Article: Pharmacodynamic and Pharmacokinetic Interactions of MDMA

[haste]

Just interested to hear people's thoughts on this article.... here

Its a pretty full on article that I don't fully get a handle on.. but all in the quest of knowledge & understanding

[Edit: Added "of MDMA" to clarify the title. BT]

 

[BigTrancer]

NOTE: Many of the drugs mentioned in this article are extremely dangerous to combine with MDMA (i.e., potentially fatal).

Here’s a brief gist of what I gleaned from this article:

Ecstasy: Pharmacodynamic and Pharmacokinetic Interactions
Source: Psychosomatics

At "raves," young people dance and ingest illicit drugs, the most common of which is MDMA (N-methyl-3,4,- methylenedioxymethamphetamine)or "ecstasy." This drug is metabolized principally through the cytochrome P450 (CYP450) 2D6 enzyme. Pharmacokinetic drug-drug interactions can occur if MDMA is combined with other recreational or therapeutic drugs that are 2D6 inhibitors. Ecstasy concentration may increase to cause toxicity. Since ecstasy is pro-serotonergic, it may also be involved in pharmacodynamic drug-drug interactions when other pro-serotonergic drugs are combined with it, leading to a central serotonin syndrome. Some drugs are both proserotonergic and CYP450 2D6 inhibitors and, if co-administered with ecstasy, may cause both pharmacokinetic and pharmacodynamic drug-drug interactions.

a. pharmacokinetic = the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body.

b. pharmacodynamics = the study of the action or effects of drugs on living organisms.

I think the difference they’re trying to outline here is that MDMA can cause a range of synergies with different drugs, and that certain drugs can cause different types of interactions to occur at the same time. Essentially, things aren’t as simple as A+B=C where drug synergies are concerned.

Since the 1980s, all-night dance parties known as "raves" have been popular among young people throughout the world. Often held in poorly ventilated surroundings and accompanied by the ingestion of illicit substances, individuals vigorously dance while listening to electronic music or viewing laser shows. Rave pills often have embossed logos that purport to identify particular drugs. In fact, they may contain inert substances or an entirely different drug, or the "true" drag may be laced with other contaminants. Without careful laboratory testing, the actual contents of an ingested drug may be impossible to determine.

The most commonly used rave drug, MDMA (N-methyl-3,4,- methylenedioxymethamphetamine), is structurally similar to both methamphetamine and mescaline. This drug-also known as ecstasy, E, Adam, Ecky, X, Bicky, or yaoto-wang-is illicitly compounded in tablets, capsules, or powder and may be embossed with a logo (e.g., Calvin Klein CK, Mitsubishi, 007, Coco Channel CC, Nike, or Rolex). Studies in the field have shown that tablets contain between 80 to 150 mg of MDMA, but they commonly contain inert substances and other drugs as well.

“Ecstasy”, taken by people at rave parties, is not guaranteed to contain any MDMA.

Emergency room physicians have become experts in the treatment of rave drug intoxications, but other medical specialists are less knowledgeable about these drags and their potential for interactions with prescribed or recreational substances. Unfortunately, large gaps exist in our understanding of this subject because few clinical studies have been done of rave drug interactions. Therefore, we must rely on case reports, in vitro studies of the metabolism of rave drugs, and knowledge of other drugs' metabolism and their potential for cytochrome P450 (CYP450) inhibition/induction to examine the pharmacodynamic and pharmacokinetic interactions of MDMA.

As we know, it can be hard to find reliable information on illicit drugs, and it’s not usually part of a person’s formal education.

MDMA Metabolism

Most of MDMA is demethylenated to 3,4-dihydroxymethamphetamine (DHMA) by CYP450 2D6,2 but other enzymes contribute (e.g., 1A2, 2B6, and 3A4).3 A smaller portion of MDMA is also N-demethylated via CYP450 1A2 and 2D6 to 3,4-methylenedioxyamphetamine (MDA).4 MDMA's further phase II metabolism is poorly understood. MDMA or one of its metabolites has been shown to be a 2D6 inhibitor in vitro,5 but whether this is also true in vivo is not known. This speculation would be consistent with the observation that small increases in dosing of MDMA lead to large increases in blood concentration, i.e., nonlinear kinetics.

MDMA ---{2D6}---> DHMA + MDA ---{?}---> ?

