One of our readers asked why we only emphasize marijuana’s downside? In the continuing effort to rid the healthcare system of opioids, cannabinoids, the active components in marijuana, have been mentioned with increased frequency. A recent article in the Annals of Internal Medicine looked at the accumulated evidence as researchers performed a meta-analysis and systemic review of the literature. Here is what they found. Spoiler alert: patients with chronic pain will have to “toke on a lot more blunts” before we have less ambiguous data.
Chronic pain is a growing problem for many Americans, especially musculoskeletal pain. “Plant-derived” non-opioid alternatives  have been proposed to lessen the adverse impacts of long-term opioid use. The active components of cannabis are the cannabinoids, primarily tetrahydrocannabinol (THC), the one that gets you “buzzed,” and cannabidiol (CBD), the one that “soothes.”CBD has some analgesic and anti-inflammatory effects“and is not believed to be psychoactive or addictive.” The authors sought more certainty about this conclusion by searching for studies in the English literature mentioning chronic pain and CBD.
They categorized articles based on the marijuana product’s ratio of THC to CBD  and their source. The two available synthetic products, dronabinol, and nabilone, FDA-approved to treat nausea and plant-based extracts. Overall, they considered 18 randomized control studies (RCT) and seven observational studies out of a potential dataset of 247 studies.
Most study participants were middle-aged, White, with mid-range levels of neuropathic pain – pain scores of 5 to 6. The RCTs were short, 1 to 2 months with placebo controls. The observational studies had longer follow-up and compared the initiation of cannabis use to usual care.
- Studies involving a high THC to CBD ratio, basically 98% THC, showed a reduction of 1.15 points on the 10-point pain scale. However, in only one small study, did this reduction meet the specification for “clinical significance,” a reduction of 30%. The two synthetics were associated with a slightly greater risk of sedation, 1.03, and dizziness, 1.47.
- Studies involving comparable THC to CBD ratios showed a slight reduction, 0.54, on the 10-point scale, again not thought to be clinically significant. There was a greater risk of sedation, 5-fold more than controls, and dizziness, a 3-fold increase. Several studies reported better sleep experienced by those receiving medication.
- Studies involving low THC to CBD levels, essentially just CBD, and the five observational studies where patients used medical cannabinoids failed to demonstrate any reduction in the use of opioids. The sample size and bias in patient selection prevented drawing any conclusions.
“The strongest evidence to date is for synthetic products with high THC-to-CBD ratios and extracted products with comparable THC-to-CBD ratios, both of which resulted in improvements in pain severity …. Small improvements in overall functioning were seen with products with comparable THC-to-CBD ratios, whereas none were seen with synthetic products with high THC-to-CBD ratios.” 
As the accompanying editorial noted, physicians should focus on “pragmatism, patient experience, known cannabinoid effects, and harm reduction.” Noting that, like all analgesics, “some persons will benefit, and others will not.”
What is perhaps more telling are the study’s limitations, primarily a lack of clear information on the amount and ratio of THC and CBD in plant extracts. This is a direct result of restrictions on research placed by the federal government, which continues to classify THC as a Schedule 1 drug, along with heroin, LSD, peyote, and methaqualone – “drugs with no currently accepted medical use and a high potential for abuse.” Despite that statement, 37 states permit the use of medical marijuana. What do the states know that the feds and our current scientific literature don’t?
A momentary lapse into science
There is a plausible physiologic connection between pain reduction and cannabinoids, specifically involving two receptors, CB1 and CB2. CB1 acts to modulate, that is, reduce incoming pain signals located at a point where it can have a local effect and reduce signals to our higher, integrating central areas of the brain. CB2 receptors are found predominantly in the periphery, inhibiting our old friends, the cytokines [DEFINE], slowing chronic inflammation, and modulating chronic pain. THC binds tightly to these receptors; CBD, in another complication of our biology, acts as a competitive inhibitor of that binding while also targeting other receptors in our perception of pain.
Specifically for neuropathic pain, the subject of many studies in the meta-analysis, animal models have shown an up-regulation of these receptors in the presence of nerve injury. It makes sense that the cannabinoids that down-regulate the same receptors would reduce pain perception. It would also suggest that they have an adjunctive rather than a primary role. The use of plant extracts, which contain other chemicals, like terpenes and flavonoids, has been shown to have a more significant impact on pain reduction than purified products, at least in the rat model.
But we will never know the value of the cannabinoids until we can do more research. Until then, we are left with these meta-analyses that show an uncertain and weak effects because of unfocused, underfunded study.
 This is a bit disingenuous, since most opioids are also plant-derived, at least initially.
 High > 2 parts THC to CD, Moderate <2:1 but more than >1:2, Low <1:2
 The researchers felt that extracts contained other chemicals that might be playing a role and therefore treated them as a separate category.
Source: Cannabis-Based Products for Chronic Pain Annals of Internal Medicine DOI: 10.7326/M21-4520
Cannabinoids and Pain: New Insights From Old Molecules Frontiers in Pharmacology DOI: 10.3389/fphar.2018.01259