Female Hormones, 5-HT2A Receptors, and Psychedelics

The potential of psychedelics for treating mental illness and improving everyday lives continues to be an area of interest for researchers and people from all walks of life. Also, the health needs and concerns of women are coming to the forefront as areas needing particular attention when studying psychedelics.

PSR recently published two articles that are opening up the conversation about women and psychedelics; Women and Psychedelics: The Big Picture and Psychedelics and Women’s Health. As part of these female-focused articles, PSR is posing the overarching question, is there a female entourage effect? This article will help answer that question by taking a closer look at the interaction between female hormones and the serotonin 5-HT_2A receptor, which is responsible for the psychedelic effect. Extrapolating this information to what is known about how psychedelics work, will provide additional insight on the entourage effect in women.

What is the Entourage Effect?

PSR has published articles discussing the entourage effect in magic mushrooms and toad secretions, which get into more of the details about this phenomenon. Briefly, the term entourage effect came out of medical marijuana research. It describes the compounds in cannabis working in synergy to produce an overall effect.

For example, as far back as 1974, researchers observed in humans and animals that the effects of marijuana were 2 to 4 times greater than what would be expected from THC alone¹ (THC, aka tetrahydrocannabinol or ∆9-THC, is the main psychoactive component in marijuana). The authors of this study stated, “It is suggested that there may be potentiation of the effects of ∆9-THC by other substances present in these marihuana samples.” More recently, a 2011 article published in British Journal of Pharmacology provides a comprehensive review of the science of cannabis synergy at the time.²

The main takeaway is that it is critical to consider the chemical variability in natural compounds in pharmaceutical research. Understanding individual chemicals is important. Still, there is much more to be learned from examining how they work together and at serotonin receptors in the brain, such as 5-HT_2A. And to the point, female hormones add another layer of complexity to the equation by exerting their effects on these receptors.

The Relationship Between Female Hormones and the 5-HT_2A Receptor

Here are a few examples from the literature showing the intriguing interactions between female hormones and the serotonin 5-HT_2A receptor.

• Research has shown that estrogen increases the density of 5-HT_2A binding sites in the brain, particularly in the anterior frontal, cingulate, and primary olfactory cortex, and the nucleus accumbens, areas of the brain are responsible for controlling mood, mental state, emotion, cognition, and behavior.³ These observations explain why drugs that block 5-HT_2A receptors (e.g., fluoxetine) and estrogen therapy can be effective for treating the symptoms of premenstrual syndrome. Intriguingly, this relationship between estrogen levels and 5-HT_2A binding sites may also give clues to the gender differences seen in schizophrenia and depression, i.e., women are diagnosed with these conditions more often than men.
• In a 2000 study, researchers found that estradiol (one of the three types of estrogen in women) combined with progesterone increased the binding potential of 5-HT_2A receptors in the cerebral cortex of post-menopausal women.⁴
• Research indicates that that disruption of estrogen levels during menopause may lead to dysregulation of the BDNF-5-HT_2A signaling pathway in the brain and causes weakened synaptic plasticity.⁵ The authors say that these changes predispose the brain to be susceptible to depression.
• A 2005 review article in BMC Women’s Health integrated information from studies in endocrinology, molecular biology, neuroscience, and epidemiology.⁶ Their findings indicated that serotonin might mediate the effects of estrogen. The authors stated, “We hypothesize that some of the physiological effects attributed to estrogen may be a consequence of estrogen-related changes in serotonin efficacy and receptor distribution.”
• In rats, estradiol, in combination with a low dose of progesterone, increased 5-HT_2A receptor mRNA gene expression in the CA2 region circuitry of the ventral hippocampus by 43% ⁷ (the hippocampus in the brain is important for short-term, long-term, and spatial memory). Estrogen combined with a higher dose of progesterone increased the expression of the gene by 84% in the CA1 region. Interestingly, mRNA expression in the frontal cortex was not affected by the hormones.

The studies above represent just a fraction of the scientific information investigating the effects of female hormones on one type of serotonin receptor. There are 13 more serotonin receptors in this family,⁸ which may have a variety of responses to female hormones (as well as a deficiency or lack of the hormones). In addition to this complexity, consider how allosteric modulation of serotonin receptors may influence the effects of estrogen, progesterone, and psychedelics.

What Does This Mean for the Effects Psychedelics Have on Women?

Scientists know that psychedelics such as psilocybin elicit their effects primarily via the serotonin 5-HT_2A receptor.⁹ The findings from the studies above indicate that the presence, absence, and combinations of female hormones affect binding to 5-HT_2A in a variety of ways. Therefore, it is feasible that the entourage effect of psychedelic compounds is different in women. Additional research into the effects of psychedelics in the unique environment of the female body would start to unravel the mystery.

Barbara E. Bauer, MS

Barb is the former Editor and one of the founders of Psychedelic Science Review. She is currently a contributing writer. Her goal is making accurate and concise psychedelic science research assessable so that researchers and private citizens can make informed decisions.

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