Key interindividual determinants in MDMA pharmacodynamics

This review (2018) examines the main interindividual determinants in MDMA pharmacodynamics and highlights the influence of factors such as gender-sex (more pronounced in women because of weight difference), race-ethnicity, and genetic traits.

Abstract

Introduction: MDMA, 3,4-methylenedioxymethamphetamine, is a synthetic phenethylamine derivative with structural and pharmacological similarities to both amphetamines and mescaline. MDMA produces characteristic amphetamine-like actions (euphoria, well-being), increases empathy, and induces pro-social effects that seem to motivate its recreational consumption and provide a basis for its potential therapeutic use.

Areas covered: The aim of this review is to present the main interindividual determinants in MDMA pharmacodynamics. The principal sources of pharmacodynamic variability are reviewed, with special emphasis on sex-gender, race-ethnicity, genetic differences, interactions, and MDMA acute toxicity, as well as possible therapeutic use.

Expert opinion: Acute MDMA effects are more pronounced in women than they are in men. Very limited data on the relationship between race-ethnicity and MDMA effects are available. MDMA metabolism includes some polymorphic enzymes that can slightly modify plasma concentrations and effects. Although a considerable number of studies exist about the acute effects of MDMA, the small number of subjects in each trial limits evaluation of the different interindividual factors and does not permit a clear conclusion about their influence. These issues should be considered when studying possible MDMA therapeutic use.”

Authors: E. Papaseit, M. Torrens, C. Pérez-Mañá, R. Muga & M. Farré

Summary

MDMA, 3,4-methylenedioxymethamphetamine, is a synthetic phenethylamine derivative that produces characteristic amphetamine-like actions (euphoria, well-being), increases empathy, and induces pro-social effects. It is used recreationally and may have potential therapeutic uses.

MDMA is a synthetic phenethylamine derivative with structural similarities to both amphetamines and mescaline. It was first developed in 1914 as a vasoconstrictor, but has since become one of the most popular psychostimulant street drugs. MDMA was included in Schedule I of the United Nations 1971 Convention on Psychotropic Substances in 1985, and since then has been continuously present on the illicit drug market. It has been newly established as one of the most widely used illicit drugs of abuse.

Recreational ecstasy users report euphoria and enhanced empathy and sociability as its main desirable effects. Controlled studies have shown that MDMA produces stimulant-like and empathogen effects, as well as sympathomimetic effects, including increased blood pressure, heart rate, temperature, mydriasis, and esophoria.

MDMA doses ranging from 26 to 465 ng/mL resulted in maximal plasma concentrations (Cmax) peaked at approximately 2 hours (Tmax), and a calculated elimination half-life (T1/2) of 8-9 hours.

MDMA is a worldwide recreational drug with a relatively low rate of morbidity- mortality, but a marked rise in acute toxicity presentations has been detected in recent years. This review article discusses the main interindividual determinants in MDMA pharmacodynamics by examining the most relevant studies conducted with healthy subjects and some cases of intoxication.

The results of the search demonstrated that MDMA acute pharmacological effects can be influenced by interindividual determinants and numerous environmental factors or interactions among these factors that might alter PK and/or PD (acute effects versus acute toxicity).

In double-blind, placebo-controlled within-subject studies, women experienced greater acute subjective effects than men, and they reported more frequently acute and sub-acute adverse effects than men. Men had higher cardiovascular and temperature responses with respect to women, and the most frequently acute adverse effects reported were sweating and nausea.

A pooled analysis of different double-blind sub-studies (MDMA dose 125 mg, 1.25 mg/kg) has recently been published that showed no gender differences in subjective or cardiovascular effects. In 2017, a pooled analysis of nine double-blind, placebo-controlled, crossover studies of MDMA was published. The results showed no gender differences in vital signs or adverse effects, but higher but not dose-dependent “bad drug effects” VAS ratings were found in women compared to men. Regarding recognition of emotions in terms of empathy and pro-sociability, two studies have focused on sex-gender differences. Both studies found that MDMA enhanced explicit and implicit emotional empathy and increased pro-social behaviour in men, but impaired the identification of negative emotions in women.

The Interpersonal Reactivity Index (IRI) showed that women have higher ratings in emotional empathy than men, and no effect of sex-gender on cognitive empathy. Pharmacokinetics of MDMA has been assessed in many studies including equal numbers of male and female subjects. There are some discrepancies in the results of studies, with women exhibiting higher MDMA concentrations than men at low doses and higher MDMA Cmax and longer half-life at high doses. Although there were no sex-gender differences in age or weight, there were PK differences in HMMA concentration between male and female subjects. The PK differences could be caused by differences in CYP2D6 and CYP1A2 activity. At the same absolute doses, women showed higher Cmax and AUC levels compared with men. This was explained by their lower body weight.

