Interactive effects of THC and CBD co-administration: a primate study

Cannabis has several therapeutic effects that are thought to originate from THC. However, this cannabinoid also produces significant side effects that limit its medical applications. Wishing to minimize...

Cannabis has several therapeutic effects that are thought to originate from THC. However, this cannabinoid also produces significant side effects that limit its medical applications. Wishing to minimize them, researchers have begun to study Cannabidiol (CBD), the second most common active compound in cannabis, and one that has medical properties of its own. Several independent studies have shown that CBD modulates many of THC’s cognitive and behavioral effects, such as memory impairment and anxiety — but results are mixed for other assays.

To gather more information on this issue, a team of U.S. researchers led by Dr. Stephen Kohut from McLean Hospital and Harvard Medical School conducted a pharmacological study on primates. They described the acute effects of either THC or CBD alone on the primate's’ ability to perform cognitive tasks, and then went on to test their interaction effects when the cannabinoids were co-administered. In addition, the researchers looked for differential effects under a chronic regimen of THC that would suggest an acquired tolerance. Their findings were published in the journal Experimental and Clinical Psychopharmacology.

The authors chose the Stop Signal Task, which tests the ability to override an action that has already been initiated (a competency that is impaired in several psychiatric disorders). In random trials, three male and three female rhesus monkeys were initially trained to press a button when a green light was turned on, but to abstain from doing so where a red light blinked in front of them. After making sure the animals had learned the task, and having collected basal performance indexes, the researchers tested them under the influence of the two cannabinoids.

The results indicated that THC acutely affected the percentage of successful trials in a dose-related manner. When the highest dosage (0.32 mg/Kg) of THC was administered, the percentage of successful trials declined from 87% to 25%, whereas lower doses (0.032 and 0.1 mg/Kg) did not affect performance. In contrast, CBD did not affect the percentage of successful trials in any of the concentrations tested (0.032, 0.1, 0.322 and 1 mg/Kg), although the performance of two animals dropped to 50% when given the highest dosage. Neither cannabinoid affected reaction times.

Having asserted THC’s disruptive effects, the authors mixed the two cannabinoids in a 1:1 and 1:3 ratio of CBD to THC (which are common in human trials). Once again, only the highest concentrations (in mg/Kg: 0.32 THC to 0.32 CBD and 0.32 THC to 1 CBD) yielded a disruptive effect on the percentage of successful trials. Notably, the 1:3 preparations significantly attenuated this loss of performance by a total of 27%, whereas the 1:1 preparations did not.

Finally, the authors analyzed the effects of chronic exposure to THC over a total of 23 days. After only 4 days of receiving daily preparations of 0.32 mg/Kg THC, there was a nine-fold increase in tolerance, meaning that nine times larger doses of THC were required to evoke similar levels of disruption in performance. By the end of the study, when the accumulated concentrations of THC were estimated at 3 mg/Kg, one of the animals still retained a perfect performance. This tolerance to THC was, however, much more evident in the monkeys treated chronically with CBD and THC, where the three animals consistently performed at control levels.

Taken together, these results  clearly showed that CBD did not exacerbate THC’s effects and even minimized them in some contexts. This was especially the case when the animals were under a chronic regimen. Despite this, some caution in generalizing these results is warranted due to the small sample of animals and the use of only one task. More research is necessary to formally characterize the interactive effects of CBD and THC over a wider range of behaviors.

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