Background: Psychedelic drugs are increasingly being researched for their therapeutic properties in terms of treatment resistant mental illnesses. However, little is known about how they impact metabolism, which has implications for those with metabolic diseases such as diabetes. Hypohydration has been argued by some to cause glucose dysregulation, particularly due to elevations in arginine vasopressin (AVP). 3,4- Methylenedioxymethamphetamine (MDMA) is known to elevate AVP, resulting in body water retention. Thus MDMA offers a paradoxical state of elevated AVP and hyperhydration, allowing us to uncouple the effects of hydration state and hydration physiology on metabolism. Aims: This study aimed to test the impact of MDMA on gluco-regulation in a tightly controlled setting. Methods: Using a non-blinded AB study design, this self-experimentation involved two female scientists who underwent one day pre-trial within-person control of diet and activity. After the pretrial control period, the experimenters did the control (CON; no-intervention) arm first, followed by the treatment (MDMA) arm. Testing involved fasting measures pre- and post-MDMA (or equivalent timepoints during CON), then a two hour 75 g oral glucose tolerance test, and a four hour follow up period. Blood samples, urine volume and specific gravity, body mass, and visual analogue scales were collected at set times throughout the testing period. Results: Relative to CON, MDMA resulted in gluco-dysregulation in both experimenters, particularly in relation to causing hyperinsulinaemia. However, plasma copeptin concentration (as a marker of AVP) only increased in one experimenter. Both experimenters had elevated cortisol during MDMA compared to CON. For one experimenter, urine volume was greater during MDMA, with no distinct differences in specific gravity; for the other experimenter (with elevated copeptin concentrations), urine volume was lower with higher specific gravity. Visual analogue scales showed only the experimenter with high copeptin had increased thirst and xerostomia. Conclusion: Overall, MDMA may be implicated in gluco-dysregulation, though caution needs to be taken when generalising from such a small study. Accordingly, these findings need to be replicated in a larger sample, as well as in conditions that are similar to a therapeutic setting. Since gluco-dysregulation occurred in both experimenters, but copeptin only increased in one experimenter, it is unlikely that AVP is the key mechanism of action. Cortisol is likely a key driver of the gluco-dysregulation reported. Preliminary recommendations are provided to help ensure the safety of MDMA therapy patients and recreational users.