Abstract
Background
3,4-Methylenedioxymethamphetamine (MDMA), a psychoactive substance, has been proposed as a novel provocation test for oxytocin deficiency. Limited evidence suggests that MDMA may also stimulate the anterior pituitary. Therefore, this analysis aimed to investigate the acute effect of MDMA on the anterior pituitary in healthy adults.
Methods
This secondary analysis utilized data from a double-blind, placebo-controlled, crossover, randomized trial. Healthy participants received a single oral dose of MDMA (100 mg) or placebo in random order. Plasma hormone levels of the anterior pituitary (adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), luteinizing hormone (LH), prolactin, growth hormone (GH)) and their peripheral endocrine glands (cortisol, free thyroxine (fT4), testosterone, and estradiol) were measured at baseline and 120 min after drug-intake. Plasma hormone changes following MDMA vs placebo were compared using the paired Wilcoxon test.
Results
Fifteen healthy participants (median (IQR) age: 35 years (26, 48); 53% female) with a mean (SD) BMI of 23.2 kg/m2 (2.1) were included. MDMA stimulated the hypothalamic–pituitary–adrenal (HPA) axis, with plasma ACTH increasing from 12 ng/L (11, 15) at baseline to 38 ng/L (25, 59) at 120 min, resulting in a significant change of ACTH (P < 0.001). This was accompanied by a cortisol increase from 347 nmol/L (252, 409) to 566 nmol/L (457, 701), resulting in a significant change of cortisol (P = 0.006). Prolactin showed a mild change of 4 μg/L (−1, 12) (P = 0.062). No effects of MDMA were observed on the remaining anterior pituitary axes.
Conclusion
MDMA strongly activates the HPA axis, in addition to stimulating oxytocin, suggesting that MDMA may serve as a novel stimulation test for assessing the two pituitary axes simultaneously. Further validation in larger patient populations is necessary.
Introduction
3,4-Methylenedioxymethamphetamine (MDMA, ‘ecstasy’) is a psychoactive substance used recreationally and investigated as a treatment for post-traumatic stress disorder (1). MDMA is known to affect multiple physiological systems, including the cardiovascular, neuropsychological, and endocrine systems, along with impacting energy homeostasis (2). Animal and human research provide robust evidence that MDMA strongly stimulates the release of oxytocin via the posterior pituitary (3). Moreover, limited evidence suggests that MDMA may also stimulate the anterior pituitary, potentially contributing to its cardiovascular effects, such as elevated heart rate, blood pressure, hyperthermia (4, 5, 6, 7), and neuropsychological effects (4, 5, 6, 8, 9, 10, 11), in addition to direct serotonergic and noradrenergic effects (12, 13).
The anterior pituitary synthesizes several hormones, including thyroid-stimulating hormone (TSH), adrenocorticotropic hormone (ACTH), growth hormone (GH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and prolactin (14). Existing literature from animal studies supports stimulative effects of MDMA on the hypothalamic–pituitary–adrenal (HPA) and -thyroid axes, with increases in plasma ACTH and cortisol, TSH and thyroxin, and prolactin levels (4, 8, 15). While human studies confirm peripheral increases in cortisol (4, 16), there is only very limited data on direct effects on ACTH, leaving it uncertain whether these changes arise from anterior pituitary activation or through direct stimulation of the adrenal glands. Furthermore, there is no data on the effect of MDMA on TSH and thyroxine secretion in humans. Evidence regarding MDMA’s effects on GH and the hypothalamic–pituitary–gonadal axis from human studies remains limited and inconsistent (15, 17, 18).
Diagnosing hypopituitarism often requires a combination of basal hormone measurements and dynamic stimulation tests, which can be complex and resource-intensive (19). While MDMA’s ability to stimulate oxytocin has been explored as a potential diagnostic test for suspected cases of hypothalamic–posterior pituitary dysfunction, its ability to stimulate the anterior pituitary remains unvalidated. If MDMA can stimulate both posterior and anterior pituitary hormones, it may serve as a novel stimulation test to assess multiple axes simultaneously. Therefore, this secondary analysis aims to investigate the effect of a single oral dose of MDMA on anterior pituitary hormones in healthy adults. We hypothesize that MDMA, besides stimulating oxytocin, would also stimulate multiple axes of the anterior pituitary.
Methods
Trial design
This is a secondary analysis of a randomized, double-blind, placebo-controlled, crossover trial in 15 healthy adults conducted between February 2021 and April 2022 (Fig. 1). The study was registered at ClinicalTrials.gov NCT04648137.
Study design and experimental session.
Citation: Endocrine Connections 14, 6; 10.1530/EC-25-0254
Participants
Healthy adults (18–65 years) were included in this study. All participants were evaluated for physical and psychological comorbidities and only included if no such conditions were present. The key exclusion criteria contained tobacco smoking (>10 cigarettes/day), regular consumption of alcoholic beverages, documented cardiovascular disease, uncontrolled arterial hypertension, previous or current major psychiatric disorder or psychotic disorder in first-degree relatives, lifetime prevalence of illicit substance use >10 times (except for tetrahydrocannabinol, THC) or any time within the previous 2 months and during the study period, and the application of any medication which may interfere with the study drug. Full in- and exclusion criteria are provided in the original study (3). Participants received financial compensation for their participation.
