Cannabis has ceiling concentration for efficacy

Tetrahydrocannabinol (THC) is effective in reducing pain, but only up to a certain plasma concentration, beyond which it appears to magnify pain, according to a new study.

Over four sessions, each separated by 2 weeks, 16 patients with painful diabetic neuropathy were randomly assigned to one of four conditions: placebo or low (1% THC), medium (4% THC), or high (7% THC) doses of cannabis. Blood samples were drawn periodically and plasma levels of THC were measured using gas chromatography-mass spectrometry.

Researchers found significant linear and curvilinear effects of THC concentration, indicating that pain does indeed change as a function of THC (p≤0.001). THC estimates were negative, suggesting that, in general, pain was inversely correlated to THC concentration.

On the other hand, THC² estimates were positive, indicative of a U-shaped relationship, such that pain is greatest at the extremes of THC concentration.

Johnson-Neyman estimates further pinpointed a THC threshold value of approximately 16 ng/mL. Below this, the slope of the interaction between THC and spontaneous pain was negative and significant (estimate, –0.04, 95 percent confidence interval [CI], –0.08 to 0.00). As plasma THC levels approached 16 ng/mL, pain became increasingly subdued.

Beyond the threshold value, however, the slope flipped, returning a positive estimate (0.09, 95 percent CI, 0.00–0.18), suggesting that at higher THC values, pain response was instead intensified.

“These findings are clinically important and stress the need for studies evaluating the plasma concentration-response effects of THC on pain. These data also suggest that the continuing trend for the cultivation of cannabis with higher levels of THC may paradoxically lead to a worsening of pain outcomes,” the researchers said.