Perimenopause and Psilocybin: Psychedelics and Midlife Mood Support for Women

As women transition from predictable monthly periods to irregular menstrual cycles, many experience a variety of hormone-related symptoms. Known as perimenopause, this time of transition can be bumpy for many. Thankfully, research has shown that psilocybin and other related psychedelics can help women through this time – both physically and emotionally [1].

“Psilocybin’s affinity for the 5-HT2A receptor may also help us understand the delicate interplay between hormonal changes and how effectively a perimenopausal woman will “trip” when she takes psychedelics.”
— Alicia Bigelow, ND

What Is Perimenopause?

Perimenopause is the transitional phase between the fertile reproductive years and menopause. Perimenopause lasts an average of seven years but can go on for as long as 14, leaving many women in physical and emotional fluctuation for the better part of a decade. Menopause, on the other hand, begins when a woman has gone 12 consecutive months or longer without a period, marking the permanent end of her fertile years [2].

Because estrogen receptors are on almost every cell in the body, perimenopause can manifest in myriad ways. Symptoms can be physical in nature, such as hot flashes, night sweats, joint pain, low libido, insomnia, and weight gain. Hormonal changes can also cause depression, anxiety, and reduced resiliency in the face of stress. 

How Psychedelics May Help in Perimenopause

Hormonal fluctuations, particularly the decline in estrogen and progesterone levels, play a pivotal role in the mental health struggles that can come with perimenopause. With the decline in estrogen levels comes a decrease in the density of a type of serotonin receptor known as the 5-HT2A receptor, resulting in reduced serotonin activity. This mechanism may explain not only mood changes but also the fluctuations in temperature regulation often experienced during perimenopause: hot flashes, night sweats, and heat and cold intolerance.

Interestingly, psilocybin and other serotonergic psychedelics such as LSD and mescaline are 5-HT2A agonists, meaning they enhance the activity of these serotonin receptors. This mechanism explains their mind-altering, antidepressant, and neuroplasticity-promoting effects. Psilocybin’s affinity for the 5-HT2A receptor may also help us understand the delicate interplay between hormonal changes and how effectively a perimenopausal woman will “trip” when she takes psychedelics [3]. 

Anti-inflammatory Effects

Another way that psilocybin can support mood is through its anti-inflammatory effects. Research has well established that depression often accompanies changes in immune activation (associated with elevations of TNF alpha, IL-6, and other signaling proteins) [4].

Estrogen deficiency also worsens immune dysfunction, increasing pro-inflammatory cytokines (namely IL-1, IL-6, and IL-18). Fortunately, research has shown that psilocybin has anti-inflammatory effects (reducing TNF alpha, IL-6, and CRP) as compared to placebo [5]. 

This evidence then begs the question: could perimenopausal and menopausal women who are using estrogen replacement therapy plus psilocybin fare better than women who just use estrogen therapy or psilocybin alone? According to the research, the answer is yes.

Improved Hormone Sensitivity

Research supports the idea that psilocybin can enhance the efficacy of estrogen hormone replacement therapy [3]. Increased estrogen levels lead to higher density and binding affinities at the 5-HT2A serotonin receptors. One study states:

“The increased levels of serotonin and increased activity of the 5-HT2A receptor caused by E2 [estradiol, a form of estrogen] could be the mechanism for E2’s antidepressant effects, in which case 5-HT2A receptor agonists could also enhance the anti-depressant effects of E2.” [3] 

What this means, more simply, is that taking psilocybin, LSD, or other serotonergic psychedelics could help make estrogen therapy work better for menopausal women. And menopausal women taking estrogen therapy may see increased benefits from psychedelics than those not on hormones. It sounds like a win-win!

What about progesterone? Progesterone, often overshadowed by estrogen, also plays a vital role in supporting peri- and menopausal women. Research has shown that progesterone has a calming effect on the brain. Progesterone acts as a natural mood stabilizer by increasing the activity of the neurotransmitter gamma-aminobutyric acid (or GABA, for short) [6]. (Other substances that affect GABA include alcohol and benzodiazepine drugs like Xanax and Valium.) Conversely, low progesterone, as is seen in menopause, is associated with lower levels of GABA in the medial prefrontal cortex (mPFC), an area of the brain that plays crucial roles in cognition and emotional regulation [7]. Additionally, progesterone helps higher estrogen (E2) levels upregulate E2 Beta receptors, which, in turn, upregulates 5-HT2A receptors [3]. 

Supplementing both estrogen and progesterone, therefore, creates a synergistic effect, optimizing benefits. 

Agents of Self-Discovery

Psychedelics such as psilocybin may also have a role in perimenopause as a tool for self-discovery. The transition out of the fertile years is an important rite of passage. This time opens the door to profound introspection and gives us the opportunity to reevaluate and redefine ourselves. Menopause presents an opportunity for self-actualization, yet we may feel stuck, defined by the confines of who we have been and what others or society have previously told us we are.

