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Cannabis use for medical purposes is on the rise, especially for the management of chronic pain. Marco Ternelli, MSc Pharm, a compounding pharmacist in Bibbiano, Italy, fields a steady stream of about 1000 such prescription requests every month, he told Medscape Medical News.

Yet despite the surge in demand, the scientific evidence supporting their use for pain management remains a complex and often contradictory picture, making it difficult for clinicians to know how to advise their patients.

“There is strong evidence from preclinical research that supports the hypothesis of cannabinoid-induced analgesia,” David Finn, PhD, professor of pharmacology and therapeutics at the University of Galway, Galway, Ireland, told Medscape Medical News. “But the clinical evidence is weaker, in large part due to low quality studies with low sample size or short duration of treatment and sometimes patient population not well-defined.”

Medical Cannabis in Europe

The regulatory landscape for medical cannabis is undergoing a significant transformation in Europe.

In Italy, authorized cannabis-based medicines can be prescribed to patients using a special form approved by the Ministry of Health.

Two cannabis-based medicines have received UK marketing authorization and can be prescribed there by specialist doctors.

Germany legalized recreational cannabis in 2024, a move that also broadened access to medical cannabis.

Other countries like France, Spain, and Denmark are in the process of establishing or expanding their medical cannabis programs.

Slovenia has also moved to regulate medical cannabis, and the Netherlands is set to break its state monopoly on its production.

Figures of medical cannabis use in Europe are difficult to find, but a recent Prohibition Partners European Cannabis Report suggested that almost half a million people had obtained it through legal routes by the end of 2024.

In 2019, the European Parliament and the European Medicinal Cannabis Association, a Brussels-based industry body representing the interests of European medicinal cannabis suppliers and manufacturers, called for unified rules and more research. Since then, more countries have regulated cannabis use for medical purposes, but gray areas remain and the regulatory landscape remains fragmented.

What Is Medical Cannabis and How Does It Work?

The Cannabis sativa plant contains more than 100 cannabinoids that interact with the body’s endocannabinoid system (ECS). The two most well-known and studied cannabinoids are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Minor cannabinoids include cannabigerol), cannabichromene, and cannabinol. Additionally, other compounds, such as terpenes like limonene, pinene, and beta-caryophyllene, as well as flavonoids, may have a role in the overall efficacy of medical cannabis.

THC is a partial agonist of CB1 receptors, which are highly concentrated throughout the central nervous system in areas related to pain modulation. This interaction is responsible for not only the main analgesic effects but also psychotomimetic properties of cannabis.

CBD acts as a negative allosteric modulator of CB1 and CB2 receptors, dampening their response to agonists like THC and natural endocannabinoids. Unlike THC, CBD is not psychotomimetic, so it does not give the “high” and it can help reduce THC’s psychotomimetic properties when used in combination. Its therapeutic potential is likely due to its influence on a broad range of molecular targets, including serotonin 1A receptor and peroxisome proliferator-activated receptor gamma. It also exhibits antioxidant properties and can reduce proinflammatory cytokines, such as interleukin (IL)-6, IL-1, and TNF-alpha.

Minor cannabinoids are non-psychotomimetic and bind to multiple receptors. “These are not selective compounds. They are very promiscuous. But many of these receptors are implicated in pain,” Kent Vrana, PhD, a professor in pharmacology at the Center for Cannabis and Natural Product Pharmaceutics at Penn State Neuroscience Institute, Pennsylvania, told Medscape Medical News.

The varying ratios of THC, CBD, and minor compounds in different products factor in their therapeutic effects and side effect profiles. Products with a higher percentage of THC are generally considered more effective for pain relief but carry a higher risk for psychotomimetic side effects. Products containing mainly or solely CBD are often favored for inflammatory conditions and are generally better tolerated.

What Does the Evidence Say About Cannabinoids for Chronic Pain?

In 2021, the International Association for the Study of Pain gathered 20 international pain researchers to systematically analyze the available evidence on the use of cannabis in pain management. They found that, overall, numerous knowledge gaps exist and that the quality of the research is flawed.

Other reviews published in 2021 found the evidence was inconsistent, with some studies showing a slight improvement in pain relief compared with placebo and side effects that included dizziness, drowsiness, nausea, vomiting, cognitive impairment, and impaired attention.

Two recent reviews, both published in February this year, have suggested that cannabis may be a promising alternative or adjunct to opioids, with some studies showing that its use can lead to a reduction or cessation of opioid prescriptions.

In the journal Medical Cannabis and Cannabinoids, researchers found convincing evidence that cannabinoids are often beneficial. Sativex, a spray with equal parts THC and CBD, for example, has been shown to reduce neuropathic pain. It is approved in Canada and Europe for cancer-related pain, often used as an adjuvant to manage pain caused by cancer or its treatments. “That is probably the one product for which we have good data,” said Emily M. Lindley, PhD, an associate professor in the Department of Orthopedics at the University of Colorado Anschutz Medical Campus. “Aside from that, I would be hard-pressed to find probably more than one, maybe two studies using the exact same product in trials.”

