Description of potential adverse events and procedures described to address these unlikely events are presented in order of relative likelihood. Contingency plans for responding to these events were all negotiated with and approved by the FDA in the context of a study of MDMA-assisted therapy in patients with posttraumatic stress disorder (PTSD), and has been adapted for this present study, as below.
Hypertension
Thus far, hypertension is the only adverse event to have occurred after the administration of MDMA in a controlled, laboratory setting (Grob et al. unpublished; Mas et al. 1999; Vollenweider et al. 1998). Typical physiological effects of MDMA include modest elevations in blood pressure and heart rate, with blood pressure and heart rate returning to normal five hours after drug administration. Clinically significant elevation in systolic blood pressure (30 mm Hg above baseline) has been recorded in less than 5% of volunteers across all human trials conducted so far. Clinically significant increases in systolic blood pressure have lasted for up to two hours and have returned to normal without any intervention. Clinically significant elevation in blood pressure and heart rate usually begins 30 minutes to an hour after drug administration, and has lasted from 20 minutes to 2 hours, with blood pressure and heart rate returning to normal within approximately five hours after drug administration. None of the cases of elevated blood pressure have required medical intervention.
Individuals with evidence of cardiovascular disorders, including hypertension, will be excluded from study participation. Blood pressure and pulse will be measured at the outset of each MDMA or placebo session, then once every 15 minutes for the first 4 hours, and then every 30 minutes for the next 2 hours. If at any time the blood pressure exceeds 160 systolic or 110 diastolic or pulse exceeds 110, measurements will be taken every 5 minutes until values stabilize and the participant remains asymptomatic, show signs of trending downward, or fall below these levels. During this time, the physician- investigators will continually evaluate the participant for increasing blood pressure and signs or symptoms of a developing hypertensive or other cardiovascular or neurologic emergency. If needed, additional care will also be provided by internist co-investigator Dr. Siegel, who will remain available for contact over emergency radio and will be on- call and on-grounds for the duration of each experimental session. The investigators will make a clinical judgment about whether additional monitoring or treatment is required. If a participant exhibits systolic > 220 or diastolic > 120, he or she will be considered to be in hypertensive crisis, and will receive immediate treatment to lower blood pressure. Reasons for transport to the local emergency room would include, but are not limited to, severe headache in the setting of hypertension, or angina or neurologic deficits regardless of blood pressure. A crash cart is immediately available and will contain nitroprusside and other antihypertensives in addition to the usual resuscitation drugs and equipment. This will allow treatment to be instituted without transferring the participant if that should become necessary. The physician-investigators may, at any time, make a clinical judgment to transfer the participant to the emergency room in the nearest local hospital (Mt. Auburn Hospital) for further observation and care.
Any participant who, during the first MDMA session, experiences sustained blood pressure of > 220 systolic or > 120 diastolic or heart rate > 75% predicted maximum will not be given a second experimental session.
Psychological distress
Reports of MDMA-assisted psychotherapy conducted prior to the scheduling of MDMA indicate that some patients receiving MDMA in a therapeutic context experienced periods of increased anxiety and even panic. In the proposed study, participants will have the intention of confronting and working on their symptoms of anxiety as well as working through difficult and painful emotions. Hence, signs of psychological distress, panic or other unpleasant psychological reactions are to be expected. Psychological distress could arise at any time after the onset of the effects of MDMA until the last effects have dissipated (approximately 3 to 5 hours after drug administration), with anxiety or distress potentially lasting for as little as 15 minutes to as long as 5 hours.
The potential for destabilizing psychological distress will be minimized by excluding individuals who might be more vulnerable to it (such as individuals diagnosed with bipolar affective disorder or with psychotic disorders), by preparing individuals before the experimental session, by creating an atmosphere of trust during the experimental session, by close monitoring and by providing non-drug integrative psychotherapy sessions. In addition, participants are encouraged to find someone who will stay with them and who will provide support during and after each experimental session.
During the preparatory sessions, participants will be made aware of the fact that difficult emotions, including grief, rage and fear or panic, may arise during experimental sessions. Every effort will be made to help participants resolve difficult symptoms and to arrive at a more comfortable and relaxed state by the conclusion of the session, including empathic listening on the part of the investigators and performance of diaphragmatic breathing by participants.
If, by the end of the 6 to 8 hour experimental session, the participant is still severely agitated or experiencing great psychological distress, the following measures will be taken: If a participant is anxious, agitated, in danger of any self harm or is suicidal at the end of the MDMA treatment session, the investigators will remain with the participant for at least two more hours. During this time, the investigators will employ affect management techniques described in the MDMA treatment manual, will talk with the participant to help him or her gain cognitive perspective of their experiences. If this situation should occur at the end of one of the sixty-minute follow-up sessions at least one of the investigators will be available to stay with the participant for at least two additional hours. If a participant remains severely anxious, agitated, in danger of self harm or suicide, or is otherwise psychologically unstable at the end of this two hour stabilization period principal investigator Dr. Halpern will decide between one of two options:
A. The psychiatry resident (who has been hired to stay overnight with the subject until the time of his or her appointment with the co-therapist investigators the next day) will be informed that the participant continues to experience psychological distress. If psychological distress is present during the next day's non-drug psychotherapy follow-up session, but this distress is not considered to meet criteria for inpatient psychiatric hospitaliztion, one or both of the co-therapist investigators will meet with the subject daily until the period of destabilization has passed. (Such a period of destabilization may result in withdrawing or suspending the participant from the study, and will be reported as an Adverse Event to the McLean Hospital and Lahey Clinic's IRBs and the FDA). At any time during this process, Dr. Halpern may make the clinical judgment to proceed to option B.
