For David Hao, a chronic pain physician at Massachusetts General Hospital in Boston, the situation with a new patient suffering from severe chronic pain is often as follows: Present possible treatments, such as steroid injections, nerve ablation painful, acupuncture, physical therapy or surgery. But toward the end of the quote, some inevitably ask, “Do you think I should try marijuana?”
Patients have heard (perhaps from family, friends, or the media) that cannabis and its derived compounds, called cannabinoids, can be helpful for pain like yours. But as a scientist, Hao gives them a candid answer: “Based on the available evidence, the benefit is questionable.” Reputable studies have so far not found that cannabinoids sufficiently reduce pain, leading the International Association for the Study of Pain in 2021 to refuse to endorse these drugs.
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The lack of evidence was underlined late last year in a review published in JAMA Network Open. That study found that 67 percent of the pain relief reported by people treated with cannabinoids was also seen among those given a placebo. This suggests that the reduction in pain was not primarily due to the compounds found in cannabis, but rather to people’s expectations that it would help them. And that positive expectation was based in part, say the authors, on overzealous media coverage.
Medical cannabis encompasses all forms of the drug, including smokable or ingestible products that contain low or high doses of tetrahydrocannabinol (THC) (responsible for producing the high associated with marijuana) or cannabidiol (CBD), a compound that does not generate high. According to the study of JAMAarticles in the popular press, including large newspapers with great circulation, regularly promote the plant as a pain treatment.
The JAMA Network Open analysis found that positive articles appeared in the media even when the reported research findings were neutral or negative, says Karin Jensen, who led the study and is a researcher in the Pain Neuroimaging Laboratory at Karolinska Institute of Sweden. National Geographic was unable to independently verify this finding because of a confidentiality agreement between the researchers and the London-based data collection company Altmetric, which prevents them from sharing the newspaper articles that Jensen’s team evaluated for the study. JAMA.
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“The media seems to be resistant to the facts in this case, because no matter what a trial says, the media will report with a positive approach. So there is no question why people keep asking for these drugs.” Jensen states.
A fifth part of Americans currently suffer from chronic pain (in Spain, the figure is around 11% of the population), according to the Centers for Disease Control and Prevention. That’s why it’s critical to patient care that future studies exploring the effect of cannabinoids on pain have results that are not positive due to bias, Hao says.
Blinding in research is a challenge with cannabis
In any clinical study, when a participant receives not the therapeutic compound, but an inert substitute such as a sugar pill, and reports positive results, the phenomenon is called the placebo effect. Reference clinical trials use a protocol known as double-blindin which neither the participants nor the scientists know who is taking the active drug and who is taking the placebo.
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Most studies testing cannabis-derived compounds used lozenges to deliver precise amounts of medication (in a few it was inhaled), and researchers ensured that the placebo smelled and tasted like the active drug. But participants can sometimes guess whether they received the active drug or a placebo based on how they feel after taking the pill. When participants know when they have received the drug versus placebo, this can skew their perception of the drug’s efficacy and skew the results of the study.
The Karolinska researchers wanted to know the magnitude of the placebo response in cannabis studies, so they evaluated 20 reports involving some 1,459 participants. A study in which they delved, for example, compared a synthetic cannabinoid, nabilone, with a placebo for patients suffering from fibromyalgia. The paper’s co-authors concluded that the drug offered significant benefits. This was partly due to problems with blinding, which caused the study, along with many others, to overstate the value of the drug.
To counter the participants’ ability to realize what they had been given, the researchers sometimes administered the drug in low doses or gave participants non-THC-containing formulas so they would not get high and know they had received the medication. .
But with a drug with which so many people are intimately familiar, successful blinding in cannabis studies requires tremendous effort, says Deepak D’Souza, a professor of psychiatry at Yale Medicine who has studied cannabis for more than two decades and is is preparing for a large clinical trial with cannabinoids at the Veterans Administration.
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“There are ways to blind well, but most studies haven’t done it. And even those methods aren’t absolutely perfect,” he says. One useful method is to have some people take very low doses while others take higher amounts, so that at least some participants do not have a psychoactive effect. Another way is to add a decongestant as a placebo so that even these people experience some physiological symptoms. A third strategy is to give everyone placebos initially, based on the hypothesis that this will make intuitions more confusing.
Gauging participants’ expectations about how much marijuana-derived products might help is also important, D’Souza says. “You can do that with simple questions,” and then discuss them after the intervention with the certainty that people who believe cannabis will be effective are likely to have more positive outcomes, she says.
The brain’s impact on pain is a key factor
Unlike some chronic illnesses, conditions that involve pain may be especially susceptible to the placebo effect. This is the case for the types of pain known as nociplastic pain. Unlike pain caused by ongoing tissue or nerve damage (nociceptive and neuropathic pain, respectively), this pain is the result of disturbances in the brain’s sensory pathways. Common conditions that trigger nociplastic pain include fibromyalgia, irritable bowel syndrome, and tension headaches, among others. This pain is just as real and damaging as other types, but it can Do not answer to the drugs and treatments usually prescribed.
Experts do not yet understand the precise mechanisms underlying nociplastic pain, but they are coming to the conclusion that thoughts play a role. In functional MRIs, for example, brain regions involved in pain perception and modulation light up when patients have especially negative thoughts about their disease.
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In Hao’s opinion, people with this type of pain may be especially prone to a placebo response. “I think it’s logical to think that, in this group of patients, the role of expectations can be potentially disproportionate,” she says, although she stresses that this has not yet been studied.
It may seem that it doesn’t matter whether the positive results people experience in cannabis trials are because they took the drug or because they thought they had, as long as their pain subsides. But it’s not like that, says Jensen. “It’s not enough to know something works. We need to know why it works to better help patients,” she says. “If we provide treatments that are effective for reasons other than the suggested mechanism, that’s not going to help people in the long term,” who might be better served by other therapies.
“It may please patients in the short term that doctors recommend cannabis,” says Jensen, “but at the moment the scientific evidence does not support treatment for pain.”