New research has found that cannabis tolerance is linked to neurometabolic alterations in the brain’s reward circuitry. The findings, published in the journal Addiction Biology, help explain why the effects of cannabis are less prominent in frequent cannabis users.

“Cannabis is the most commonly used illicit drug in the world, with 4% of the global population reportedly using the substance. However due to a changing legal landscape, and rising interest in therapeutic utility, there is an increasing trend in (long-term) use,” said Natasha L. Mason (@NL_Mason), a PhD candidate at Maastricht University and the corresponding author of the new study.

“Importantly, a growing body of evidence suggests that the acute effects of cannabis are less prominent in regular cannabis users, suggesting development of tolerance to the impairing, as well as the rewarding, effects of the drug. Although this development of tolerance is quite well established, the neurobiological mechanisms underlying it are not.”

“These neurobiological mechanisms are important to elucidate, both in the context of therapeutic use of cannabis-based medications (e.g. deciding on dose in long-term treatment), as well as in the context of public health and safety of cannabis use when performing day-to-day operations (e.g. developing traffic laws),” Mason said.

In the double‐blind study, 12 occasional and 12 frequent cannabis users consumed the drug or a placebo before undergoing brain imaging scans. The participants also completed a measure of their reaction times and attentional lapses, along with an assessment of their subjective high.

The researchers observed significant differences between the occasional users, who consumed cannabis 1 time a month to 3 times a week, and the frequent users, who consumed the drug at least 4 times a week. In particular, cannabis resulted in alterations in the brain’s reward circuitry, including decreases in functional connectivity, in occasional users. But these changes were absent in chronic users.

“In the occasional users, we found that cannabis altered reward system circuitry in the brain, which was associated with our behavioral measures (increased feelings of high and decreased sustained attention). Such changes were absent in the chronic cannabis users, who did not show any brain changes or any cognitive impairment,” Mason told PsyPost.

“The finding that cannabis altered reward circuitry and distorted behavior in occasional users, but not chronic users, suggests the lack of behavioral response to cannabis intoxication in chronic users arrives from a blunted responsiveness in their reward circuitry, thus identifying a neurobiological mechanism of tolerance.”

“Cannabis tolerance is not a final, permanent state that is achieved after chronic cannabis use, but rather a temporary state of decreased sensitivity to cannabis exposure that dynamically fluctuates across the spectrum of a full-to-no experience of cannabis effects, depending on the pattern of cannabis use,” Mason added.

“However, little is known about cannabis use patterns and motives underlying such patterns among medical and recreational users, and the impact of changes in cannabis use patterns have not been studied in the lab. Thus knowledge on frequency, dose and duration of cannabis use that is needed to achieve, maintain or lessen tolerance however is very limited, but will be of importance in the context of cannabis therapeutics and in legal settings when evaluating the impact of cannabis exposure on human function.”

The study, “Reduced responsiveness of the reward system is associated with tolerance to cannabis impairment in chronic users“, was authored by Natasha L. Mason, Eef L. Theunissen, Nadia R.P.W. Hutten, Desmond H.Y. Tse, Stefan W. Toennes, Jacobus F.A. Jansen, Peter Stiers, and Johannes G. Ramaekers.