Mechanism of Action

The mechanism of action of MDMA is incompletely understood, but it is believed to inhibit the reuptake of serotonin (5-HT), to facilitate serotonin release, and to a lesser extent cause dopamine and noradrenaline.7 The serotonin boost can produce a sense of emotional closeness, elation, and sensory delight. MDMA acute adverse effects may include increased heart rate and blood pressure, tremor, sweating, bruxism, and life-threatening hyperthermia that may be further complicated by rhabdomyolysis, disseminated intravascular coagulation, and acute renal failure. Because MDMA users are aware of its toxic potential, they often drink fluids to prevent hyperthermia. (A teen told one of the authors [J.R.O.] that profits from bottled water can top money made on MDMA at some raves.) MDMA users also carry lollipops or pacifiers to alleviate the bruxism side effect.

This is pretty clear, I think, we cover this material a lot on BL.

Metabolic Pharmacogenetics of MDMA

Since the CYP450 2D6 enzyme is the primary metabolic pathway, individuals with genetic variations of this enzyme (e.g., slow metabolizers or ultra rapid metabolizers) will have variable concentrations of the parent compound and metabolites.2,8 Even extensive 2D6 metabolizers will be vulnerable to increased blood concentration of MDMA when a potent 2D6 inhibitor is added, since large increases in the blood level can occur because of nonlinear kinetics.

This is a generalization of the statement we often refer to that some 1 in 10 Caucasian people and slightly different ratios of other populations are naturally hypersensitive to MDMA due to a deficiency in the P450 2D6 enzyme. One might therefore expect that some proportion of the population are also naturally insensitive to MDMA due to the converse situation.

Pharmacokinetic Drug-Drug Interactions With MDMA

Potent 2D6 inhibitors block the most important metabolic pathway of MDMA. An in vitro study showed that fluoxetine, paroxetine, and cocaine all inhibited MDMA metabolism,8 and one can predict that these and other coadministered drugs that are potent 2D6 inhibitors may substantially increase the concentration of MDMA in vivo, such as bupropion, haloperidol metabolites,9 methadone, quinidine, ritonavir, pimozide, and others.

MDMA metabolism (i.e., eliminating the drug from the body and returning to baseline) can be inhibited in part by either slowing the reuptake of serotonin in the brain, or slowing the action of the liver enzymes. This section deals with the enzymes.

However, drugs that inhibit most or all of the CYP450 pathways (e.g., 1A2, 2B6, 3A4) will likely have even a more profound effect. For instance, it is well known that the acute usage of ritonavir inhibits 2B6, 2C9, 2C19, 2D6, and 3A4.10-12 Several cases have been reported of life-threatening interactions or death in individuals who ingested MDMA while taking ritonavir.13,14 In one case, it was estimated that the blood concentration was 10-fold higher than what might have been expected from the dose of MDMA ingested. Although not as potent as 2D6 inhibitors, other protease inhibitors that also inhibit 2D6 and 3A4 may be similarly implicated in increasing MDMA concentrations when co-administered.15 Like ritonavir, fluoxetine is a potent CYP450 2D6 inhibitor, and it also inhibits 2B6, 2C9, 2C19, and 3A4 to some extent. Amiodarone is a potent inhibitor of CYP450 1A2, 2C9, 2D6, and 3A4,16 and it may be potentially dangerous in coadministration.

OK... we're talking about metabolism of MDMA, which is not quite as simple as we sometimes make it out to be on BL. There's a bunch of different enzymes like 2D6, some of them are named in the above paragraph. MDMA is metabolised mostly by 2D6 and to a lesser extent other enzymes such as 3A4, 1A2 and 2B6. Inhibiting the actions of some or all of these enzymes can cause a resulting decrease in the rate that MDMA is metabolised, giving much higher concentrations of MDMA in the blood for longer (in a way that may be very unpleasant and ). Even inhibiting the relatively less-important enzymes can lead to a small increase in MDMA levels (i.e., the grapefruit juice method).

Pharmacodynamic Drug-Drug Interactions With MDMA

MDMA's pro-serotonergic effects can be augmented by ingestion of other pro-serotonergic drugs. These drugs may be ingested inadvertently as contaminants of MDMA (e.g., amphetamines, MDA)17 or taken to enhance MDMA effects (e.g., cocaine, dextromethorphan). Pro- serotonergic drugs (e.g., fluoxetine, amphetamines, St. John's wort, tramadol, venlafaxine, lithium, clomipramine, and others) prescribed for medical disorders may increase the likelihood and severity of MDMA's serotonin effects. A florid central serotonin syndrome involving autonomie, cognitive, and neuromuscular symptoms may develop. Moderate symptoms manifest as sweating, shivering, hyperreflexia, and agitation; severe symptoms include myoclonus, diarrhea, and fever.18 The most serious cases of central serotonin syndrome can develop with drugs that block both serotonin "exits"- reuptake and monoamine oxidase. Cases of toxicity or death have been reported from MDMA interactions with the monoamine oxidase inhibitor phenelzine19,20 and the reversible monoamine oxidase inhibitor meclobemide.21 Linezolid, a new antibacterial, is a mild reversible monoamine oxidase inhibitor.

