THC and the 5-HT2A Receptor: What’s Going On?

Although cannabis isn’t often recognized as a member of the psychedelic family, marijuana and psychedelics share many common features. Moderate to high doses of cannabis can result in psychedelic-type effects such as synesthesia, enhanced perception of music, the emergence of unconscious emotions, and unrestrained creativity.¹ Another similarity that cannabis shares with psychedelics is in receptor binding. 

Scientists classify a drug as psychedelic if it binds to serotonin 5-HT_2A receptors (5-HT_2AR) as an agonist or partial agonist.² Emerging research suggests that THC (tetrahydrocannabinol) interacts with 5-HT_2AR, which is known for its role in facilitating psychedelic experiences.³

What is the 5-HT_2A Receptor?

5-HT_2AR, sometimes colloquially called psychedelic receptors, are widely distributed through the central nervous system and are particularly prevalent in the learning and cognition centers of the brain.² 

Preclinical studies have demonstrated that 5-HT_2AR antagonists boast antipsychotic and antidepressant properties. 5-HT_2AR agonists, on the other hand, possess cognition-enhancing and hallucinogenic properties.⁴ An extensive body of preclinical and human evidence suggests the activation of 5-HT_2AR is responsible for generating hallucinatory experiences and the behavioral effects that accompany them.^5,6 

The Interaction Between THC and 5-HT_2AR

Much cannabis research is focused on its interactions at the body’s cannabinoid receptors, which are members of the G protein-coupled receptor family.⁷ However, a 2018 preclinical study set out to explore how THC behaves at the 5-HT_2AR.³ The study, which was carried out on mice, tested the effects of chronic THC exposure on 5-HT_2AR  in cortical regions of the brain. The researchers found that long-term exposure to THC sensitized 5-HT_2AR triggered a psychosis-type alteration in their signaling mechanism. 

These findings suggest that THC’s binding with the 5-HT2_AR leads to the overactivation of the pro-hallucinogenic signaling pathways. Consequently, this functional alteration of the receptor may lead to increased susceptibility of psychotic states, schizophrenic-type responses, and hallucinations. Other research also indicated that an increased density in the functional conformation of 5-HT_2AR had been found in schizophrenic patients’ brains.⁸

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How Does THC Bind to 5-HT2A and Influence its Activity?

According to Ibarra-Lecue et al., interactions between the endocannabinoid and serotonergic systems have been widely reported. Unfortunately, studies that assess the effects of cannabinoids on 5-HT_2AR functionality are limited. The authors suggest that a CB₁R/5-HT_2AR heteromer may hold the key to understanding this interaction, at least in part (CB1R is the cannabinoid receptor type 1). Heteromers are macromolecular complexes composed of at least two functional receptor units and display biochemical properties that are noticeably different from those of its individual components. 

A 2015 study on mice showed that CB₁ and 5-HT_2A receptors create novel effects when they interact.⁹ When CB₁ receptors entwine with 5-HT_2AR, new signaling pathways fire up that lead to memory impairment, cognitive deficits, anxiolytic properties, and pro-social effects. These effects were reduced in mice when deletions were made in the genes that code for 5-HT_2AR. 

What Are the Implications of These Findings?

The implications of this research are significant for cannabis therapy. Cannabis may hold immense potential as a therapeutic agent, but memory impairment and cognitive impairments often inhibit its use. The data presented by Ibarra-Lecue et al. and Viñals et al. suggest that CB₁R/5-HT_2AR heteromers may be responsible for the less desirable qualities of THC. These heterocomplexes could potentially be disrupted to dissociate the cognitive impairment linked to THC use. 

Nonetheless, this research is still in its infancy. Viñals et al acknowledge that there may be more subtle mechanisms at play than the mere expression of heteromeric receptors. Future studies may also reveal more about the entanglement of the endocannabinoid and serotonergic systems.

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