B. Hospitalization for stabilization: Individuals requiring hospitalization due to study participation will be suspended from the study until after recovery or stabilization, at which time the co-therapist investigators will carefully evaluate the participant's emotional status. If this response occurs during the first experimental session, the investigators may elect to forego the second administration and drop the subject from the study. This decision will be made after submission of a report to the IRBs and the FDA.
Participants may contact the investigators 24 hours a day throughout the course of the study. The investigators can schedule an additional psychotherapy session if requested to do so by the participant.
For those participants engaged in an ongoing therapeutic relationship, we will actively involve their outside therapists in the management of any psychiatric complications of treatment.
In the event of a participant's experiencing severe, persisting emotional distress, such as panic attacks, severe generalized anxiety, or persisting insomnia following an MDMA session, the investigators may prescribe a benzodiazepine or zolpidem as a "rescue medication." If a participant should become psychotic or suicidal, arrangements will be made for him or her to be admitted to the nearest inpatient psychiatric facility of their choice or directly to McLean Hospital. Residual symptoms will be addressed during the frequent follow-up psychotherapy visits with the investigators.
Angina or Myocardial infarction
If a participant experiences ischemic type chest pain, whether or not it is associated with hypertensive crisis, he or she will undergo a STAT ECG, receive oxygen and an IV and will be monitored as described above. He or she will be given nitroglycerin 0.4 mg SL q 5 minutes PRN chest pain pending transport to the hospital. If further evaluation at the hospital reveals that the participant has had an acute myocardial infarction (AMI), he or she will be well within the time frame required for definitive therapy. The American College of Cardiology/American Heart Association guidelines for the treatment of AMI recommend percutaneous transluminal coronary angioplasty (PTCA) as the treatment of choice when it can be performed within 90 minutes of arrival at the hospital in patients who present within 12 hours of an episode of chest pain lasting more than 30 minutes and who have ECG evidence of AMI (J Am Coll Cardiol 34:890, 1999).
Stroke
If any participant has neurologic deficits, whether or not they are associated with hypertensive crisis, he or she will receive oxygen and an IV and will be monitored as described above. He or she will be transported to the Mt. Auburn Hospital for a head CT scan and further management. If evaluation at the hospital reveals a nonhemorrhagic stroke, there will be time to administer recombinant tissue plasminogen within the 3 hour time frame recommended in the American Academy of Neurology/American Heart Association guidelines (Neurology 47:835, 1996).
Hyponatremia
Hyponatremia (low blood sodium or high blood water) has occurred after use of ecstasy in uncontrolled settings, perhaps as a result of MDMA effects and user behavior (drinking excessive water in order to stave off dehydration) (Henry and Rella 2001). A modest dose of MDMA (47.5 mg) has been demonstrated to induce arginine vasopressin (AVP) release in humans (Forsling et al. 2001). Researchers and therapists have not generally monitored for hyponatremia after MDMA administration. However, hyponatremia has not been reported either in case reports of MDMA-assisted therapy conducted before the scheduling of MDMA or in recently conducted clinical trials.
History of hyponatremia or detection of hyponatremia on initial physical examination will be cause for exclusion from the proposed study. Participants will be given electrolyte-containing solutions such as Gatorade instead of water in order to decrease the likelihood of dilutional hyponatremia. They will not be allowed to drink more than 3 L of fluids, and fluid intake will be appropriately spread out across the session. If there are any signs or symptoms of hyponatremia, a stat serum sodium will be drawn and fluids will be withheld until the results are obtained. If the serum sodium is less than 125mEq/L, serum and urine osmolality and sodium will be measured, and the patient will be transported to the Mt. Auburn Hospital, where further intervention can be provided.
Hyperthermia
Cases of hyperthermia in ecstasy users are probably due in large part to an interaction between drug effects, high ambient temperature found at some dance events, and prolonged or vigorous exercise (Henry and Rella 2001). No cases of hyperthermia have been reported in studies wherein MDMA was administered to humans in a controlled environment. Hyperthermia is unlikely to arise in the proposed study because participants will not be exercising and will be in an environment with controlled ambient temperature, which will be kept comfortably cool.
Body temperature will be measured and reviewed at the outset and then every thirty minutes for 6 hours with a tympanic temperature sensor and an automatic temperature sensor will be recording core body temperature throughout the experiment for later detailed review. The physician may also call for more frequent tympanic temperature measurements in the event of clinically significant changes. Ambient temperature will be measured and reviewed hourly four six hours, starting immediately after drug administration. If temperature rises more than 1 C, attempts will be made to lower it by removing blankets and layers of clothing, decreasing the ambient temperature and, if necessary, directing a fan toward the patient. If at any time the temperature rises more than 1.5 C above baseline despite these efforts, acetominophen will be administered, ice packs will be used, blood will be drawn for stat CBC, electrolytes, BUN, creatinine, glucose, CPK, PT, PTT, platelets and liver enzymes, and urine will be collected for urinalysis. If there are significant abnormalities in these tests, if the temperature continues to rise, or if an elevated temperature is associated with delirium or muscle rigidity the participant will be transferred to the emergency room of the Mt. Auburn Hospital.
If, during the first MDMA session, a participant's temperature rises more than 1 C and does not rapidly come down after the above adjustments have been made in blankets, clothing, ambient temperature and ventilation, then that participant will not be given a second experimental session.
In order to avoid dehydration, participants will be encouraged to drink at least 750 - 1500 mL (and up to 3 L) of an electrolyte-containing fluid (such as Gatorade) during the session depending on their size, level of activity, and body temperature.