Study procedure and study drug
The trial consisted of a screening and baseline evaluation and two 7 h main visits (Fig. 1). Between the two main visits, a wash-out period of at least 14 days was met. Participants were randomized to be given either MDMA or a placebo first. For the main visits, participants arrived in the morning after 8 hours of food fasting. They were prohibited from drinking alcohol 24 h before each visit and were instructed to abstain from other substance use during the study. To ensure that recent or active use of illicit substances did not interfere with MDMA effects during the study, urine drug screening was performed at the beginning of each visit. Only participants with negative results for substance use were eligible to proceed.
The visits took place in a quiet standard hospital patient room with one participant and one investigator present. The blood for sampling was drawn from an intravenous catheter in the antecubital vein inserted 30 min before the first blood sample was taken. Before each visit, female participants were screened for pregnancy. Visits were scheduled during the follicular phase to adjust for cyclical variations. A standardized breakfast was offered before drug intake. Participants received a single oral 100 mg MDMA dose. The oral placebo was prepared as identical opaque gelatine capsules but contained only mannitol. Blood pressure, heart rate, and tympanic body temperature were repeatedly measured 60 min before, at drug intake, and every 30 min after drug intake. Adverse effects of special interest were assessed 60 min before and 360 min after drug administration using a pre-defined 66-item list-of-complaints. Additional adverse events were assessed during and 3 days after each experimental session.
Based on previous findings showing a peak cortisol response to MDMA at 120 min, coinciding with its primary effects on the serotonergic system, we selected this timepoint to assess hormonal responses (3, 12).
Blood samples
Blood samples for this analysis were collected at baseline before drug intake and at 120 min. The samples were immediately centrifuged at 4°C for 10 min at 100 g and processed into aliquots. They were then stored at −80°C until batch analysis. EDTA plasma aliquots from 0 to 120 min were used for ACTH measurements. ACTH was measured using chemoluminescent immunoassay (CLIA). Serum aliquots from 0 to 120 min were used for the measurement of TSH, fT4, cortisol, LH, testosterone, estradiol, prolactin, and GH. They were all measured using electrochemoluminescent immunoassay (ECLIA). Serum aliquots from 0 to 120 min were used for the measurement of oxytocin and copeptin. Copeptin was measured using time-resolved amplified cryptate emission immunoassay (TRACE). Oxytocin was measured using the Oxytocin ELISA kit (Enzo Life Sciences, USA, sensitivity 15 pg/mL (range 15.6–1,000.0 pg/mL)). FSH was not assessed.
Objectives and statistical analysis
The main objective of this study was to evaluate the effect of a single oral dose of MDMA on the anterior pituitary in healthy adults.
Demographic data were summarized using the median (IQR) for continuous variables and absolute (relative) frequencies for categorical variables. The primary endpoint was the change in plasma levels of each hormone (ACTH, cortisol, TSH, fT4, prolactin, GH, LH, testosterone, estradiol, copeptin, and oxytocin) from baseline to 120 min following MDMA vs placebo. Changes in hormone levels (Δhormone-MDMA and Δhormone-Placebo) were calculated by subtracting the 120 min value from the corresponding baseline level value. The percentage increases or decreases in hormone levels were calculated by the following formula: ((hormone level at 120 min − baseline hormone level)/baseline hormone level) × 100. A Wilcoxon test was used for comparisons, and boxplots visually represent hormone dynamics across conditions.
We further assessed the correlation (Spearman’s) between hormonal changes with cardiovascular and psychoactive effects following MDMA administration. Psychoactive effects were measured using visual analogue scale (VAS) ratings for ‘any drug effect’ (0 = no effect, 10 = maximum effect), with changes calculated as the difference from baseline to 120 min. Cardiovascular effects included systolic and diastolic blood pressure, heart rate, and temperature measured at baseline and 120 min. All hypothesis testing was two-sided, with P-values <0.05 considered statistically significant. All analyses were conducted in R (version 4.4.2).
Results
Baseline characteristics
In total, 15 healthy adults were included in this analysis. The median age was 35 years (IQR, 26, 48), consisting of 53% (n = 8) females and 47% (n = 7) males. Baseline characteristics are summarized in Table 1.
Baseline characteristics.
| Age (years) | 35 (26–48) |
| Sex | |
| male | 7 (47%) |
| female | 8 (53%) |
| Ethnicity | |
| Caucasian | 15 (100%) |
| Weight (kg) | 70 (10) |
| Height (cm) | 173 (10) |
| BMI (kg/m2) | 23.2 (2.1) |
| Systolic blood pressure (mmHg) | 123 (10) |
| Diastolic blood pressure (mmHg) | 70 (6) |
| Nicotine use, yes | 3 (20%) |
| Cigarettes per day | 4 (3, 5) |
| Lifetime drug use, yes | 4 (27%) |
| Drug use per lifetime | 2 (2, 3) |
| Occasional alcohol intake, yes | 4 (27%) |
| Alcohol intake per week in standard glasses | 1 (1, 2) |
Data presented as mean (SD), median (IQR), or frequency (%). BMI, body mass index.
Anterior pituitary hormones in response to MDMA or placebo
The plasma level of each hormone at baseline, after 120 min, the change and percentage increase or decrease in response to MDMA or placebo are illustrated in Figs 2, 3, and 4 and summarized in Table 2.
