Good or bad 'trip'? A possible role of 5HT2A receptors number in predicting the response to psychedelics

Introduction: Recent years have seen a returning interest in the psychedelic substances application in psychiatric practice. Despite promising preliminary results [1], there are also risks associated with these compounds. It is not clear how to determine which one the person will experience - desired effects or increased anxiety, paranoia or other disturbing symptoms, commonly known as the „bad trip.“ We raised a hypothesis that an increased number of 5HT2A receptors [5HT2Ar] could be associated with the negative experience. To investigate it, we decided to analyze the 5HT2Ar role in psychiatric disorders to conclude their possible involvement in the psychedelic response.

Methods: Literature search in Medline, Pubmed, Web of Science, and Google Scholar was performed. Selection criterion was “5HT2A receptors”. Critic review of selected articles was made.

Results: The primary mechanism of action psychedelic drugs is the agonism of serotonin 5HT2Ar. [2] People who have depression and anxiety disorders have higher levels of these receptors in prefrontal cortex. [3] Overactivation of these receptors is associated with anxiety, insomnia [4,5]. It has been found that suicide victims have higher levels of 5HT2Ar [6]. SSRI drugs raise serotonin levels in the brain almost instantly, but the therapeutic effect is delayed, and one of the proposed explanations is that they down-regulate 5HT2Ar in the time frame of two weeks [3].

Conclusions: Existing evidence points to a possibility that the number of expressed 5HT2Ar could be one of the determining factors for response to psychedelic substances. If a person experiences symptoms of depression or anxiety – a negative experience would be more likely. Increased numbers of 5HT2Ar are found in various psychiatric conditions. It may be brains compensatory mechanism when homeostasis is disturbed. However, this system is extremely sensitive to changes, and overactivation may occur. Therefore, safe setting requirements should be applied when treating people with anxiety or depressive disorders with psychedelics to ensure harm reduction. More research in this area is needed.