Sex Differences in Psychedelic Responses

Males and females are biologically different. This article explores how biological sex affects our responses to psychedelic substances.

“The female subjects experienced more intense psychoactive effects than the male subjects, with higher scores for thought disturbances, perceptual changes, and fear of losing body control.”

— Katharine Chan, MSc, BSc, PMP

Male and Female Physiological Differences

The main physiological differences between males and females arise from their genetic, hormonal, and reproductive systems. Here are some key differences:

• Chromosomes: Males typically have an XY chromosomal pattern. Females generally have an XX chromosomal pattern.
• Hormones: Males produce higher levels of testosterone, which influences muscle mass, body hair growth, and secondary sexual characteristics. Females produce more estrogen and progesterone, which regulate menstrual cycles, reproduction, and fat distribution.
• Reproductive Systems: The male reproductive system includes the testes, which produce sperm and testosterone. The female reproductive system includes the ovaries, which produce eggs and hormones, and the uterus, which supports fetal development during pregnancy.
• Physical Characteristics: Males tend to have greater muscle mass, larger heart and lung capacity, and a higher basal metabolic rate. Females typically have higher body fat percentages, wider hips, and a different fat distribution, particularly around the breasts and hips.
• Brain Structure and Function: Some studies suggest structural differences in certain brain regions, with females often having a larger hippocampus (related to memory) and males showing differences in regions associated with spatial navigation.
• Immune System: Females generally have more robust immune responses but are more prone to autoimmune diseases than males. Males tend to have weaker immune responses and have a higher morbidity and mortality rate for infectious diseases.

These differences can influence everything from disease susceptibility to drug metabolism and physical performance.

Predominately Male Research Subjects

Despite these sex differences, psychedelic research (and general research) has predominantly included male subjects.

Males have historically been the default subject in health research for several reasons, many of which stem from cultural, scientific, and logistical factors. Here are some of the key reasons:

Assumptions of Biological Uniformity

Researchers often assumed that they could generalize findings from male subjects to women. Historically, researchers believed that men and women were biologically similar enough that sex-specific studies were unnecessary, except in reproductive health.

Complexity and Variability of Female Physiology

Women’s hormonal cycles, particularly related to menstruation, pregnancy, and menopause, introduce variability in physiological responses. Researchers have often viewed this complexity as a confounding factor that makes studies more difficult to design and analyze. As a result, they opted to study men to avoid this perceived “variability.”

Protection of Women of Childbearing Age

In the mid-20th century, concerns over the potential effects of experimental drugs on pregnancy led to the exclusion of women from clinical trials.

This exclusion was partly a reaction to the thalidomide tragedy in the late 1950s and early 1960s when a drug taken by pregnant women caused severe birth defects. As a precaution, women, especially of childbearing age, were excluded from many studies, further skewing research towards male subjects.

Military and Workforce Research

Researchers conducted much early medical research on military populations or male-dominated workforces. Since men comprised most of these groups, the focus naturally shifted to male subjects, creating a long-standing bias in health research.

Historical Gender Bias

Medical research has historically reflected broader societal biases that prioritized male health concerns over female ones. This bias often led to neglecting the specific health needs of women, who researchers frequently underrepresented in clinical trials and medical studies.

Cost and Efficiency

Excluding women from studies was also seen as a way to reduce costs and simplify research. With fewer variables to account for, such as hormonal fluctuations, researchers believed they could produce more straightforward results by focusing on men.

This male-centric approach has led to gaps in understanding how diseases, medications, and treatments affect women, sometimes resulting in worse outcomes for female patients.

In recent decades, however, there has been a push for more inclusive research that accounts for sex differences in health, largely due to advocacy and changes in research policies.

A 2021 article published in The Conversation shared a flow diagram that researchers can use to design studies that account for the complexities of female physiology and helps answer questions such as the following:

• Is the phenomenon I am investigating influenced by female hormones?
• Should all females in my cohort use the same contraception?
• On which day of the menstrual cycle should I test my participants for the most reliable result?

Estrogen and Serotonin Interactions

Estrogen’s Influence on Serotonin Neurotransmission

A 2024 paper explored the potential differences in psychedelic actions based on biological sex by focusing on estrogen and serotonin interactions. Estrogen is the most studied steroid hormone, and the serotonin system plays a central role in the mechanisms of psychedelics. Therefore, estrogen-serotonin interactions may affect the efficacy of psychedelics in female participants.

Estrogen impacts serotonin neurotransmission by influencing its synthesis and release. Estrogen promotes the production of serotonin by increasing the expression of tryptophan hydroxylase, the enzyme responsible for converting the amino acid tryptophan into serotonin. This increase boosts serotonin availability in the brain.

Estrogen influences the sensitivity and responsiveness of various serotonin receptor subtypes in the brain. For instance, estrogen can reduce the activity of 5-HT1A receptors, which are often linked to depression and anxiety when overactive. Thus, estrogen may enhance mood and reduce anxiety.