Plasma ACTH and cortisol after MDMA stimulation or placebo. Data are expressed as box plots. The horizontal line shows the median, boxes are IQR, and whiskers are the most extreme values lying within the box edge and 1.5 × IQR. Wilcoxon test was used for paired groups with nonparametric data. (A) ACTH change in response to MDMA or placebo. (B) ACTH percentage change in response to MDMA or placebo. (C) Cortisol change in response to MDMA or placebo. (D) Cortisol percentage change in response to MDMA or placebo. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.
Citation: Endocrine Connections 14, 6; 10.1530/EC-25-0254
Plasma prolactin levels after MDMA stimulation or placebo. Data are expressed as box plots. The horizontal line shows the median, boxes are IQR, and whiskers are the most extreme values lying within the box edge and 1.5 × IQR. Wilcoxon test was used for paired groups with nonparametric data. (A) Prolactin change in response to MDMA and placebo. (B) Prolactin percentage change in response to MDMA or placebo. ns = P > 0.05.
Citation: Endocrine Connections 14, 6; 10.1530/EC-25-0254
Plasma TSH, fT4, LH, testosterone, estradiol, and GH levels after MDMA stimulation or placebo. Data are expressed as box plots. The horizontal line shows the median, boxes are IQR, and whiskers are the most extreme values lying within the box edge and 1.5 × IQR. Wilcoxon test was used for paired groups with nonparametric data. Plasma TSH change (A), fT4 change (C), LH change (E), testosterone change (G), estradiol change (I), GH change (K) in response to MDMA or placebo. TSH percentage change (B), fT4 percentage change (D), LH percentage change (F), testosterone percentage change (H), estradiol percentage change (J), GH percentage change (L) in response to the MDMA or placebo. ns = P > 0.05.
Citation: Endocrine Connections 14, 6; 10.1530/EC-25-0254
Plasma hormone levels in response to MDMA or placebo.
| Placebo | MDMA | |||||||
|---|---|---|---|---|---|---|---|---|
| Baseline | 120 min | Absolute change | Percentage change | Baseline | 120 min | Absolute change | Percentage change | |
| ACTH | 12.1 (10.1, 16.1) | 10.4 (8.5, 12.8) | −2 (−5.4, 1.7) | −16 (−36, 19) | 11.7 (10.5, 14.9) | 37.6 (24.5, 58.9) | 24.6 (9.9, 47.1) | 221 (51, 369) |
| Cortisol | 375 (250, 446) | 268 (178, 294) | −89 (−222, 0) | −11 (−49, 0) | 347 (252, 409) | 566 (457, 701) | 211 (76, 412) | 68 (18, 167) |
| TSH | 1.5 (1.4, 1.7) | 1.2 (1.0, 1.5) | −0.4 (−0.5, −0.2) | −28 (−36, −11) | 1.3 (1.2, 2.0) | 1.0 (0.8, 1.3) | −0.4 (−0.7, −0.2) | −32 (−44, −16) |
| fT4 | 15.3 (14.0, 16.1) | 14.9 (13.9, 15.9) | −0.1 (−0.4, 0.3) | −1 (−3, 2) | 15.4 (13.9, 16.6) | 14.8 (13.8, 16.0) | −0.3 (−0.6, 0.0) | −2 (−4, 0) |
| GH | 0.3 (0.1, 2.4) | 0.1 (0.1, 0.6) | −0.1 (−2.2, 0.0) | −54 (−86, −36) | 0.4 (0.1, 1.9) | 0.1 (0.1, 0.2) | −0.2 (−1.8, −0.0) | −66 (−90, −34) |
| LH | 4.3 (3.4, 8.1) | 7.4 (3.2, 9.4) | −0.3 (−1.1, 0.6) | −3 (−24, 16) | 6.2 (3.9, 10.8) | 6.3 (4.5, 17.4) | 0.2 (−1.2, 2.2) | 5 (−18, 33) |
| Estradiol | 111 (92, 286) | 121 (92, 236) | 0 (−23, 0) | 0 (−9, 0) | 142 (92, 262) | 134 (92, 198) | −1 (−24, 0) | 0 (−12, 0) |
| Testosterone | 19.5 (16.6, 23.4) | 18.1 (14.1, 21.5) | −1.4 (−4.2, −0.5) | −7 (−24, −2) | 19.7 (16.9, 22.8) | 16.3 (13.3, 22.0) | −3.2 (−3.6, −1.9) | −17 (−19, −11) |
| Prolactin | 9.7 (8.0, 12.0) | 7.3 (6.2, 12.9) | −0.7 (−4.0, 0.2) | −11 (−36, 2) | 11.5 (7.0, 16.0) | 13.7 (10.4, 21.8) | 3.8 (−1.1, 12.4) | 53 (−16, 136) |
| Oxytocin | 71 (52, 85) | 66.7 (53.5, 94.7) | 1.3 (−13.7, 16.9) | 2 (−15, 29) | 74.7 (54.5, 94.3) | 503.7 (192.1, 588.8) | 432.5 (99.2, 517.8) | 493 (157, 884) |
| Copeptin | 3.2 (2.5, 4.3) | 2.8 (2.1, 3.5) | −0.7 (−1.2, −0.1) | −18 (−32, −5) | 3.4 (2.3, 4.2) | 3.2 (2.8, 4.4) | −0.2 (−0.6, 0.5) | −6 (−16, 22) |
Data presented as median (IQR).
