Can men and women react differently to psychedelics?

A summary of: Potential Differences in Psychedelic Actions Based on Biological Sex

Sheida Shadani, Kyna Conn, Zane B Andrews, Claire J Foldi
Endocrinology, Volume 165, Issue 8, August 2024

As the exploration of these substances gains momentum, an intriguing question arises: Are there sex-dependent differences in response to psychedelics?!
Understanding this is crucial for developing personalized and effective treatments. This inquiry delves into the complex interplay between hormones, brain chemistry, and psychedelic substances, aiming to uncover whether biological sex plays a significant role in shaping the psychedelic experience.
*To note when referring to psychedelics here, we are referencing classic psychedelics and/or serotonergic (5-HT) psychedelics ie LSD, Psilocybin, DMT, 5-MEO-DMT, Mescaline, and MDMA (not classic, but primarily utilizes the 5HT system)

Feel free to skip ahead to the summary below, but before I begin…

For women, the felt experience of psychedelics can be deeply influenced by hormonal fluctuations, particularly the levels of estrogen and progesterone. These hormones interact with the serotonin system, which is central to the action of psychedelics, potentially leading to more pronounced emotional and introspective journeys.

Psychedelics can be uniquely transformational for men by facilitating a break from traditional societal expectations and emotional barriers. Men may find that psychedelics help in accessing and expressing repressed emotions, promoting psychological flexibility, and enhancing empathy and connectedness.

Regardless of what gender one may identify with, there is a journey inward that allows for reconnection with true essence, values, and desires. This introspective journey can lead to greater self-awareness, self-acceptance, and self-love. In the medical field, it’s easy to view psychedelic therapy (PAT) as another drug therapy for curing illness, but every health challenge comes with a unique personal challenge, and it’s become very apparent that it is not enough to treat symptoms. We must care for the whole person: body, mind, and soul. PAT offers this option. By peeling away the layers of societal conditioning and personal defense mechanisms, psychedelics can help all people rediscover their inner strength, creativity, and intuition.

#bridgescienceandspirit

Onward to the summary of findings! Here is a summary of a recently published study about how psychedelics can affect women differently than men and why.

Potential Differences in Psychedelic Actions Based on Biological Sex

Introductory points:

Neglect of Sex as a Biological Variable (SABV): Historically, medical research often favored male participants, leading to a lack of understanding about sex-specific treatment responses.
Recent Policy Changes: Despite policies to increase female participation in research, sex-specific effects of psychedelics remain unclear.

Key Findings and Concepts

Estrogen interacts with the serotonin system, significantly influencing how psychedelics work in the brain.
During the peak of estrogen in the estrous cycle, there’s higher expression of the serotonin 5-HT2A receptor and lower expression of the 5-HT1A receptor.
Estrogen enhances serotonin production, inhibits its reuptake, reduces its breakdown, and increases neural activity.
This makes more serotonin available and heightens receptor sensitivity.
As a result, estrogen can modulate the effects of psychedelics, potentially making them more effective by enhancing brain plasticity.
Essentially, estrogen’s interaction with serotonin can alter the efficacy of psychedelics, especially depending on hormonal states.

Influence of Estrogen on Psychedelics:
- Estrogen interacts with the serotonin system, which is central to the action of psychedelics.
- Estrogen affects serotonin synthesis, release, and receptor sensitivity, potentially altering the efficacy of psychedelics in women.
How Estrogen Affects Serotonin:
- Making Serotonin:
  - Tryptophan Hydroxylase (TPH): Estrogen boosts the production of tryptophan hydroxylase, the enzyme that helps make serotonin, leading to more serotonin in the brain.
- Releasing and Keeping Serotonin:
  - Serotonin Reuptake Transporter (SERT): Estrogen reduces the activity of the SERT gene, which normally reabsorbs serotonin back into the neuron. This means serotonin stays longer in the brain's synapses, making its effects stronger.
- Receptor Sensitivity:
  - Receptor Modulation: Estrogen changes how sensitive and numerous serotonin receptors are, especially the 5-HT2A receptor, which is key for the effects of psychedelics. This change can influence how the brain responds to psychedelics.
Impact on Psychedelic Effects:
- Menstrual Cycle Changes: Estrogen rise and fall twice during the menstrual cycle, which can change how intensely one might experience a psychedelic or even how effective they can be.
  
  Estrogen levels rise during the mid-follicular phase and then drop after ovulation.
  This is followed by a secondary rise in estrogen levels during the mid-luteal phase with a decrease at the end of the menstrual cycle.
  Higher estrogen levels might lead to an increased felt effect of serotonergic psychedelics by increasing serotonin activity.
- Life Stages: Different stages of life (like puberty, pregnancy, menopause) involve big changes in estrogen levels, which can affect how well psychedelics work and how they feel. This could also present an opportunity to research how serotonergic psychedelics could support changes in hormones when those changes cause unmanageable symptoms likes pain, headaches, and severe mood fluctuations.
- Sex Differences: Since estrogen levels are different in men and women, the hormone's interaction with serotonin can lead to different responses to psychedelics. This means that men and women might experience and benefit from psychedelic therapy in unique ways.

