Many swear the drug can relieve chronic pain. But experts say the evidence for this is «dubious» — and it could just be a placebo effect. In a review of clinical trials of cannabinoids for pain relief, researchers found that there were not enough differences compared to placebo.
Patients have heard — perhaps from family, friends or the media — that cannabis and/or its derived compounds, called cannabinoids, can be helpful for pain like theirs. But as scientist Hao gives them an honest answer, «Based on the available data, the benefit is questionable». Authoritative studies have yet to find that cannabinoids sufficiently reduce pain, leading the International Association for the Study of Pain to refuse to approve these drugs in 2021.
The lack of evidence was highlighted 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 observed among those who received a placebo. This suggests that the pain reduction was not primarily due to the compounds in cannabis, but to people's expectations that it would help. And those positive expectations were based in part, the authors say, on overly enthusiastic media coverage.
Medical marijuana includes all forms of the drug, including smokable or ingestible products containing low or elevated doses of tetrahydrocannabinol (THC), responsible for the high associated with marijuana, or cannabidiol (CBD), a compound that does not cause a high. Articles in the popular press, including major mainstream newspapers, regularly promote the plant as a pain reliever, according to a JAMA study.
The JAMA Network Open analysis showed that positive articles appeared in the media even when the reported findings of the study were neutral or negative, says Karin Jensen, who led the study and is a researcher in the Neuroimaging of Pain Laboratory at the Karolinska Institute in Sweden. National Geographic was unable to independently verify the finding because of a confidentiality agreement between the researchers and London-based data collection firm Altmetric that prevents them from sharing news articles that Jensen's team evaluated for the JAMA study.
In this case, the media doesn't seem inclined to accept the facts because whatever the study says, the media will report it from a positive perspective. So it's no wonder why people keep asking for these drugs. According to the Centers for Disease Control and Prevention, one-fifth of Americans currently experience chronic pain. That's why it's crucial to patient care that future studies examining the effects of cannabinoids on pain produce results that aren't skewed in favor of positive outcomes due to bias.
Blind research on cannabis is challenging
In any clinical trial, when a participant receives an inert substitute, such as a sugar pill, rather than a therapeutic compound and reports positive results, this phenomenon is called the placebo effect. The gold standard clinical trials use a protocol known as double-blind, in which neither the participants nor the scientists know who is taking the active drug and who is taking the placebo.
Most studies testing cannabis-derived compounds have used pills to deliver the exact amount of drug (a few have included inhalation), and researchers make sure the placebo smells and tastes like the active drug. But participants can sometimes guess whether they were given the active drug or the placebo, depending on how they feel after taking the pill. When participants know when they have received the drug and when they have received the placebo, it can skew their perception of the drug's effectiveness and skew the results of the study.
Researchers at Karolinska University wanted to understand how big the placebo response was in cannabis studies, so they evaluated 20 reports involving about 1,459 participants. For example, one study they delved into compared the synthetic cannabinoid drug nabilone to a placebo for patients suffering from the pain condition fibromyalgia. The co-authors of the paper concluded that the drug provided significant benefits. This was in part due to problems with the blinded method, which caused this study, like many others, to overestimate the value of the drug.
There are ways to blind well, but most studies haven't done that. And even those methods are not absolutely perfect. One useful approach is to get some people to take very low doses and others to take higher doses, so that at least some participants don't have a psychoactive effect. Another way is to add an anti-rejection drug as a placebo so that even those people experience some physiologic symptoms. A third strategy is to initially give everyone a placebo, on the hypothesis that this will make the guessing more confounded.
Measuring participants' expectations about how much marijuana-derived products can help is also important, D'Souza says. This can be done with simple questions and then analyzed after the intervention, knowing in advance that people who believe in the efficacy of cannabis are likely to have more positive outcomes.
The brain's influence on pain is key
Unlike some chronic diseases, conditions accompanied by pain may be particularly 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 results from changes in the sensory pathways of the brain. Common conditions that cause nociplastic pain include fibromyalgia, irritable bowel syndrome, and tension headaches, among others. This pain is just as real and just as damaging as the other types, but it may not be treatable with the medications and treatments that are commonly prescribed.
Experts do not yet understand the exact mechanisms underlying nociplastic pain, but they conclude that thoughts play an important role. For example, in functional MRI scans, areas of the brain associated with pain perception and modulation light up when patients think particularly negative thoughts about their condition.
People with such pain may be particularly prone to respond to placebos, Hao believes. «I think it goes without saying that in this group of patients, the role of expectations may be potentially exaggerated»
— he says, though he emphasizes that this remains to be explored.
It may seem like it doesn't matter whether the positive results people experience in cannabis trials arise from taking the drug or from thinking they've done it, as long as their pain is reduced. But that's not the case, 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 a treatment that is effective for reasons other than the proposed mechanism, it's not going to help people in the long term» who might be better served by other treatments.
Another weed problem
Nausea. Severe abdominal pain. A compulsive urge to bathe. These are some of the signs of cannabinoid vomiting syndrome, a condition that is becoming increasingly common. The number of hospitalizations related to cannabinoid hyperemesis syndrome (CHS), a condition associated with frequent and prolonged marijuana use, has increased significantly, with the rate climbing nearly threefold by early 2025. Researchers are still trying to understand what makes some people so vulnerable to CHS.
