Women’s Health and Psychedelics - New Insights

In 2019, Psychedelic Science Review published articles summarizing a few studies that focused on gender-dependent effects of psychedelics. These included “Psychedelics and Women’s Health” and “Female Hormones, 5-HT_2A Receptors, and Psychedelics.” There has been considerable progress in this area over the past five years, and this article aims to provide an update on those advances.

The unique pharmacology of female animals is still a relatively new and unexplored topic. Accordingly, there are still many opportunities for pioneering discoveries of broad, sweeping importance. Below are summaries of the sex-related differences that were observed in several studies published since 2019.

Sex Differences with Microdosing DMT

This 2019 study by Cameron et al. explored the effects of low doses (1 mg/kg) of DMT (dimethyltryptamine) administered on a chronic (~ 2 months), intermittent (every third day) basis on mood and anxiety-related behaviors in rats.¹

Fear Extinction Learning –
- Both male and female rats showed improved fear extinction learning with chronic, intermittent low doses of DMT.
- While no sex differences were observed, both groups displayed significant improvements in fear reduction.
Antidepressant-like Effects –
- Both sexes showed decreased immobility in the forced swim test (FST, a known model for measuring the effectiveness of antidepressants).
- Female rats showed a significant decrease in immobility (p = 0.02), suggesting stronger antidepressant-like effects compared to males (with males, the trend was not statistically significant after controlling for multiple hypothesis testing).
Body Weight and Metabolic Effects –
- Male rats treated with DMT gained a significant amount of body weight compared to the control, female rats did not.
- This points to a gender-specific metabolic response to DMT microdosing, where males may experience different metabolic alterations than females under the same dosing regimen.
Neurobiological Changes – In the analysis of dendritic spine density in the prefrontal cortex (PFC), male and female rats showed different responses.
- Male rats did not show changes in dendritic spine density, whereas female rats demonstrated a significant decrease in spine density per unit length in the PFC (pre-frontal cortex).
- This suggests a potential sex-specific neuroplastic response to chronic DMT microdosing.

Sex Differences in Response to 5-MeO-DMT

This 2020 article in The Journal of Medicinal Chemistry by Dunlap et al. compared the psychoplastogenic effects of various compounds, primarily focusing on the structural modifications of N,N-Dimethyltryptamine (DMT) to produce derivatives with reduced hallucinogenic potential and enhanced neurotherapeutic properties.² In the paper, the authors reported murine head-twitch response (HTR) data for 5-MeO-DMT and differentiated between the male and female mice.

Female mice demonstrated a more pronounced response to 5-MeO-DMT in HTR assays, which may suggest sex-specific pharmacodynamics that could be relevant in clinical settings (Figure 1).
5-MeO-DMT caused a more robust dose-dependent HTR in female mice than in males.

Figure 1: (click to enlarge) Mouse HTR assays demonstrate that psychoplastogenic isoDMTs exhibit reduced hallucinogenic potential. Male and female mice were administered drugs via intraperitoneal injection, and the number of head-twitches was recorded over the next 20 min (n =3−8 mice per condition).² Data are represented as mean ± SEM. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001, as compared to the vehicle control following a oneway ANOVA with Dunnett’s post hoc test. V = vehicle, 28 = 5-MeO-DMT, 6 = 6-MeO-isoDMT, 30 = 6-MeO-DMT, 5 = 5-MeO-isoDMT.

Sex Differences in the Response to DOI

Vohara et al. examined the effects of DOI (1-(2,5dimethoxy-4-iodophenyl)-2-aminopropane)on prepulse inhibition (PPI) of startle in male and female mice.³ PPI is a measure of sensorimotor gating that is often disrupted in psychiatric conditions. The mice received an intraperitoneal dose of DOI at 0.5 mg/kg.

Startle Amplitude and PPI:

The study found a positive correlation between increased startle amplitude and PPI in male mice.
In female mice, the increase in PPI occurred independently of changes in startle amplitude.

In other words, if a male mouse has a strong reaction to a loud sound, it’s also likely to be better at staying calm if it gets a little warning before the sound. And, even if a female mouse does not react strongly to the loud sound, she can still manage to remain calm when given a small warning signal. In real-world terms, these behaviors indicate that male and female mice might handle alertness and sudden changes in their environment differently. Male mice might rely more on how strongly they respond to adjust their readiness for subsequent stimuli, while female mice manage their response independently of how strong their initial reaction was.

Head-Twitch Response:

The data revealed that DOI significantly increased HTR in both male and female mice.

Coupling the HTR, startle amplitude, and PPI data suggests that –

while the mechanisms influencing startle response and PPI are sex-dependent, the basic hallucinogenic response measured by HTR is not.

Sex and Mouse Strain Differences in Response to DOI

In a 2022 study, Jaster et al. discovered several intriguing sex-dependent responses when they examined the impact of DOI on the HTR in two strains of male and female mice.⁴ They also assessed the in vivo 5-HT_2A-dependent signaling, and investigated the pharmacokinetic characteristics of DOI in different sexes.