MDMA stimulated the HPA axis, with plasma ACTH increasing from 12 ng/L (11, 15) at baseline to 38 ng/L (25, 59) at 120 min (Supplementary Fig. 1A (see section on Supplementary materials given at the end of the article)), resulting in a significant absolute change of 25 ng/L (10, 47) (P < 0.001) (Fig. 2A) and a percentage change of 221 (51, 369) (Fig. 2B). This was accompanied by a cortisol increase from 347 nmol/L (252, 409) to 566 nmol/L (457, 701) (Supplementary Fig. 1A), resulting in a significant absolute change of 211 nmol/L (76, 412) (P = 0.006) (Fig. 2C) and a percentage change of 68 (18, 167) (Fig. 2D). Under placebo, no significant change was observed for plasma ACTH, and a physiological decrease in plasma cortisol was detected (Supplementary Fig. 1A and B).
MDMA mildly stimulated the lactotroph axis, with plasma prolactin increasing from 12 μg/L (7, 16) at baseline to 14 μg/L (10, 22) at 120 min (Supplementary Fig. 2A), resulting in a non-significant absolute change of 4 μg/L (−1, 12) (P = 0.062) (Fig. 3A) and percentage change of 53 (−16, 136) (Fig. 3B). Under placebo, no change was observed for plasma prolactin (Supplementary Fig. 2A).
MDMA had no effect on the somatotropic, pituitary gonadotropin, and pituitary–thyroid axes (Fig. 4). Similarly, under placebo, no significant change was observed for these axes (Supplementary Fig. 2B, C, D, E, F, G).
Posterior pituitary hormones in response to MDMA
The plasma level of both posterior pituitary hormones at baseline, after 120 min, and the change in response to MDMA or placebo are illustrated in Supplementary Figs 3 and 4 and summarized in Table 2.
MDMA stimulated oxytocin, with plasma oxytocin increasing from 75 pg/mL (55, 94) at baseline to 504 pg/mL (192, 589) at 120 min (Supplementary Fig. 3B), resulting in a significant absolute change of 433 pg/mL (99, 518) (P < 0.001) (Supplementary Fig. 4A) and a percentage change of 493 (157, 884) (Supplementary Fig. 4B). MDMA had no effect on copeptin (Supplementary Figs 3A, 4A, B). Under placebo, no relevant changes in oxytocin or copeptin occurred.
Correlation of blood pressure, heart rate, and temperature to changes in ACTH or cortisol
The correlations between the different pituitary hormones and their peripheral hormones, systolic blood pressure, diastolic blood pressure, heart rate, temperature, and VAS following MDMA administration are illustrated in Supplementary Fig. 5.
Significant correlations were found between the increase in ACTH and increase in systolic blood pressure (r = 0.61, P < 0.001), increase in diastolic blood pressure (r = 0.5, P = 0.005), and increase in heart rate (r = 0.5, P = 0.006). No correlation was found between changes in ACTH and temperature (r = 0.1, P = 0.590). Similarly, significant correlations were found between the increase in cortisol and increase in systolic blood pressure (r = 0.62, P < 0.001), increase in diastolic blood pressure (r = 0.43, P = 0.019), and increase in heart rate (r = 0.39, P = 0.032). No correlation was found between the changes in cortisol and temperature (r = 0.28, P = 0.139). Significant correlations were observed between the psychoactive effects and an increase in ACTH (r = 0.57, P < 0.001) and an increase in cortisol (r = 0.66, P < 0.001).
Safety summary
The safety profile of MDMA and placebo is summarized in Table 3. MDMA administration was associated with moderate increases in clinical safety parameters compared to placebo, including higher maximum systolic blood pressure (146 vs 129 mmHg), diastolic blood pressure (84 vs 78 mmHg), and heart rate (92 vs 78 bpm). At 360 min post-administration, participants in the MDMA group more frequently reported fatigue (53%), lack of appetite (67%), lack of concentration (53%), and dry mouth (53%), while these symptoms were rare or absent in the placebo group. At 3-day follow-up, transient symptoms such as headache (33%), fatigue (40%), dullness (33%), and lack of energy (13%) were also more common after MDMA than placebo.
Safety measures.
| MDMA | Placebo | |
|---|---|---|
| Clinical safety measures | ||
| Maximum systolic blood pleasure (mmHg) | 146 (13) | 129 (9) |
| Maximum diastolic blood pleasure (mmHg) | 84 (9) | 78 (9) |
| Percentage change systolic blood pressure | 18.9 (3.6, 20.5) | 0.0 (−6.1, 4.8) |
| Percentage change diastolic blood pressure | 8.4 (−1.3, 20.0) | −2.9 (−7.5, 6.5) |
| Maximum heart rate, in bpm | 92 (14) | 78 (9) |
| Maximum tympanic temperature (°C) | 37.1 (0.3) | 37.0 (0.3) |
| Adverse effects of special interest assessed at 360 min after drug administration | ||
| Fatigue | 8 (53%) | 4 (27%) |
| Lack of appetite | 10 (67%) | 0 (0%) |
| Lack of concentration | 8 (53%) | 1 (7%) |
| Dry mouth | 8 (53%) | 0 (0%) |
| Adverse effects of special interest assessed three days after each visit via phone calls | ||
| Headache | 5 (33%) | 1 (7%) |
| Fatigue | 6 (40%) | 1 (7%) |
| Lack of energy | 2 (13%) | 0 (0%) |
| Dullness | 5 (33%) | 1 (7%) |
| Adverse events | ||
| Transient mild hypokalaemia (n) | 2 (13%) | 0 (0%) |
Data presented as mean (SD), median (IQR), and frequency (%).
