3,4-Methylenedioxymethamphetamine (MDMA; 'ecstasy') is an increasingly popular recreational drug in the US, Western Europe and Australia. In animals, including nonhuman primates, MDMA is known to damage brain serotonin (5-hydroxytryptamine; 5-HT) neurons. It is not known whether MDMA damages serotonin neurons in the human brain but there is some indication that it may. Although the large majority of individuals who have used MDMA recreationally do not develop acute complications, as the popularity of MDMA has increased, so have reports of adverse nonpsychiatric and psychiatric consequences associated with use of the drug. Further, since manifestations of MDMA-induced serotonin injury might only become apparent with age, or under periods of stress, it is possible that some individuals with no apparent abnormalities might develop complications over time.

Pharmacological challenge paradigms have been useful for elucidating the phenomenology and neurobiology of panic attacks. A drawback of the pharmacological challenge method is that individual differences in baseline arousal and outcome expectancy can lead to different subjective and physiological drug responses. One method for eliminating differences in baseline arousal and expectancy is to perform pharmacological challenges during non‐rapid eye movement (non‐REM) sleep. In the present study, fourteen healthy male volunteers received caffeine (5 mg/kg) and placebo (normal saline) during non‐REM sleep on two successive nights, in a single‐blind manner. Caffeine, compared to placebo, was associated with increased arousal, sleep disruption, and elevations in adrenocorticotropic hormone (ACTH) and cortisol. In one subject, caffeine infusion during sleep induced a panic attack. These findings indicate that caffeine leads to increased arousal and hypothalamic‐pituitary‐adrenal axis (HPA) axis activation in the absence of high baseline anxiety and expectancy bias. Further, they suggest that similar techniques can be employed in patient populations to elucidate the neurobiology of sleep panic attacks. Depression and Anxiety 5:21–28, 1997. © 1997 Wiley‐Liss, Inc.

The present study sought to determine whether social phobics, like patients with panic disorder, have increased sensitivity to the panicogenic effects of pentagastrin. Intravenous pentagastrin and placebo were administered in a double-blind fashion to 19 social phobics, 11 patients with panic disorder, and 19 healthy controls while they participated in a structured social interaction task. Behavioral, cardiovascular, and neuroendocrine responses were obtained. Pentagastrin led to panic attacks in 47% of the social phobics, 64% of the panic disorder patients, and 11% of the healthy controls. The social interaction itself increased anxiety, blood pressure, and pulse in all three groups. These findings suggest that the panicogenic effects of pentagastrin are not limited to patients with panic disorder and provide further evidence for shared neurobiology in social phobia and panic disorder.

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Pentagastrin, a cholecystokinin (CCK) agonist, produces anxiety and panic in patients with panic disorder and social phobia. Preclinical data suggests that pentagastrin-induced anxiogenesis may be mediated via 5-HT3 receptors. In the present study, 14 patients with panic disorder or social phobia underwent pharmacological challenge in three conditions: (1) pretreatment with saline followed by pentagastrin infusion; (2) pretreatment with ondansetron followed by pentagastrin infusion; and (3) pretreatment with saline followed by saline infusion. As expected, pentagastrin administration led to increased anxiety, physical symptoms of panic attacks, pulse, plasma adrenocorticotropic hormone (ACTH), and cortisol. Pentagastrin's behavioral effects were not blocked by ondansetron, and in fact, tended to be exaggerated. Ondansetron pretreatment did not alter the pentagastrin-induced cortisol increase but significantly prolonged the pentagastrin-induced increase in ACTH. These findings suggest that pentagastrin's behavioral effects are not mediated by 5HT3 receptors. Mechanisms by which peripherally administered CCK agonists lead to anxiety remain to be elucidated.