Recurrent episodes of nausea, vomiting and severe abdominal pain. Compulsive bathing. You might not think of these as potential consequences of regular cannabis use — especially since it's known to have an anti-nausea effect in people undergoing chemotherapy. But these are actually classic signs of cannabinoid hyperemesis syndrome (CHS), a mysterious gastrointestinal condition associated with frequent and long-term marijuana use. First described in 2004 by doctors in Australia, CHS affects about 2.75 million people in the U.S. each year, and cases are on the rise: according to a study published in the October 2024 issue of JAMA, the number of CHS-related emergency room visits in the U.S. and Canada has doubled.
What is behind the increase in cases of cannabinoid hyperemesis syndrome (CHS)? One reason may be that marijuana has become more accessible as a result of the expanding legalization of cannabis for recreational use. Research supports this conclusion. In a 2024 paper published in the Journal of Clinical Gastroenterology, researchers compared the number of hospitalizations for CHS at a large hospital in Massachusetts in 2012 and 2021, that is, before and after the legalization of cannabis in the state, and found a significant increase in the number of cases.
However, why some people are more susceptible to this condition than others is still a mystery. Researchers are trying to make sense of this curious condition. Who is at risk and why? The main risk factor for CHS is heavy cannabis use, such as almost daily or repeated use over several years. A person can develop the syndrome at any time, even after long-term cannabis use.
However, «most people who smoke cannabis on a daily basis do not experience it. In those who suffer from CHS, the condition is not permanent. The symptoms occur cyclically. If they were persistent, it would cause the person to stop using cannabis» — emphasizes Christopher N. Andrews, clinical professor of gastroenterology at the University of Calgary.
https://doi.org/10.1111/nmo.13606
In a 2019 review of 271 cases, researchers found that the average age of CHS patients was 30 years old, and 69 percent were male. They also found that 68 percent of people with the syndrome used cannabis daily, and the average duration of use before CHS occurred was 6.6 years. What could be making some people more susceptible? Most likely, it could be related to the endocannabinoid system, which functions differently in all people.
The human endocannabinoid system regulates many vital functions, including learning, memory, pain perception and immune response. It includes cannabinoid receptors located in the brain and gut that respond to body signals, as well as endogenous cannabinoids similar to those found in the cannabis plant. CHS may be related to an imbalance in the hypothalamic-pituitary-adrenal (HPA) system, which is responsible for the stress response. The brain's endocannabinoid system modulates the stress response, and cannabis can shift this balance which can cause symptoms.
There may also be a genetic predisposition to CHS, and depression and anxiety are common among patients with the syndrome. «Paradoxically, we don't understand exactly what triggers this condition at any particular time» — says David Levinthal, director of the Center for Neurogastroenterology and Motility at the University of Pittsburgh Medical Center. He cites lack of sleep and high stress levels among the main contributing factors to CHS.
The symptoms of CHS have much in common with those of cyclic vomiting syndrome (CVS), a chronic disorder involving the interaction between the gut and the brain that is manifested by recurrent episodes of nausea and vomiting alternating with asymptomatic periods.
The biggest difference between the two syndromes is that it is chronic cannabis use that causes CHS exacerbations. There is debate as to whether cannabinoid hyperemesis syndrome is a subspecies of cyclic vomiting syndrome with a different trigger. Regardless of classification, it can be a serious condition that can cause complications if left untreated. Complications can include severe dehydration and electrolyte imbalance, which can lead to kidney damage, heart rhythm abnormalities and seizures. In addition, frequent vomiting can lead to erosion of tooth enamel and eventually tooth loss, she adds.
According to the American Gastroenterological Association (AGA), a diagnosis of cannabis-related cyclic vomiting syndrome (CHS) requires at least three episodes of nausea, vomiting and abdominal pain within a year, each lasting less than a week; cannabis use more than four days a week for more than a year; and disappearance of symptoms after cessation of cannabis use for at least six months.
During an exacerbation, many CHS patients often take hot baths or showers several times a day to relieve discomfort. Patients with CHS often report temporary relief of symptoms after bathing in hot water, which can lead to compulsive behavior. This may indicate the involvement of the hypothalamus, responsible for body temperature regulation, in the pathogenesis of CHS.
A lesser-known treatment is applying capsaicin cream (0.1%) to the abdominal area, which may help reduce the nausea and vomiting associated with CHS. A study published in the journal Academic Emergency Medicine found that patients with nausea and vomiting caused by CHS experienced a significant reduction in symptoms within an hour of applying capsaicin cream.
To date, cannabis cessation remains the only long-term solution to the problem. However, abrupt cessation of use can lead to cannabis withdrawal symptoms such as anxiety, irritability, aggression, sleep disturbances, depression and loss of appetite. Working with a counselor and using tricyclic antidepressants (such as amitriptyline) can help with the marijuana withdrawal process. Another option is to gradually reduce the dose of THC.
For those who can't quit smoking completely, Andrews suggests alternative approaches to improving CHS symptoms, such as reducing the frequency of cannabis use and avoiding concentrates. He adds that switching to more balanced formulas of THC and other cannabinoids such as cannabidiol (CBD), which do not cause a «buzz» effect, may be beneficial; however, these hybrid formulas are less effective. In the meantime, scientists continue to investigate the mechanisms underlying this mysterious condition and seek more effective treatments.