Discussion
This study has two key findings. First, MDMA strongly increased ACTH and cortisol, indicating also anterior pituitary stimulation in addition to stimulating oxytocin. Second, this stimulation correlated with increases in blood pressure, heart rate, and psychoactive effects.
ACTH acts as the main stimulus for cortisol production, regulating metabolism, immune response, and stress adaptation (20). Short-term activation of the HPA axis induces catabolic effects (20). Previous studies have consistently shown MDMA-induced cortisol elevation (4, 5, 6). In animal models and humans, MDMA stimulates the HPA axis via the monoamine system, promoting mainly transporter-mediated release of serotonin (5-HT) and noradrenaline (2, 6, 21, 22, 23). MDMA particularly enhances 5-HT activity while also increasing norepinephrine and, to a lower extent, dopamine (2, 6, 12, 21, 22, 23, 24). Supporting this, rodent studies showed that MDMA-induced corticosterone release is significantly reduced by 5-HT2 antagonists and 5-HT reuptake inhibitors (6). Likewise, human studies demonstrated that blocking both the serotonin transporter (SERT) and norepinephrine transporter (NET) with duloxetine eliminates the MDMA-induced increase in plasma cortisol (12, 23). Notably, inhibition of NET using reboxetine, which specifically prevents MDMA-induced norepinephrine release, had no effect on MDMA-induced cortisol release. This indicates that 5-HT is the primary trigger for MDMA-induced cortisol stimulation, while norepinephrine has little to no effect (23, 25). In rats, MDMA was also found to stimulate ACTH (26). However, in humans, it remains unclear whether MDMA stimulates cortisol secretion via pituitary activation or has direct effects on the adrenal glands. To date, only one small study of four healthy adults has reported MDMA-induced ACTH elevations (5), limiting generalizability. Our results now provide clear evidence that MDMA increases cortisol via ACTH, most likely through the serotonergic system activation.
Similar to the activation of the HPA axis, MDMA has been shown to stimulate prolactin secretion via the serotoninergic system (6, 16). Research in rhesus monkeys further supports this, indicating that prolactin release occurs through serotonin release and direct activation of 5-HT2A receptors (27). Consistent with these data, we observed an increase in prolactin after MDMA administration. Although the observed increase is modest, we interpret it as a genuine biological signal, as Straumann et al. demonstrated a pronounced elevation of prolactin, peaking at 120 min (16). Prolactin also plays a key role in stress regulation (28, 29). Stress itself induces prolactin secretion, while hyperprolactinemia stimulates the HPA axis (29). Given that MDMA activates both stress hormone axes via serotonin and directly enhances the noradrenergic system by increasing noradrenaline (1, 2, 6, 21, 22), a stimulation of the cardiovascular system is expected. Our results demonstrate a clear correlation between the HPA and prolactin axis activation with increases in heart rate, systolic and diastolic blood pressure. MDMA releases noradrenaline (12). As norepinephrine is a key activator of the sympathetic system (30, 31, 32), the observed correlation may be driven primarily by noradrenaline as the common factor. Supporting this, it has previously been shown that carvedilol, an α1 and β-adrenoreceptor antagonist, attenuated MDMA-induced cardiostimulatory response (32). Together, these findings suggest that MDMA-induced HPA axis stimulation may contribute to sympathetic activation but is not the primary driver of its cardiovascular effects.
Interestingly, some rodent studies suggested that the MDMA-mediated increase in body temperature, heart frequency, and blood pressure may be moderated by the pituitary–thyroid system stimulation (8, 9, 11), partly via enhancing pro-TRH gene expression and TRH biosynthesis (8, 9, 10). However, unlike in rodent studies, our findings did not show any MDMA-induced activation of the pituitary–thyroid axis or correlations with changes in temperature. This indicates that the MDMA-mediated increase in sympathetic tone and temperature is independent of the pituitary–thyroid system in humans. Supporting this, MDMA-induced hyperthermia has been linked to norepinephrine-mediated mechanisms, including α1-receptor activation, which causes vasoconstriction and reduced heat dissipation, and β3-receptor activation, which induces mitochondrial uncoupling and increased heat production (33).
There is no conclusive evidence regarding MDMA’s effect on the remaining anterior pituitary hormones. GH secretion is primarily controlled by stimulatory GH-releasing hormone and inhibitory somatostatin, but is also influenced by noradrenergic, serotonergic, and dopaminergic pathways, all of which MDMA activates (2, 6, 15, 16, 21, 22, 34, 35). Thus, one would anticipate a stimulation of GH release after MDMA. Surprisingly, Kobeissy et al. reported GH suppression in rats (17), and Gouzoulis et al. found blunted GH release in humans following MDMA (15), raising questions about the mediation via the monoamine system. In our study, GH levels remained unchanged. Since GH regulation involves both stimulatory (α2-adrenergic) and inhibitory (α1-/β-adrenergic) catecholaminergic effects (34), our findings suggest that GH response may be more directly linked to noradrenergic activity.
