring the therapeutic effect is,” he says. At least so far, Dr. Grant says, studies have suggested that low-dose cannabis is a relatively safe pain treatment and provides relief comparable to the relief provided by some commonly used drugs such as the anticonvulsant lamotrigine, although not as much relief as some antidepressants.
The effectiveness of cannabis against low- to mid-grade chronic pain has, in fact, widened discussions about its potential as a safer alternative to prescription opioids. A 2014 analysis found that US state laws permitting medical cannabis “are associated with significantly lower state-level opioid overdose mortality rates.”3 In a 2019 commentary, Thomas Clark, PhD, a professor of biology at Indiana University South Bend, cited evidence that moderate use of marijuana can help to reduce reliance on prescriptions for multiple drug classes. The result of fewer overdose deaths from more dangerous drugs, he argued, should be factored into the potential health benefits of cannabis.4
A Drug of Many Contradictions
What is becoming clear, Dr. Grant says, is that cannabis seems to have a biphasic effect for many indications. It is ineffective at low doses, effective at modest doses, and then again ineffective, even harmful, at high doses. This effect can be readily observed with anxiety: Although cannabis has calming and antianxiety effects when taken in low to moderate doses, it can produce significant anxiety and even paranoia and hallucinations at higher doses.
“[CBD] may be a useful treatment for some forms of psychosis or schizophrenia.”
–Igor Grant, MD
Another study in rats is examining the potential of CBD to treat alcohol addiction by targeting what is known as the “craving effect.” Craving, Dr. Grant says, can lead to relapse by creating a neural memory of the high and an urge to avoid the discomfort of withdrawal. “There is a little bit of evidence in the animal literature that cannabidiol may actually lessen this craving effect,” he says. The potential effect, if confirmed in humans, would suggest that although some cannabis constituents such as THC can produce addiction, CBD may have the opposite effect.
Hymie Anisman, PhD, professor of neuroscience at Carleton University in Ottawa, Ontario, Canada, cowrote a 2019 commentary pointing out that most studies examining the potential of cannabinoids to treat posttraumatic stress disorder have been small and of low quality.5 Nonetheless, he and his coauthors concluded that the few reported studies support further detailed investigation into the potential therapy. The number of untested claims has only proliferated since his commentary.
“I'm more confused now than I was then,” Dr. Anisman says. Even so, he senses “a lot of excitement in Canada about cannabis research and the potential for various therapeutics.” The rub is that “much more needs to be done,” he says. “We also take for granted that what happens in rodents will naturally translate to humans, and it doesn't always work like that.”
More research tools may be on the way. After decades with only 1 federally approved cannabis growing facility at the University of Mississippi, the US Drug Enforcement Administration announced in May 2021 that it had issued memoranda of agreement to several additional growers. “I think it's definitely a positive step,” Dr. Grant says. More growing facilities may help to supply plants with a broader diversity of THC:CBD ratios, enable more methods of administration such as edibles and vaping, and achieve higher phytocannabinoid concentrations that reflect what real-world users are consuming.
An even more helpful step from a public health standpoint, Dr. Grant says, would be legislation that moves cannabis to a more permissive category of controlled substances to ease the ability of research centers such as his to study the effects of products that are legal at the state level. “What are Californians using and what are Coloradoans using, and what are the good, bad, and ugly effects of that? We just don't know,” he says. As more people turn to cannabis for recreation or medicine, finding out will become increasingly urgent.