5-HT2A receptors, which are important in the effects of psychedelics, become more responsive under the influence of estrogen, potentially enhancing the effects of serotonergic drugs like psilocybin, mescaline, or LSD.

Estrogen increases the release of serotonin into synapses, which boosts its availability for communication between neurons. This effect can improve mood and emotional regulation, as serotonin is closely tied to these functions.

Estrogen may inhibit serotonin reuptake by blocking the serotonin transporter (SERT), which helps remove serotonin from the synaptic cleft. This action allows serotonin to stay longer in the synapse, amplifying its effects on mood and emotional regulation.

Implications for Psychedelic Research

Estrogen and serotonin interaction could alter the effectiveness of psychedelics in females by affecting therapeutic outcomes across menstrual cycles and developmental stages. Exploring this connection in psychedelic research could enhance therapeutic outcomes, particularly for conditions that have sex-specific prevalence.

The paper concluded with the following:

“By including men and women in clinical and preclinical studies with experimental designs that have adequate statistical power, and by examining the effects of psychedelics across different menstrual cycle stages and developmental stages in female participants, we can ensure a more comprehensive understanding of psychedelic efficacy. Additionally, using standardized behavioral assays with known estrous effects can aid in data interpretation. This approach paves the way for more tailored and effective treatments for psychiatric conditions across sexes.”

Learn More About Psychedelics and Women’s Health

• Watch Dr. Allison Feduccia Speak About Women in Psychedelics – Allison Feduccia, PhD Interview
• Dive into the Potential of Psychedelic Therapy for Women’s Health Issues
• Discover Psilocybin for Women: Nurturing a Holistic Approach to Well-Being
• Find Out More on Perimenopause and Psilocybin: Psychedelics and Midlife Mood Support for Women
• Read About Psychedelics and Perinatal/Postpartum Mood and Anxiety Disorders (PMADs) with Kate Kincaid, LPC

Sex Differences and Subjective Effects of MDMA Use

MDMA, the main component of Ecstasy, primarily releases serotonin (5-HT), which plays a key role in mood and anxiety disorders — conditions more common in women.

A 2001 study analyzed pooled data from three controlled studies to examine possible gender differences in the psychological and physiological effects of MDMA in healthy volunteers with minimal MDMA experience.

There were 74 participants in total, including 54 males and 20 females. Researchers administered MDMA in oral doses ranging from 70–150 mg (1.35–1.8 mg/kg) under double-blind, placebo-controlled conditions.

Subjective effects were measured using standardized psychometric rating scales. Physiological effects included blood pressure, heart rate, and peripheral body temperature. Researchers monitored adverse effects during the experiment and 24 hours afterward.

The results showed that the female subjects experienced more intense psychoactive effects than the male subjects, with higher scores for thought disturbances, perceptual changes, and fear of losing body control.

In the female group, the intensity of perceptual changes positively correlated with the MDMA dose, and acute adverse effects and post-experimental sequelae occurred more frequently compared to the male group. Lastly, the male participants had greater increases in blood pressure than female participants.

The paper concluded that women show stronger responses to MDMA’s 5-HT-releasing effects compared to men when receiving the same dose per kilogram of body weight. Higher doses of MDMA produced more hallucinogenic perceptual changes, particularly in women.

Sex Differences and Ketamine Discontinuation Symptoms

A 2014 study investigated gender differences in discontinuation symptoms associated with ketamine use. In 2009, the Taiwanese juridical system introduced new regulations on ketamine. Authorities caught those using ketamine and required them to attend an educational program.

The researchers administered a questionnaire to collect data on demographics, discontinuation symptoms, use of other substances, and self-reported experiences of memory impairment and urinary discomfort. The researchers analyzed gender differences.

Researchers surveyed a total of 1,614 ketamine users, 83.8% of whom were males with an average age of 26.3 ± 5.4 years. The results showed that female users reported significantly more discontinuation symptoms such as anxiety, dysphoria, and tremors compared to males. Females self-reported more severe cognitive impairments and urinary symptoms than males.

The researchers concluded that they observed gender differences in discontinuation symptoms, substance use patterns, and the severity of impairment linked to ketamine use. However, the underlying causes of these gender differences need further research. The study aims to encourage additional research in this field.

Sex-Dependent Effects of Psilocybin on Brain Reactivity (Rat Model)

A 2023 study used Sprague-Dawley rats to understand the sex-specific effects of psilocin on the reactivity and behavioral response in the central nucleus of the amygdala (CeA).

Since mental health disorders impact CeA function, reduced amygdala reactivity or connectivity from psychedelics is linked to positive therapeutic outcomes in humans.