Although some animal studies in male rats report significant pituitary–gonadal axis suppression after acute MDMA administration, others could not confirm these findings (18, 21). Gonadotropin-releasing hormone (GnRH) neurons regulate LH and FSH release (14, 36). 5-HT plays a crucial role in this regulation, as 5-HT receptors are present in the preoptic area, where GnRH neurons reside (21, 36). Lesions in the dorsal raphe nucleus (a key 5-HT source) and pharmacological inhibition of 5-HT receptors suppress LH surges (36). Interestingly, most GnRH neurons are inhibited by 5-HT1 receptor activation, while a subset of these neurons is activated via 5-HT2 receptor (36), suggesting a balance of excitatory and inhibitory effects. In line with this, we observed no MDMA-induced changes in the pituitary–gonadotropin axis, suggesting that MDMA-driven serotonergic activation does not disrupt this equilibrium.
Overall, these results suggest that MDMA is a potent activator of two hormone axes with potential clinical relevance. Recently, MDMA has been proposed as a novel provocation test for suspected oxytocin deficiency and is currently under investigation as a diagnostic tool in clinical practice (3). Beyond its effects on the posterior pituitary, MDMA’s strong activation of the HPA axis raises the question of whether it could serve as an alternative diagnostic test in, e.g., adrenal insufficiency or differential diagnosis of Cushing’s disease. Currently, the insulin tolerance test (ITT) and the ACTH stimulation test are the primary diagnostic tools for evaluating adrenal insufficiency (37, 38). Nonetheless, both tests have substantial drawbacks. While the ITT raises substantial safety concerns, the better-tolerated stimulation test shows considerable variation due to interpretative and technical challenges (37). For differentiating pituitary vs extrapituitary ACTH-dependent Cushing’s syndrome, the CRH stimulation test is the primary diagnostic tool; however, due to an ongoing CRH shortage, alternative diagnostic tests are needed (39, 40). The European Society of Endocrinology recommends alternatives, although neither is fully satisfactory. Given its robust corticotrope activation, an MDMA stimulation test could be a promising test. However, further validation in patient populations is required.
Our study presents limitations and strengths. Only two timepoints were measured, which does not exclude missed increases of hormone levels. However, studies showed that both cortisol and prolactin levels peaked 120 min after MDMA (16), along with a strong MDMA-mediated stimulation of the monoamine system at this time (12). Furthermore, only a single high dose of MDMA was administered. Low-dose MDMA for clinical use is currently under investigation. While the small sample size of 15 healthy participants may restrict the generalizability of our results, the observed findings remain clear. Overall, our findings provide novel insights into the effects of MDMA. The study was performed in a highly standardized and controlled environment, minimizing potential confounding factors.
In conclusion, our findings demonstrate that MDMA robustly stimulates the HPA axis and the oxytocin system.
Supplementary materials
This is linked to the online version of the paper at https://doi.org/10.1530/EC-25-0254.
Declaration of interest
ML is a consultant for Mind Medicine Inc. All other authors declare no competing interests.
Funding
MCC received a grant from the Swiss National Science Foundation (32473B162608). CA received research grants from the Swiss Academy of Medical Sciences, G & J Bangerter-Rhyner Foundation, Hemmi-Foundation, University of Basel, and the Swiss Society for Endocrinology and Diabetology.
Author contribution statement
CA wrote the protocol and contributed to data collection. SC and CA did the analysis and interpretation, literature search and wrote the manuscript. ML and MCC edited the protocol, contributed to data analysis and interpretation, edited the manuscript, and supervised all steps of the conduct of the study. SC and CA covered all statistical aspects of the study and planned and performed data analysis. CA, SC, and MCC verified the data and had access to all raw data, and all authors had final responsibility for the decision to submit for publication.
Data sharing
We may share de-identified, individual participant-level data that underlie the results reported in this article and related documents, including the study protocol and the statistical analysis plan. Data will be available upon publication of our main manuscript upon receipt of a request detailing the study hypothesis and statistical analysis plan. All requests should be sent to the corresponding author. Based on the scientific rigor of the proposal, the steering committee of this study will discuss all requests and decide whether data sharing is appropriate. All applicants are asked to sign a data access agreement.
Ethics statement
This trial was conducted between February 2021 and April 2022 at the University Hospital Basel, Switzerland (Fig. 1). The study complied with the Declaration of Helsinki and was authorized by the Ethics Committee Northwest Switzerland. The use of MDMA was approved by the Swiss Federal Office for Public Health. Written informed consent was provided by all participants. The study was registered at ClinicalTrials.gov NCT04648137.
Acknowledgments
The authors thank Nina Hutter for her help during the study.