Head-Twitch Response:

Female C57BL/6J mice displayed a significantly higher number of DOI-induced HTRs compared to their male counterparts (Figure 2). This was quantified in experiments where both low (0.5 mg/kg) and moderate (2 mg/kg) doses of DOI were administered.
At a DOI dose of 2 mg/kg, female mice exhibited heightened HTR compared to males during the first 90 minutes post-administration.
- The statistical analysis (two-way ANOVA) showed significant interactions between time and dose, as well as sex and dose, indicating that both the timing and the amount of DOI significantly influenced HTR and that these effects were sex-dependent.
Interestingly, there was no significant difference in HTR counts between males and females when the researchers used 129S6/SvEv strain mice.

Figure 2: (click to enlarge) Effect of DOI on HTR in male (n = 12–15) and female (n = 10–15) C57BL/6J mice.⁴ A) Time-course showing HTR counts in 15 min blocks corresponding to different doses of DOI (0.5 mg/kg and 2 mg/kg) or vehicle. Back arrow shows the administration time-point (t = 0).

Pharmacokinetics and Pharmacodynamics:

This aspect of the study revealed some very significant findings.

Brain and Plasma Concentrations:
- Brain and plasma concentrations of DOI were lower in female mice compared to male mice at both 30 and 60 minutes after administration. This suggests faster metabolism or different distribution dynamics in females.
- At 30 minutes post-DOI administration, the concentration of DOI in the frontal cortex of male mice was significantly higher than in females.
5-HT_2A Receptor Signaling:
- Despite differences in plasma DOI concentrations, the activation of the 5-HT_2A receptor as measured by downstream signaling did not show significant sex differences. This implies that while the exposure levels of DOI differ between sexes, the receptor-level response to DOI might be similar once it binds to the receptor.

Differences in Amygdala Activity and Reactivity With Psilocin

A 2023 study by Effinger et al. provides insights into how psilocin, the active metabolite of psilocybin, affects central amygdala (CeA) activity and reactivity in the brain of male and female Sprague-Dawley rats.⁵ The rats received 2 mg/kg of psilocin dissolved in 2% glacial acetic acid via a subcutaneous injection. Data were gathered 2, 6, and 28 days post administration.

Psilocin’s Effects on CeA Activity

The primary method of measuring CeA activity was the expression of c-Fos, a gene that is upregulated following neuronal activation.

Females showed an acute increase in c-Fos expression in the CeA, indicating heightened neuronal activity. This was consistent across the central amygdala but was particularly notable in the capsular division of the CeA.
Similar increases in c-Fos expression in males were observed, however, the authors noted that the pattern of expression and the specific areas of the CeA affected were not as distinctly elevated as in females.
These data suggest that there are variations in how psilocin modulates neuronal circuits in males and females.

How the CeA Responds to an Aversive Stimulus with Psilocin

Responses from the CeA were assessed by observing the reactions of rats to an aversive air-puff stimulus.

Females showed heightened responsiveness to the air-puff stimulus. Behaviorally, this was reflected in increased threat responding behaviors but not in exploratory behavior or general locomotion.
The immediate effects of psilocin on CeA reactivity in males were less pronounced. Interestingly, males showed a time-dependent decrease in CeA reactivity starting as early as two days post-administration and persisting up to 28 days.

These observations suggest that females may experience more intense and immediate changes in CeA reactivity and behavioral output in response to psilocin, whereas males may exhibit more subdued immediate effects but significant long-term decreases in reactivity.

Long-Term Effects on CeA Reactivity

Long-term changes in CeA reactivity were particularly notable in how they diverged between sexes:

Females showed long-term increases in CeA reactivity at specific follow-up time points, but these did not display a consistent pattern as seen in males. This suggests a less predictable or stable long-term effect of psilocin on CeA activity in females.
Males showed a consistent decrease in CeA reactivity over the long term, indicating a sustained suppression of reactivity to the aversive stimulus. This was unlike the pattern seen in females and suggests a sex-specific mechanism in how psilocin influences neural plasticity and reactivity over time.

The comparative data from the study indicate that while both sexes respond to psilocin with initial increases in CeA activity, the duration, consistency, and behavioral implications of these responses are distinctly sex-dependent.

In 2024, Kelly et al. reported that the tryptamine 4-HO-DiPT had strong agonist activity at human 5-HT2A/2B/2C receptors and was almost a full agonist at 5-HT2A.⁶ Although the authors observed comparable receptor activity in adult C57BL/6 J male and female mice, they noted sex differences in a fear extinction model. When female mice were given 4-OH-DiPT before extinction training, they showed less anxiety in the light-dark box test, novelty suppressed feeding, and the elevated plus maze. The data were significant at the high dose (3 mg/kg i.p.) for both sexes but only the females at the low dose (1 mg/kg i.p.). The authors reasoned that “4-OH-DiPT activates interneurons to enhance GABAergic inhibition onto principal neurons in the BLA [basolateral amygdala].”

Conclusions and Path Forward

Recent studies reveal that psychedelic drugs including DMT, 5-MeO-DMT, DOI, and psilocin affect female rodents differently than males, underscoring the need to more fully embrace and investigate sex as a biological variable in psychedelic research. Women are unique in their physiological and psychological makeup. Understanding the mechanisms behind these differences is crucial for developing tailored dosages and therapeutic strategies that optimize outcomes and minimize risks for women in clinical trials.