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The Other Active Ingredient in Marijuana

Unlike THC, cannabidiol may decrease psychotic symptoms.

In a recent article published in the New England Journal of Medicine, Orrin Devinsky and colleagues reported that an ingredient in marijuana called cannabidiol can decrease the number of seizures in individuals with Lennox-Gastaut Syndrome, a devastating neurodevelopmental disorder that causes severe seizures. Other data suggest that cannabidiol may also be beneficial in persons with psychotic illness.

There are at least two (and likely more) active ingredients found in marijuana (MJ): delta-9-tetrahydrocannabinol (THC) and cannabidiol. The structures of these two chemicals are quite similar, but they have very different effects.

THC is responsible for the behavioral/recreational influences of MJ. There is considerable evidence that early, consistent use of THC is associated with an increased risk of developing a chronic psychotic illness. On the other hand, cannabidiol may have antipsychotic properties.

THC causes behavioral effects by stimulating a neurotransmitter receptor in the brain called the cannabinoid 1 (CB1) receptor. There are at least two neuromodulators made in the brain (2AG and anandamide) that stimulate the CB1 receptor. This endogenous cannabinoid system is involved in regulating a variety of essential bodily systems, including those related to diet, energy utilization, and pain.

Although cannabidiol is similar in structure to THC, it does not directly interact with CB1 receptors. However, it does influence a specific serotonin receptor as well as interact with other transmitter systems. Therefore, even though cannabidiol resembles THC structurally and is found in MJ, it is a very different drug.

The Devinsky et al study indicating that cannabidiol may be able to decrease seizure frequency when added to a conventional antiepileptic treatment regimen is potentially exciting and could offer hope in a very difficult-to-treat disorder.

In addition, recent work by Philip McGuire and colleagues demonstrated that cannabidiol may have antipsychotic properties. These investigators added cannabidiol or placebo in a double-blind manner to concurrent treatment of individuals with schizophrenia and found that cannabidiol led to further improvement in psychotic symptoms.

An earlier study showed that cannabidiol had antipsychotic properties that matched that of a currently used antipsychotic medication. Cannabidiol does not appear to have strong effects on the dopamine transmitter system. Therefore, it is likely that the antipsychotic effect of this agent works through a different mechanism than that of currently available antipsychotic drugs.

It is intriguing that a plant contains two powerful substances that are closely related structurally but have very different biological properties. Makers of recreational MJ are able to breed plants with varying amounts of THC and cannabidiol.

Apparently, the higher the ratio of THC to cannabidiol, the more pleasurable the recreational experience. Therefore, plants are being created with very low levels of cannabidiol. Unfortunately, it is also likely that the higher the ratio of THC to cannabidiol, the greater the risk of acute and chronic psychotic side effects, especially in younger individuals.

Two trends are likely to become apparent over the next decade. First, with increasing legal use of high THC/low cannabidiol recreational MJ, more will become known about the role of THC in the risk of MJ-induced psychosis. Second, the beneficial effects and risks of cannabidiol will be clarified. These will be interesting trends to watch.

This post was written by Eugene Rubin M.D., Ph.D. and Charles Zorumski M.D.


Devinsky, O., Patel, A.D., Cross, J.H., Villanueva, V., Wirrell, E.C., Privitera, M., Greenwood, S.M., et al. (2018). Effect of cannabidiol on drop seizures in the Lennox-Gastaut syndrome. New Engl J Med. 378:1888-1897.

McGuire, P., Robson, P., Cubala, W.J., Vasile, D., Morrison, P.D., Barron, R., Taylor, A., & Wright, S. (2018). Cannabidiol (CBD) as an adjunctive therapy in schizophrenia: a multicenter randomized controlled trial. Am J Psychiatry. 175:225-231.

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