References
- 1↑
Hysek CM , Simmler LD , Ineichen M , et al. The norepinephrine transporter inhibitor reboxetine reduces stimulant effects of MDMA (“ecstasy”) in humans. Clin Pharmacol Ther 2011 90 246–255. (https://doi.org/10.1038/clpt.2011.78)
- 2↑
de la Torre R , Farre M , Roset PN , et al. Human pharmacology of MDMA: pharmacokinetics, metabolism, and disposition. Ther Drug Monit 2004 26 137–144. (https://doi.org/10.1097/00007691-200404000-00009)
- 3↑
Atila C , Holze F , Murugesu R , et al. Oxytocin in response to MDMA provocation test in patients with arginine vasopressin deficiency (central diabetes insipidus): a single-centre, case-control study with nested, randomised, double-blind, placebo-controlled crossover trial. Lancet Diabetes Endocrinol 2023 11 454–464. (https://doi.org/10.1016/S2213-8587(23)00120-1)
- 4↑
Harris DS , Baggott M , Mendelson JH , et al. Subjective and hormonal effects of 3,4-methylenedioxymethamphetamine (MDMA) in humans. Psychopharmacology 2002 162 396–405. (https://doi.org/10.1007/s00213-002-1131-1)
- 5↑
Grob CS , Poland RE , Chang L , et al. Psychobiologic effects of 3,4-methylenedioxymethamphetamine in humans: methodological considerations and preliminary observations. Behav Brain Res 1996 73 103–107. (https://doi.org/10.1016/0166-4328(96)00078-2)
- 6↑
Mas M , Farre M , de la Torre R , et al. Cardiovascular and neuroendocrine effects and pharmacokinetics of 3,4-methylenedioxymethamphetamine in humans. J Pharmacol Exp Ther 1999 290 136–145. (https://doi.org/10.1016/s0022-3565(24)34877-3)
- 7↑
Papazoglou AS & Leite AR . Prolactin levels and cardiovascular disease: a complicate relationship or a confounding association? Eur J Prev Cardiol 2023 32 612–615. (https://doi.org/10.1093/eurjpc/zwad176)
- 8↑
Fekete C & Lechan RM . Neuroendocrine implications for the association between cocaine- and amphetamine regulated transcript (CART) and hypophysiotropic thyrotropin-releasing hormone (TRH). Peptides 2006 27 2012–2018. (https://doi.org/10.1016/j.peptides.2005.11.029)
- 9↑
Fekete C , Mihaly E , Luo LG , et al. Association of cocaine- and amphetamine-regulated transcript-immunoreactive elements with thyrotropin-releasing hormone-synthesizing neurons in the hypothalamic paraventricular nucleus and its role in the regulation of the hypothalamic-pituitary-thyroid axis during fasting. J Neurosci 2000 20 9224–9234. (https://doi.org/10.1523/JNEUROSCI.20-24-09224.2000)
- 10↑
Meng Q , Kim HC , Oh S , et al. Cocaine- and amphetamine-regulated transcript (CART) peptide plays critical role in psychostimulant-induced depression. Biomol Ther 2018 26 425–431. (https://doi.org/10.4062/biomolther.2018.141)
- 11↑
Sprague JE , Banks ML , Cook VJ , et al. Hypothalamic-pituitary-thyroid axis and sympathetic nervous system involvement in hyperthermia induced by 3,4-methylenedioxymethamphetamine (ecstasy). J Pharmacol Exp Ther 2003 305 159–166. (https://doi.org/10.1124/jpet.102.044982)
- 12↑
Hysek CM , Simmler LD , Nicola V , et al. Duloxetine inhibits effects of MDMA (“ecstasy”) in vitro and in humans in a randomized placebo-controlled laboratory study. PLoS One 2012 7 e36476. (https://doi.org/10.1371/journal.pone.0036476)
- 13↑
Liechti ME . Effects of MDMA on body temperature in humans. Temperature 2014 1 179–187. (https://doi.org/10.4161/23328940.2014.955433)
- 14↑
Sadiq NM & Tadi P . Physiology, pituitary hormones. In StatPearls. Treasure Island, FL, USA: StatPearls Publishing. (https://www.ncbi.nlm.nih.gov/books/NBK557556/)
- 15↑
Gouzoulis E , von Bardeleben U , Rupp A , et al. Neuroendocrine and cardiovascular effects of MDE in healthy volunteers. Neuropsychopharmacology 1993 8 187–193. (https://doi.org/10.1038/npp.1993.20)
- 16↑
Straumann I , Avedisian I , Klaiber A , et al. Acute effects of R-MDMA, S-MDMA, and racemic MDMA in a randomized double-blind cross-over trial in healthy participants. Neuropsychopharmacology 2024 50 362–371. (https://doi.org/10.1038/s41386-024-01972-6)
- 17↑
Kobeissy FH , Jeung JA , Warren MW , et al. Changes in leptin, ghrelin, growth hormone and neuropeptide-Y after an acute model of MDMA and methamphetamine exposure in rats. Addict Biol 2008 13 15–25. (https://doi.org/10.1111/j.1369-1600.2007.00083.x)
- 18↑
Dickerson SM , Walker DM , Reveron ME , et al. The recreational drug ecstasy disrupts the hypothalamic–pituitary–gonadal reproductive axis in adult male rats. Neuroendocrinology 2008 88 95–102. (https://doi.org/10.1159/000119691)
- 19↑