Sex Differences in Psychiatric Conditions

Mood Disorders: Women are more susceptible to mood disorders like premenstrual dysphoric disorder (a severe form of PMS), postpartum depression, and perimenopausal depression due to hormonal fluctuations.
Eating Disorders and Substance Use: Higher prevalence of eating disorders and increasing substance use disorders in women highlight the need for sex-specific research.

Pharmacokinetic and Pharmacodynamic Variations aka What a drug does to the body and what the body does to the drug:

Drug Absorption and Metabolism: Women often experience slower drug absorption and metabolism, leading to higher plasma levels and increased risk of side effects. This is due to slower absorption rates, for example, as women tend to have slower gastric emptying times and reduced gut motility compared to men. Certain enzyes in the liver that break down drugs may also work more slowly in women, which would affect the metabolism rate of certain drugs. Something to remember is that there are always exceptions and certain genetic differences can also influence enzymes and subsequently the metabolism of drugs. Women generally have higher body fat percentage and lower body water percentage versus men, which can also result in differences in higher concentrations of drugs in the plasma.
Hormonal Influences: Estrogen and other sex hormones, like progesterone, affect drug receptor binding and sensitivity, impacting the efficacy and side effects of psychiatric medications.
Increased Risk of Side Effects:
- Prolonged Exposure: Because drugs can stay in the system longer, women can be more likely to experience prolonged exposure to both the therapeutic effects and the potential toxic effects of medications.
- Higher Sensitivity: The higher plasma levels of drugs can lead to an increased incidence of side effects. Women may experience more severe or more frequent side effects than men at the same dosage of a drug.
- Pharmacodynamic Differences: Women’s bodies may respond differently to drugs at the receptor level, meaning that even with the same drug concentration, the effects can be different, sometimes leading to a higher intensity of effect and/or higher risk of adverse reactions.

Actions of Psychedelics in the Human Brain

Global Connectivity Changes: Serotonergic psychedelics alter brain connectivity, leading to changes in perception, emotion, and cognition. These effects are mediated by the serotonin 2A receptor (5-HT2AR).
Therapeutic Potential: Psychedelics show promise in treating conditions like depression and anxiety, and sex-specific effects are still not well-studied.

Animal Models in Psychedelic Research

Sex-Specific Responses: Animal studies often use one sex, usually males, limiting understanding of sex differences.
Behavioral and Neurobiological Differences: Research shows varying responses to psychedelics between male and female animals, emphasizing the need for inclusive studies.

Potential Mechanisms Driving Sex Differences

Estrogen and Serotonin Interaction:
- Estrogen enhances serotonin production and availability, influencing the efficacy of psychedelics.
- Different estrogen receptor subtypes (ERα and ERβ) play distinct roles in mood regulation and response to psychedelics.

Challenges and Recommendations

Incorporating SABV: Addressing sex differences in psychedelic research requires overcoming traditional biases, ethical concerns, and increased complexity in study designs.
Comprehensive Studies: Future research should include both sexes, consider menstrual cycle stages, and use standardized assays to better understand psychedelic efficacy.

Conclusion

Importance of SABV: Incorporating sex as a biological variable is crucial for advancing psychedelic therapies.
Role of Estrogen: Understanding estrogen's influence on serotonin and psychedelics can lead to more effective, personalized treatments for psychiatric conditions in women.

Key Takeaways

Historical Neglect of SABV (Sex as a Biological Variable): Male participants have been favored in research, leading to gaps in understanding sex-specific responses to psychedelics.
Estrogen's Role: Estrogen significantly influences serotonin neurotransmission, affecting psychedelic efficacy in women.
Pharmacokinetics and Pharmacodynamics: Women experience slower drug absorption and metabolism, with hormonal influences impacting drug efficacy.
Brain Connectivity: Psychedelics alter brain connectivity, but sex-specific effects are understudied.
Animal Studies: Research shows sex-specific responses to psychedelics in animals, highlighting the need for inclusive studies.
Mechanistic Insights: Estrogen-serotonin interactions play a crucial role in sex differences observed in response to psychedelics.
Research Challenges: Addressing SABV in psychedelic research involves overcoming biases, ethical concerns, and study complexity.
Future Directions: Comprehensive studies including both sexes and considering hormonal influences are essential for developing effective psychedelic therapies.
Research and Clinical Implications:
- Need for Inclusive Research: To understand these sex-specific effects fully, it is essential to include both male and female participants in psychedelic research. This helps in developing tailored treatment protocols that account for hormonal influences.
- Personalized Medicine: Recognizing the role of estrogen in modulating the serotonin system can lead to more personalized and effective psychedelic therapies, particularly for women experiencing hormonal fluctuations or imbalances.

Estrogen plays a crucial role in modulating the serotonin system, which is central to the action of classic psychedelics. It enhances serotonin synthesis, increases its availability, and modulates receptor sensitivity. These interactions can significantly influence the efficacy of psychedelic treatments, as well as the experience, leading to potential variations in response based on hormonal levels and sex. Understanding these mechanisms is vital for developing personalized and effective therapeutic strategies in psychedelic medicine, as well as the foundation to developing treatments for unresolved health challenges, especially when traditional therapies have fallen short.

For a list of what the research community is discovering when it comes to psychedelics and estrogen, PMS, postpartum, and more, check out this previous blog post: Female Hormones & Psychedelics.

Key Takeaways

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