The researchers measured CeA reactivity using fiber photometry combined with an aversive air-puff stimulus. The air-puff stimulus involved blowing a puff of air towards the rat’s face. They measured CeA activity using the activity marker c-Fos (an immediate early gene that they upregulate following neuronal activity). The rats received an injection of either a saline solution or psilocin.

The results showed that psilocin causes sex-specific changes in the activity and responsiveness of the CeA in rats. In female rats, psilocin increases the expression of the immediate early gene cFos in the capsular part of the CeA but not in male rats. In males, psilocin leads to a long-lasting decrease in CeA activity that persists for up to 28 days after taking the drug, but not in female rats.

The authors concluded that their findings indicate that psilocin affects CeA activity differently in males and females, possibly due to differences in how their brain circuits adapt to the drug. More studies should “explore cell-type/receptor-type specificity as well as in probing potential circuit-based mediators contributing to these observed alterations in CeA reactivity.”

Sex Differences and Synthetic Cannabinoids

A 2020 paper reviewed the effects of psychoactive substances in male and female animal and human subjects. One of the substances included synthetic cannabinoids and found the following sex differences in psychedelic responses.

Cannabis Sensitivity

Women report greater sensitivity to the effects of smoked cannabis and lower doses of orally administered THC. They are more prone to addiction once cannabis use begins and are more likely to develop problematic cannabis use more quickly and experience more intense withdrawal symptoms than men.

Although women show higher sensitivity to cannabis and cannabinoids, they develop tolerance at higher doses, making them less sensitive to the effects of THC at those levels.

Synthetic Cannabinoid Receptor Agonist (SCRA) Use and Gender Differences

Research on gender differences in the use and effects of synthetic cannabinoid receptor agonists (SCRAs) is limited. In 2010, 73.9% of SCRA-related poison center calls in Texas involved males, with common symptoms including tachycardia, agitation, drowsiness, vomiting, hallucinations, and nausea.

Sex-Dependent Side Effects

Males more often require emergency room assistance after SCRA use compared to cannabis use (78% vs. 66%), while the reverse is seen in females (22% for SCRAs vs. 34% for cannabis). This finding suggests that males may be more susceptible to SCRA-related side effects, though some studies suggest otherwise. For instance, a study reviewing psychiatric unit patients found that while psychosis rates were similar between sexes after SCRA use, women exhibited significantly more agitation than male users.

Therefore, researchers are merely scratching the surface when it comes to the differences in psychedelic responses between males and females. What we do know is that sex is a biological variable. Sex-specific psychedelic research is on the rise. Only time will tell how those differences shape our psychedelic experiences and their therapeutic potential.

References

• Arnegard, M. E., Whitten, L. A., Hunter, C., & Clayton, J. A. (2020). Sex as a Biological Variable: A 5-Year Progress Report and Call to Action. Journal of Women’s Health, 29(6), 858–864. https://doi.org/10.1089/jwh.2019.8247.

• Chen, W.-Y., Huang, M.-C., & Lin, S.-K. (2014). Gender Differences in Subjective Discontinuation Symptoms Associated with Ketamine Use. Substance Abuse Treatment, Prevention, and Policy, 9(1). https://doi.org/10.1186/1747-597x-9-39.

• Effinger, D., Quadir, S. G., Ramage, M., Cone, M., & Herman, M. A. (2023). Sex-Specific Effects of Psychedelic Drug Exposure on Central Amygdala Reactivity and Behavioral Responding. Translational Psychiatry, 13(1). https://doi.org/10.1038/s41398-023-02414-5.

• Fattore, L., Marti, M., Mostallino, R., & Castelli, M. P. (2020). Sex and Gender Differences in the Effects of Novel Psychoactive Substances. Brain Sciences, 10(9), 606. https://doi.org/10.3390/brainsci10090606.

• Jh, K., & Ar, S. (2011, July 1). Thalidomide: The Tragedy of Birth Defects and the Effective Treatment of Disease. Toxicological Sciences: An Official Journal of the Society of Toxicology. https://pubmed.ncbi.nlm.nih.gov/21507989/.

• Knowles, O., & Lamon, S. (2021, October 4). Why Are Males Still the Default Subjects in Medical Research? The Conversation. https://theconversation.com/why-are-males-still-the-default-subjects-in-medical-research-167545.

• Liechti, M. E., Gamma, A., & Vollenweider, F. X. (2001). Gender Differences in the Subjective Effects of MDMA. Psychopharmacology, 154(2), 161–168. https://doi.org/10.1007/s002130000648.

• Sheida Shadani, Conn, K., Andrews, Z. B., & Foldi, C. J. (2024). Potential Differences in Psychedelic Actions Based on Biological Sex. Endocrinology, 165(8). https://doi.org/10.1210/endocr/bqae083.

• Wikipedia Contributors. (2024, August 23). Sex Differences in Human Physiology. Wikipedia. https://en.wikipedia.org/wiki/Sex_differences_in_human_physiology.