The REBUS model, or relaxed beliefs under psychedelics, helps explain just how psilocybin offers us a path to become free from these old patterns of thinking [8]. By increasing global connectivity in the brain and turning down signals in areas of our brain (the default mode network) that hold onto rigid beliefs, psilocybin softens our default way of being in the world. It allows us to consider life from new perspectives [9]. 

A Comprehensive Approach to Hormonal Harmony

The transition from the reproductive years through perimenopause and into menopause can be a journey full of challenges. That said, it is also one with numerous opportunities for growth. It is a time ripe with the possibility of reinventing and reinventing ourselves in this latter portion of our lives. Understanding the intricate interplay of hormones, including estrogen and progesterone, and how the use of psilocybin can positively impact them provides a nuanced perspective on mood regulation during this phase of life. 

Empowerment in the perimenopausal transition into menopause does not only come from understanding the hormonal intricacies. It also comes from embracing a comprehensive approach to well-being, which may include the use of psychedelics. Combining these tools with mindfulness practices, healthy nutrition, joyful movement, restful sleep, therapy, and other aspects of a healthy lifestyle can create a synergistic effect, promoting emotional resilience during perimenopause and beyond. Empowerment lies in making informed choices that align with each individual’s specific needs and values.

While the potential therapeutic benefits of psychedelics and hormonal support in mood regulation are promising, it’s important to approach their use with an individualized approach. Seeking guidance from experienced professionals and integrating psychedelic experiences into a comprehensive wellness plan is imperative.

Moreover, the interaction between psychedelics and hormonal systems is an evolving field of research. Women considering psychedelics as part of their perimenopausal journey should stay informed about the latest developments to make empowered choices aligned with their well-being.

As we navigate the terrain of perimenopause, may we approach it with intention, excitement, curiosity, and a commitment to holistic approaches tailored to each individual’s needs.

References:

1. Klatzkin, R. R., Morrow, A. L., Light, K. C., Pedersen, C. A., & Girdler, S. S. (2016). Histories of Depression, Allopregnanolone Responses to Stress, and Premenstrual Symptoms in Women. Biological Psychology, 115, 3-10. https://doi.org/10.1016/j.biopsycho.2005.02.007/
   
2. Santoro, N., Epperson, C. N., & Mathews, S. B. (2016). Menopausal Symptoms and Their Management. Endocrinology and Metabolism Clinics, 45(3), 497–515. https://doi.org/10.1016/j.ecl.2015.05.001/
   
3. Rybaczyk, L. A., Bashaw, M. J., Pathak, D. R., Moody, S. M., Gilders, R. M., & Holzschu, D. L. (2005). An Overlooked Connection: Serotonergic Mediation of Estrogen-Related Physiology and Pathology. BMC Women’s Health, 5(1). https://doi.org/10.1186/1472-6874-5-12/
   
4. Turek, J., & Gąsior, Ł. (2023). Estrogen Fluctuations During the Menopausal Transition Are a Risk Factor for Depressive Disorders. Pharmacological Reports, 75. https://doi.org/10.1007/s43440-022-00444-2/
   
5. Mason, N. L., Szabo, A., Kuypers, K. P. C., Mallaroni, P. A., de la Torre Fornell, R., Reckweg, J. T., Tse, D. H. Y., Hutten, N. R. P. W., Feilding, A., & Ramaekers, J. G. (2023). Psilocybin Induces Acute and Persisting Alterations in Immune Status in Healthy Volunteers: An Experimental, Placebo-Controlled Study. Brain, Behavior, and Immunity, 114, 299–310. https://doi.org/10.1016/j.bbi.2023.09.004/
   
6. Stefaniak, M., Dmoch-Gajzlerska, E., Katarzyna Jankowska, Rogowski, A., Kajdy, A., & Maksym, R. (2023). Progesterone and Its Metabolites Play a Beneficial Role in Affect Regulation in the Female Brain. Pharmaceuticals, 16(4), 520–520. https://doi.org/10.3390/ph16040520/
   
7. Tran, K. H., Luki, J., Hanstock, S., Hanstock, C. C., Seres, P., Aitchison, K., Shandro, T., & Jean-Michel Le Melledo. (2022). Decreased GABA+ Levels in the Medial Prefrontal Cortex of Perimenopausal Women: A 3T 1H-MRS Study. The International Journal of Neuropsychopharmacology, 26(1), 32–41. https://doi.org/10.1093/ijnp/pyac066/
   
8. Carhart-Harris, R. L., & Friston, K. J. (2019b). REBUS and the Anarchic Brain: Toward a Unified Model of the Brain Action of Psychedelics. Pharmacological Reviews, 71(3), 316–344. https://doi.org/10.1124/pr.118.017160/
   
9. Gattuso, J. J., Perkins, D., Ruffell, S., Lawrence, A. J., Hoyer, D., Jacobson, L. H., Timmermann, C., Castle, D., Rossell, S. L., Downey, L. A., Pagni, B. A., Galvão-Coelho, N. L., Nutt, D., & Sarris, J. (2022). Default Mode Network Modulation by Psychedelics: A Systematic Review. International Journal of Neuropsychopharmacology, 26(3). https://doi.org/10.1093/ijnp/pyac074/