Fleseriu M , Christ-Crain M , Langlois F , et al. Hypopituitarism. Lancet 2024 403 2632–2648. (https://doi.org/10.1016/S0140-6736(24)00342-8)
- 20↑
Thau L , Gandhi J & Sharma S . Physiology, cortisol. In StatPearls. Treasure Island, FL, USA: StatPearls Publishing. (https://www.ncbi.nlm.nih.gov/books/NBK538239/)
- 21↑
Duca Y , Aversa A , Condorelli RA , et al. Substance abuse and male hypogonadism. J Clin Med 2019 8 732. (https://doi.org/10.3390/jcm8050732)
- 22↑
Zaretsky TG , Jagodnik KM , Barsic R , et al. The psychedelic future of post-traumatic stress disorder treatment. Curr Neuropharmacol 2024 22 636–735. (https://doi.org/10.2174/1570159X22666231027111147)
- 23↑
Seibert J , Hysek CM , Penno CA , et al. Acute effects of 3,4-methylenedioxymethamphetamine and methylphenidate on circulating steroid levels in healthy subjects. Neuroendocrinology 2014 100 17–25. (https://doi.org/10.1159/000364879)
- 24↑
Hysek CM , Schmid Y , Simmler LD , et al. MDMA enhances emotional empathy and prosocial behavior. Soc Cogn Affect Neurosci 2014 9 1645–1652. (https://doi.org/10.1093/scan/nst161)
- 25↑
Hysek CM , Domes G & Liechti ME . MDMA enhances “mind reading” of positive emotions and impairs “mind reading” of negative emotions. Psychopharmacology 2012 222 293–302. (https://doi.org/10.1007/s00213-012-2645-9)
- 26↑
Zaretsky DV , Zaretskaia MV , Dimicco JA , et al. Independent of 5-HT1A receptors, neurons in the paraventricular hypothalamus mediate ACTH responses from MDMA. Neurosci Lett 2013 555 42–46. (https://doi.org/10.1016/j.neulet.2013.07.053)
- 27↑
Murnane KS , Kimmel HL , Rice KC , et al. The neuropharmacology of prolactin secretion elicited by 3,4-methylenedioxymethamphetamine (“ecstasy”): a concurrent microdialysis and plasma analysis study. Horm Behav 2012 61 181–190. (https://doi.org/10.1016/j.yhbeh.2011.10.012)
- 28↑
Freeman ME , Kanyicska B , Lerant A , et al. Prolactin: structure, function, and regulation of secretion. Physiol Rev 2000 80 1523–1631. (https://doi.org/10.1152/physrev.2000.80.4.1523)
- 29↑
Levine S & Muneyyirci-Delale O . Stress-induced hyperprolactinemia: pathophysiology and clinical approach. Obstet Gynecol Int 2018 2018 9253083. (https://doi.org/10.1155/2018/9253083)
- 30↑
Wyss JM . The role of the sympathetic nervous system in hypertension. Curr Opin Nephrol Hypertens 1993 2 265–273. (https://doi.org/10.1097/00041552-199303000-00014)
- 31↑
Puzserova A & Bernatova I . Blood pressure regulation in stress: focus on nitric oxide-dependent mechanisms. Physiol Res 2016 65 (Supplement 3) S309–S342. (https://doi.org/10.33549/physiolres.933442)
- 32↑
Hysek CM , Schmid Y , Rickli A , et al. Carvedilol inhibits the cardiostimulant and thermogenic effects of MDMA in humans: lost in translation. Br J Pharmacol 2013 170 1273–1275. (https://doi.org/10.1111/bph.12398)
- 33↑
Liechti ME . Effects of MDMA on body temperature in humans. Temperature 2014 1 192–200. (https://doi.org/10.4161/23328940.2014.955433)
- 34↑
Bioletto F , Varaldo E , Gasco V , et al. Central and peripheral regulation of the GH/IGF-1 axis: GHRH and beyond. Rev Endocr Metab Disord 2024 26 321–342. (https://doi.org/10.1007/s11154-024-09933-6)
- 35↑
Vance ML , Kaiser DL , Frohman LA , et al. Role of dopamine in the regulation of growth hormone secretion: dopamine and bromocriptine augment growth hormone (GH)-releasing hormone-stimulated GH secretion in normal man. J Clin Endocrinol Metab 1987 64 1136–1141. (https://doi.org/10.1210/jcem-64-6-1136)
- 36↑
Buo C , Bearss RJ , Novak AG , et al. Serotonin stimulates female preoptic area kisspeptin neurons via activation of type 2 serotonin receptors in mice. Front Endocrinol 2023 14 1212854. (https://doi.org/10.3389/fendo.2023.1212854)
- 37↑
Birtolo MF , Antonini S , Saladino A , et al. ACTH stimulation test for the diagnosis of secondary adrenal insufficiency: light and shadow. Biomedicines 2023 11 904. (https://doi.org/10.3390/biomedicines11030904)
- 38↑
Lewis A , Thant AA , Aslam A , et al. Diagnosis and management of adrenal insufficiency. Clin Med 2023 23 115–118. (https://doi.org/10.7861/clinmed.2023-0067)
- 39↑
Colao A , Scaroni C , Mezosi E , et al. Diagnostic work-up of ACTH-dependent Cushing’s syndrome in the context of CRH shortage: recommendation of a task force from the European Society of Endocrinology. Eur J Endocrinol 2024 191 R32–R35. (https://doi.org/10.1093/ejendo/lvae073)
- 40↑
Arnaldi G , Angeli A , Atkinson AB , et al. Diagnosis and complications of Cushing’s syndrome: a consensus statement. J Clin Endocrinol Metab 2003 88 5593–5602. (https://doi.org/10.1210/jc.2003-030871)
