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Cambridge University Science Magazine
The main active compound in marijuana, delta-9-tetrahydrocannabinol (THC), has both beneficial and detrimental effects on humans. THC was previously known to bind to CB1R receptors to initiate neurological pathways and produce these effects, but the mechanisms had not been elucidated. In a study recently published in PLOS Biology, a group of researchers from Barcelona, Spain, as well as Paris, France, and Norwich, UK, have now discovered details of the pathways and have found that positive and negative effects occur via different routes.

“This research is important because it identifies a way to reduce some of what, in medical treatment, are usually thought of as THC’s unwanted side effects, while maintaining several important benefits including pain reduction”

Dr Peter McCormick, study author at the University of East Anglia

The researchers administered cannabis to knockout mice which lacked the brain serotonin receptor 5-HT2AR. In these mice, the negative effect of amnesia disappeared, whilst the positive effect of pain relief was undiminished. Further investigation suggested that in normal mice, the serotonin receptor formed an activated complex with CB1R which led to the memory impairment. Preventing formation of such complexes (in this case by using mice which lacked the serotonin receptor component) was sufficient to prevent detrimental side effects in mice, without altering the analgesic effect. This indicated that memory loss was induced via a serotonin-dependent pathway, whilst the pathway inducing analgesia was serotonin-independent.

This distinction between pathways for positive and negative effects, if it is also seen in humans, could be important clinically. If researchers could selectively block formation of the CB1R-5-HT2AR complex in humans, they could enable the therapeutic effects of THC but reduce or even eliminate the damaging side effects. The development of techniques that could do this is still far off, but this research is an important step towards such a clinical breakthrough.

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