The above paragraph lists a number of drugs that are serotonergic; i.e., they 'increase the amount' of serotonin in the brain by causing its release or slowing its reuptake. The authors reiterate here the danger of combining any of these drugs with MDMA, particularly in the case of drugs which both release and inhibit reuptake.

MAOIs are also included here too - [Neuro: most of the neurotransmitters (dopamine, serotonin, etc) are monoamines; after being released into the synaptic space, neurotransmitters are either 'reuptaken' into the proximal nerve or destroyed by monoamine oxidase in the synaptic cleft; monoamine oxidase inhibitors slow the destruction process, which in the case of MDMA+MAOI can result in serotonin syndrome].

Combined Pharmacokinetic and Pharmacodynamic Drug-Drug Interactions With MDMA

Some MDMA users will "pre-load" with citalopram or another serotonin reuptake inhibitor (SRI) because they believe that co- administration will protect against possible toxic CNS effects. It has been shown that co-administered SRIs can block the subjective effects and increases in blood pressure and heart rate of MDMA but not the effects of hyperthermia.23 Unfortunately, combined pharmacokinetic and pharmacodynamic drug-drug interactions can ensue when some SRIs that are also potent CYP450 2D6 inhibitors (e.g., fluoxetine, paroxetine) increase both the concentration of MDMA (pharmacokinetic) and serotonergic activity (pharmacodynamic). MDMA users may also consume other drugs at the same time to enhance their experience. Cocaine is both an SRI and a moderate 2D6 inhibitor and may have similar effects as fluoxetine and paroxetine.8

Hmm... perhaps this is a case of a little info being dangerous. Post-loading with SSRI is a step sometimes taken by people in order to reduce the possibility of neurotoxic damage and/or help them return to 'normal' moods... but pre-loading seems pointless to me, as we know (and the authors state above) that SSRIs can reduce/remove the 'ecstasy' effects making it virtually impossible to peak on MDMA. Before I read this article I don't think I was aware that cocaine was a 2D6 inhibitor, very interesting.

Other Common Drug Combinations With MDMA

There are two other drugs that are commonly ingested with MDMA: alcohol and sildenafil. A clinical study has shown that the MDMA plasma concentrations increase 9%-15% when taken with alcohol. More important, the combination leads to a longer-lasting feeling of euphoria and the false impression that one's performance of a task has improved when it has actually been impaired.24 This discrepancy may fuel potentially dangerous actions. Sildenafil is sometimes combined with MDMA (termed "sextasy"), but since the former is a CYP450 3A4 substrate, no additional interactive pharmacokinetic or pharmacodynamic effects occur.

The above refers to a study that was linked in the Drugs in the Media forum a while ago -- link. As for sildenafil, well... that's also known as Viagra. While they say no drug-drug interactions occur, I would avoid mixing MDMA and Viagra due to the potential for overstimulation or cardiac problems.

Conclusion

MDMA became a popular rave drug because of its intense effects and because it was believed to have few toxic effects. This has proven to be false. Ingested alone, it has the potential for serious acute toxicity. Taken with other therapeutic and recreational drugs, it has the potential for complicated pharmacokinetic and pharmacodynamic drug interactions.

(Psychosomatics 2004; 45:84-87)

Somewhat of a doom and gloom conclusion regarding MDMA, however I guess I can see their point given how much research they've just presented which says all these drugs can be extremely dangerous to mix with E. In brief, I guess I'd summarise the whole article by saying that some people think MDMA is a relatively 'safe' drug, but it can interact in a number of ways with many commonly prescribed pharmaceutical drugs, and/or illicit chemicals, which people may be taking on a regular basis. These interactions may be of different types and severities, but they can 'add-on' to produce an effect that is more than the sum of its parts. This is why drug synergies are inherently risky, as the interactions can be non-linear and unpredictable.

Hope that helps, if there's any questions or comments please add them to this thread. If I've glossed over something too broadly or made any big bloopers, please correct me! I'm usually not too bad at science-to-English translation, but I'm not a neurologist either.

BigTrancer

 

[haste]

Thanks BT, much appreciated

 

[Cowboy Mac]

Thanks for that haste, really good read. Anyone interested in this kind of field should check out MAPS as they have a lot of good research studies regarding such things as pharmacokinetics and pharmacological effects in humans, and other excellent research.

 

[BigTrancer]

*bump*