Paroxetine Ecstasy

Methylenedioxy compounds such as piperonyl butoxide are used to make insecticides more effective by inhibiting the insect enzymes that inactivate the insecticide (Fig. 8.21). Some drugs such as paroxetine and 3,4-methylenedioxymethamphetamine (ecstasy) also contain this functional group. 

SLC6A4 (SERT) SERT plays a role in the reuptake and clearance of serotonin in the brain. Like the other SLC6A family members, SERT transports its substrates in a Na+-dependent fashion and is dependent on CL and possibly on the countertransport of K+. Substrates of SERT include serotonin (5-HT), various tryptamine derivatives, and neurotoxins such as 3,4-methylene-dioxymethamphetamine (MDMA ecstasy) and fenfluramine. SERT is the specific target of the selective serotonin reuptake inhibitors (e.g., fluoxetine and paroxetine) and one of several targets of tricyclic antidepressants e.g., amitriptyline). Genetic variants of SERT have been associated with an array of behavioral and neurological disorders. The precise mechanism by which a reduced activity of SERT, caused by either a genetic variant or an antidepressant, ultimately affects mood and behavior is not known. 

The psychological effects of ecstasy (MDMA, methylenedi-oxymethamfetamine) may be reduced if citalopram has previously been given. It seems likely that other SSRIs will also reduce or block some of the effects of ecstasy, but increased serotonin effects may, in theory, also be possible. An isolated report describes a neurotoxic reaction in a man taking citalopram when he took unknown amounts of ecstasy. Fluoxetine and paroxetine may decrease the metabolism of ecstasy. 

In a placebo-controlled, randomised, crossover study, 7 healthy subjects were given ecstasy 100 mg on the last day of taking paroxetine 20 mg daily for 3 days. Paroxetine raised the maximum serum levels and AUC of ecstasy by 17% and 27%, respectively. ... 

The study of ecstasy with citalopram was primarily undertaken to find out how eestasy works, but on the basis of these results and animal studies it seems likely that patients already taking citalopram may not be able to get as high on usual doses of ecstasy, and some adverse effects may also be redueed. Furthermore, if the proposed mechanism of interaction is correct, the same is also likely to be true if they are taking any other SSRI and some cases have been reported. However, be aware of possible pharmaeokinetie interaetions with some SSRIs that are potent CYP2D6 inhibitors (e.g. fluoxetine, paroxetine), which may increase ecstasy levels. There is also a risk of increased serotonergic activity and there have been a few reports of interaetions involving other sympathomimetics and SSRIs or related drugs, see Phentermine + Fluoxetine , p.205. 

Farre M, Abanades S, Roset PN, Peiro AM, Torrens M, O Mathuna B, Segura M, de la Torre R (2007) Pharmacological interaction between 3,4-methylenedioxymethamphetamine (ecstasy) and paroxetine pharmacological effects and pharmacokinetics. J Pharmacol Exp Ther 323 954-962... 

---