How MDMAs Pharmacology and Pharmacokinetics Drive Desired Effects and Harms

This review (2014) looks at the desired effects and the possible harms that MDMA can elicit. One could argue that the review in unjustly harsh and implies negative effects not commonly experienced.

Abstract

“3,4‐Methylenedioxymethamphetamine (MDMA) is an agent of abuse that has been used by over 16 million Americans. Increased energy, elevated mood, bonding with others, and psychedelic effects are desired effects while liver damage, extended depressed mood, sexual assault, rhabdomyolysis, serotonin syndrome, multiorgan failure, cardiovascular events, arrhythmias, and death are possible adverse effects. These desirable and adverse effects of MDMA are extensions of its fascinating pharmacologic and pharmacokinetic profile. In addition to methamphatemine like effects, MDMA also has mescaline like effects and increases the release of cortisol, oxytocin, and antidiuretic hormone. The desirable effects of MDMA are accentuated by the rave or electronic dance music scene where warm temperatures, vigorous dancing, loud music, and light shows accentuate some of the responses. However, the same environment increases the risk of certain harms. Knowledge of the constellation of these factors is needed for education, prevention of harm, and treatment.”

Author: C. Michael White

Notes

Note: the review calls MDMA a ‘drug of abuse’, whilst this may be a term that was once favored, it hardly seems fitting as one could better call it a therapeutic with major potential.

The first part of this review deals with the prevalence of use. It finds that in the US 5% of people have ever used, and 0.8% have used MDMA in the last year (2012, from ‘National Survey on Drug Use and Health‘)

“According to the National Survey on Drug Use and Health in 2012, there were 16.2 million people in the US who have ever used MDMA and 2.6 million people who have used MDMA in the past-year.”

The number of emergency visits that were related to MDMA use (and dancing, heat, etc, definitely also see Ecstasy by Julie Holland) was 5,542, a mere 2.5% as much as that for cocaine use.

The following claim is made without citation “In the mid-1990s, the majority of tablets sold as MDMA actually had no MDMA in them but rather contained other amphetamine and psychedelic substances.” The closest source (citation 4; Parrott, 2013) actually states the exact opposite: “During the 1980s and early 1990s there were few problems with the purity of ecstasy tablets, and the biochemical evidence shows that they nearly always contained MDMA. During the mid-1990s, the majority of ecstasy tablets continued to contain MDMADuring the late 1990s, the proportion of
ecstasy tablets containing MDMA increased to around 80–90%.

Both the positive and negative effects of MDMA are discussed. The former alas only described tersely and without reference to the possible (then already done) therapeutic usages. The first negative effects discussed are presented as extensions of the desirable effects. The author may have meant that the same pharmacodynamics that elicit the positive effects, lead to the negative effects too.

Another review (Hall & Henry, 2006) is cited as the source for continued anxiety effects after MDMA use. That review starts the conclusion with the following sentence, “It is clear that despite large-scale consumption of MDMA, serious acute illness remains relatively rare.” That being said, the review itself cites two other papers for continued anxiety. Pallanti and Mazzi (1992) describe three case reports of precipitation of panic disorder after MDMA use and the resolution with the help of SSRIs. McCann and Ricaurte (1992) describe one case report. Alas, in both cases it is not certainly established if it was actual (pure) MDMA that was used (but see above, the purity is usually quite high).

Other negative effects such as serotonin syndrome, hyponatremia (low sodium/salt in blood), and bad choices because of enhanced socialization (STDs, taking other drugs). MDMA has also been found to induce short-term memory loss. Two of the metabolites (HHA, and HHMA) can induce liver injury. The reference given here again goes to the review by Hall & Henry (2006) which cites Andreu and colleagues (1998) saying “It represented 20% of all liver failure and 36% of non-viral liver failure in patients <25 yr of age.

The original study for this claim is on 62 patients with acute liver failure at one ICU between 1994 and 1996. Of those patients, five (8%) were there because of MDMA-induced liver failure. Then split into 25 years and younger/older (26 and 36 patients), and excluding those with viral hepatitis (12 and 18), you get the headline figure of 36% (5 out of 14).

Heart rate and blood pressure do also increase and can cause negative outcomes (e.g. stroke). The possibility of sudden cardiac death is also discussed and various predications that may put people at risk of coronary artery disease.

The review then looks at the pharmacokinetics and drug interactions with MDMA. One randomized, double-blind, crossover study (n=10) by Peiró and colleagues (2012) is highlighted which showed the increase in blood pressure.

The metabolic pathways of MDMA are then discussed. It is mostly cleared through cytochrome metabolism (particularly CYP2D6 enzymes). Some people (1-8%) are poor metabolizers (because of deficits in the CYP2D6 alleles), but this interaction with MDMA has not been studied well. The same goes for COMT activity which breaks down the HHMA and HHA metabolites, some people have genes that lead to lower activity.

Final remarks are made about testing kits that are provided at festivals. Instead of praising these services, the paper focuses on the false sense of security a test might give, whilst not testing for all other compounds.

This paper does describe the effects of MDMA accurately but does so without going into detail on the effects or the prevalence of these effects (next to the one time mentioned above). Although MDMA, in general, may be neurotoxic depending on the circumstances and lead to other negative outcomes, this paper does not present the positive effects that people experience in recreational use, the very low incidence of adverse events, and the potential therapeutic use accurately.

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