Another group of researchers reported in the journal Biomedicines that the evidence for cannabinoids is mixed across conditions. Some randomized controlled trials showed moderate evidence of cannabinoid efficacy in relieving neuropathic pain and reasonable evidence for symptom relief in multiple sclerosis. Weaker evidence was found for the relief of headache and migraine. The evidence remains inconsistent for pain relief in fibromyalgia, cancer-related pain, and musculoskeletal pain. The main risks and side effects linked to the use of cannabinoids are addiction and tolerance, especially with THC. Some patients report increased levels of anxiety, psychosis, and cognitive impairment. Other risks include drug interactions, particularly with medications metabolized by cytochromes P450, a family of enzymes involved in the oxidation and reduction of lipid-soluble compounds.

Some studies included in the Biomedicines review showed that many patients view cannabis to be safer than opioids and report subjective improvement in quality of life despite the level of their pain remaining the same. “Are we conflating the euphoria with the analgesia?” Vrana asked. Or maybe cannabinoids have a holistic effect, said Rachael Rzasa Lynn, MD, an anesthesiologist and pain management expert at UCHealth Pain Management Clinic at Anschutz Medical Campus.

This potential holistic effect was examined in a small study published in 2023 in Journal of Cannabis Research. That study compared the holistic effects of medical cannabis with those of opioids on the pain experience of Finnish patients with chronic pain. It found that both substances were perceived as equally effective in reducing pain intensity, but cannabinoids were associated with more positive emotional and holistic effects and an overall sense of well-being. The authors suggested that the psychoactive effects of medical cannabis, rather than being solely negative, may be a part of its therapeutic mechanism.

Lindley and Rzasa Lynn have also compared the short-term acute effects of a THC and minimal CBD vaporized combination with those of placebo and oxycodone. The study, which is yet to be published, showed that cannabis provided a significant relief in chronic back pain, more than both placebo and oxycodone.

Why Is It Hard to Find Agreement?

C sativa has been used as a remedy for millennia. But the classification of cannabis as a narcotic drug has severely hampered research into its therapeutic potential, explained Rzasa Lynn. Beyond the regulatory hurdles, there are several inherent challenges in conducting high-quality clinical trials on medical cannabis, particularly for chronic pain, she said.

Cannabis is not a single compound but a complex plant. Treatments are nuanced, with significant variations in routes of administration such as oils, flowers, and edibles. Different growth conditions produce different cannabinoid profiles, and there can be high batch-to-batch inconsistency. This makes it difficult to standardize interventions and compare results across studies. “It’s not like a single pill at a couple of doses. It’s so much more complicated,” Lindley said.

The plant extract contains hundreds of pharmacologically active molecules, explained Finn. This complexity makes pharmacokinetics challenging. He added that different people might respond differently to the same extract. “To some extent, cannabis is used by patients as a personalized medicine. They’re choosing the THC and CBD concentrations that work for them. They’re titrating those to suit their needs. But randomized controlled trials often aren’t configured in that sort of a way,” he said.

Synthetic products might solve this problem, but the experts agreed that it is likely the combination of the wide range of compounds in the plant working together that enhances the overall therapeutic impact. “We don’t know what we might be losing if we use a pure product,” Rzasa Lynn said.

Also, pain is a complex and subjective experience that varies widely between patients and even within the same patient over time. “Chronic pain is distinct from what most people experience day to day with acute pain. It behaves a little bit differently in the face of treatment over prolonged periods,” said Rzasa Lynn. “This creates limitations for measuring outcomes.”

Another challenge is to find a “good patient population,” she said. “When you’re running a clinical trial, you want the human equivalent of a lab rat, but pain can be really difficult to narrow in a way that you can easily compare one patient to another, not only because it’s subjective but also because there are so many different physiological pathologies that can lead to pain as the outcome, and they all may respond very differently to different types of treatment.”

What Should Clinicians Know?

Lindley said clinicians should create an environment where patients feel comfortable discussing their interest in the use of cannabis. Many patients are exploring cannabis on their own, and even if a clinician is not an expert, expressing a willingness to learn with the patient can be a productive approach, she said. “Too often it’s just swept under the rug.”

Rzasa Lynn said it is important to evaluate if cannabis is truly providing a functional benefit. “We got so focused on pain as this unidimensional number, 0-10, and that is our success,” she said. “But the goal of any pain-reducing treatment is to improve global function. And that’s not just physical function, but that’s social engagement, and that’s work around the house, and that’s sleeping well, and everything that goes into quality of life.”

If a patient is using high doses of cannabis but still reports inadequate pain control and poor function, the use of these products should be questioned, she explained. This conversation should be framed around the patient’s goals and their perception of how cannabis helps achieve them. “Is it really making you better? Because if it was that effective, I think you probably wouldn’t be here right now.”

Ternelli, Finn, Lindley, and Rzasa Lynn reported having no relevant financial relationships. Vrana reported receiving an unrestricted research grant from Pennsylvania Options for Wellness. 

Manuela Callari is a freelance science journalist specializing in human and planetary health. Her work has been published in The Medical Republic, Rare Disease Advisor, The Guardian, MIT Technology Review, and others.