The pain-relieving effects of cannabidiol (CBD) may be linked to its influence on affective processes, new research shows.

In a pilot study, investigators from the University of Syracuse, Syracuse, New York, found that patient expectectatons regarding analgesia appear to be integral to CBD’s purported ability to modulate pain outcomes.

“Our initial findings show that both the pharmacological action of CBD and psychological expectancies of believing that you’ve received CBD differentially engage and enhance central nervous system [CNS] processes that inhibit pain,” Martin De Vita, MS, doctoral candidate and study co-author, told Medscape Medical News.

“While CBD did not completely eliminate the pain or reduce pain intensity, it made it significantly less unpleasant,” he added.

The study was published online April 22 in Experimental and Clinical Psychopharmacology.

A Key Driver of Medical Cannabis Use

Relief of chronic pain has long been one of the primary factors driving use of medicinal cannabis. Clinical research has mostly focused on Δ9-tetrahydrocannabinol (THC) in combination with CBD or other cannabinoids. Investigations into the mechanisms underlying CBD’s effects and its role in analgesia apart from THC have been sparse.

Even fewer studies have directly investigated the role of cannabinoids or CBD for acute pain modulation.

To assess the effects of CBD and expectancy on acute pain reactivity, the researchers conducted a crossover, balanced placebo study that involved healthy adults aged 18 to 30 years. Participants were given either inactive coconut oil or CBD and were told that they had received either inactive coconut oil or CBD. Participants who received CBD were given 50 mg of pure, hemp-derived CBD sublingually in a 0.3-mL solution.

The study enrolled 15 participants, 67% of whom had never used CBD; 86.7% were either current users or had ever used cannabis. Participants were randomly assigned to one of four experimental sessions: control (told inactive, given inactive), expectancy (told active, given inactive), drug (told inactive, given active), and expectancy+drug (told active, given active).

Participants were then exposed to six experimental heat pain trials that measured pain threshold and tolerance. This was followed by visual analogue scale assessments to measure pain intensity and unpleasantness.

Central pain inhibition and perception of pain intensity were assessed with two dynamic pain tests, the conditioned pain modulation (CPM), and offset analgesia (OA).

The findings showed that participants experienced significantly greater reductions in pain unpleasantness in the expectancy condition (paired-samples ?[14] = 3.36; P = .006; d = .860), the drug condition (?[14] = 3.17; P = .007; d = .820), and the expectancy+drug condition (?[14] = 2.36; P=.033; d = .616) in comparison with the control condition.

A significant, greater degree of pain inhibition (CPM response) was noted in the expectancy (?[14] = -2.75; P = .016; d = -.84) and drug (?[14] = -3.20; P = .006; d = -.84) conditions in comparison with the expectancy+drug condition.

A significant instruction effect on OA (?[1,4] =  7.58; P = .016; effect size = .351] was also seen. No notable effects were noted in pain threshold, tolerance, or intensity.

“What we found is that CBD and expectancies for receiving CBD, both independently and combined, improve the affective or emotional component of pain,” De Vita said.

“We also saw that CBD and expectancy engaged CNS processes that inhibit pain, albeit differentially, which supports our hypothesis that CBD acts on the CNS from both pharmacological and expectancy or placebo analgesia perspectives,” he added.

In addition to sample size, study limitations include the use of experimental pain measures, single sublingual CBD dosing, age, and lack of drug screening for other cannabinoids.

Still Hope for CBD in Acute Pain Treatment?

Commenting for Medscape Medical News, Michelle Sexton, ND, assistant adjunct professor of anesthesiology at the University of California, San Diego, and a researcher with extensive experience in cannabinoid pharmacology and the use of cannabinoids for pain conditions, said, “When you look at the totality of the literature, I don’t recall anything ever pointing to CBD as a great pain reliever.

“It doesn’t compare well to the analgesic effects of THC. They’re not equipotent molecules, nor do they have similar mechanisms of action,” she said.

Sexton’s view has been borne out in a randomized, double-blind, placebo-controlled trial of the use of oral CBD 400 mg as an adjunct to standard care for adult patients who presented to the emergency department with acute, nontraumatic back pain. These findings, which were published April 21 in the Australian Medical Journal, showed no evidence that CBD was beneficial for pain or other outcomes.

Sexton also expressed methodologic concerns. “The CPM measure is not a well-accepted output for patients with pain, and it was the only significant effect the study showed,” she said. She noted that the P value was low for that result and that 95% confidence intervals were missing.

“You have to be really selective about how you do your trial design and what patient population you select,” she said.

De Vita acknowledged that the findings are preliminary, that more data are needed about individual patient differences and potential confounders that might influence the findings, and that larger sample sizes would enhance statistical power.

“For this first human experimental study, we were primarily interested in the drug and expectancy effects and interactions with spatial pain,” he said.

“Until now, people have wondered whether or not CBD has value in pain, and it appears that it’s a little bit of a placebo effect and a little bit of pharmacological effect and that differs, depending on the aspects of pain that you are looking at,” he added.

The next step is to study the mechanisms underlying these findings, De Vita said.

De Vita has disclosed no relevant financial relationships. He is currently completing a clinical psychology internship at Brooke Army Medical Center, Joint Base San Antonio, San Antonio, Texas. The views expressed are his own and do not reflect the official policy or position of the Brooke Army Medical Center, the US Army Medical Department, the US Army Office of the Surgeon General, the Department of the Army, the Department of the Air Force, and the Department of Defense. Sexton is a consultant to Verséa Pharmaceuticals.

Exp Clin Psychopharmacol. Published online April 22, 2021. Abstract

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