Clinical Pharmacology of 3,4-Methylenedioxy Amphetamines

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MDMA is an emerging drug of abuse with up to 14.6% of young adults in the US having tried this potentially addictive and toxic drug. Because of the increasing popularity of MDMA and its relatives we propose human studies to characterize pharmacologic effects. We will test the dose-, enantiomer-, and gender- dependent pharmacokinetic (PK) and pharmacodynamic (PD) response to MDMA ("Ecstasy") and one active metabolite, MDA. Our data show that MDMA has non-linear and enantiomer selective kinetics with disproportional increases in drug exposure with increasing doses. We will determine the contributions of increasing bioavailability and/or inhibition of metabolism on the kinetics and effects of S(+)- and R(-)-MDMA. Using chiral capillary GC-MS and LC-tandem MS we have developed and validated sensitive and specific analytic methods to measure the isomers of MDMA and metabolites in plasma, urine and sweat (using patches and a ventilated capsule method, useful in biomonitoring of MDMA abuse). Synthesis and administration of deuterium labelled enantiomers of MDMA and MDA will be used to characterize bioavailability and clearance of drug and metabolite. Psychopharmacologic effects are evaluated under well-controlled laboratory conditions with subjects housed on the UCSF GCRC. Cardiovascular PD effects are measured non-invasively with trans-thoracic 2-dimensional echocardiography and impedance cardiography. We have an active IND for the human study of MDMA and are well experienced with administration of safe and tolerable doses that produce minimal physiological response. Experiment 1 will determine possible isotope effects of deuterium-labelled MDMA and the pharmacodynamic effects of intravenous MDMA. The bioavailability and effects of gender and dose on the pharmacology of optically pure S(+)- and R(-)- MDMA will be assessed in Experiment 2. Experiment 3 will investigate the PK and PD of a single modest oral dose of MDA, an MDMA metabolite that is also a drug of abuse. This experiment will help define the mechanism of action of MDA and also provide a useful data on metabolic pathways of MDMA. Experiment 4 will investigate the mechanisms undedying MDMA-induced hyponatremia, a significant complication of MDMA abuse seen in primarily female "rave" party participants. Case reports suggest that water retention and loss of sodium may play a role in the development of hyponatremia, possibly due to MDMA-induced antidiuretic hormone (vasopressin) secretion. The effect of exercise and water loading on sodium and water homeostasis will be tested in subjects receiving a low oral dose of MDMA. In Experiment 5 we will investigate the effect of the alpha-blocker prazosin on the response to MDMA. Alpha-blockers may attenuate MDMA actions in humans. This experiment will investigate the role of alpha-1 adrenergic receptors in the action of MDMA and will provide preliminary data on the possible use of prazosin in the treatment of acute MDMA toxicity.