A key factor to consider with respect to sex-gender differences in women is the phase of the menstrual and oestrous cycles and the associated reproductive hormone release. Women are more sensitive to MDMA negative effects than men.

The terms ethnicity and race are used interchangeably, but have distinct definitions. Ethnicity and race may account for differences observed in the PK and PD of many drugs, resulting in drug response variability.

Only two double-blind controlled clinical trials have specifically compared MDMA PK parameters across racial/multiethnic groups. The results show that MDMA plasma concentrations are significantly greater in African-Americans compared to white and Hispanic/Latino subjects at a low dose, but no pharmacokinetic differences are observed at a higher dose.

  1. Genetic differences-Genetic polymorphisms

Cytochrome P450 isoenzymes catalyze phase I drug metabolism and are highly polymorphic. CYP450 isoenzymes have been identified as sources of variability in MDMA responses and the effect of CYP2D6 on MDMA PK has been documented quite well by different laboratories and in meaningful sample sizes.

The CYP2D6 isoenzyme is involved in the metabolism of numerous drugs, and has a large interindividual variation. The black population has a low representation in MDMA clinical trials.

A pooled analysis of eight controlled studies with a total of 139 individuals showed that PM individuals showed higher MDMA and MDA plasma concentrations, more rapid onset of increases in systolic blood pressure, and a higher score in psychotropic effects than IM and EM subjects. Results of gender differences in CYP2D6 activity are controversial. A higher metabolism of dextromethorphan was observed in EM women than EM men, and CYP1A2 is involved in only 2% of drug metabolism.

Genetic factors account for 75% of variation in CYP1A2 activity, with environmental factors such as smoking by induction making up the remaining difference. Women seem to have more CYP1A2 activity than men.

CYP2C19, CYP2B6, and CYP2D6 are involved in the metabolism of approximately 10-15% of drugs, respectively. CYP2B6 is highly polymorphic and subjects can be phenotypically categorized as UM, EM, IM, and PM, according to its functional alleles.

Catechol-O-methyltransferase (COMT) is an enzyme involved in the metabolism of catecholamines and oestrogens. Individuals with the met allele have a 3- to 4-fold lower enzyme activity, which leads to higher levels of extracellular dopamine and greater effects on blood pressure and subjective effects on MDMA.

The serotonin transporter (5-HTT) plays a key role in serotonin transmission. The long (l) allele is associated with a higher serotonin transporter mRNA transcription, whilst the short (s) allele causes lower transcription. Individuals with the G allele in the oxytocin receptor gene are more empathic, report more positive emotions and greater sociability, and are judged by others to be more social. The exogenous administration of oxytocin produces more social effects in carriers of the G allele.

Individuals with a PM CYP2D6 phenotype, 5-HTTLPR and/or COMT val158met and sex-gender are at increased risk of adverse MDMA reactions.

Multiple MDMA dose effects have been researched extensively. The most common pattern of ecstasy consumption is bingeing (repeated MDMA consumption), which can be achieved by taking several tablets simultaneously or at intervals over a time period.

The pharmacology of MDMA and its metabolites was studied in subjects with the CYP2D64/4 genotype. It was found that the pharmacology of MDMA was nonlinear and based on a mechanism-based inhibition of CYP2D6.

A single dose of MDMA (100 mg) changed the phenotype from EM/IM to PM. Two repeated doses of MDMA produced the same phenotype change, with an MDMA accumulation after the second dose.

After a second MDMA dose, plasma concentrations of MDMA and MDA were higher than expected, but HMMA and HMA concentrations were lower than expected. These effects were due to a non-linearity of MDMA PK and a CYP2D6 metabolic auto-inhibition that lasts over 24 h.

A double-blind placebo controlled study was performed in which 14 healthy poly-drug MDMA users received 75 plus 50 mg of MDMA separated in time by 4 hours. The results showed that MDMA impaired tracking performance and subjective effects increased during the night.

Acute MDMA/ecstasy toxicity can develop in some individuals, especially those who are of a particular predisposition or have coexistent medical conditions. These effects include loss of appetite, trismus, bruxism, nausea, muscle aches, stiffness, ataxia, blurred vision, increased sweating, anxiety, tachycardia, insomnia, and fatigue.

Recent data from over 50,000 self-declared ecstasy users estimated that 8% of all presentations involved ecstasy use. These presentations were associated with acute stimulant/sympathomimetic toxicity and hyperpyrexia.

The largest series of ecstasy-related deaths has outlined the main ecstasy user profile, with a mean age of 26 years, and a mean MDMA concentration of 8,430 ng/mL in direct fatal MDMA toxicity cases and 2,900 ng/mL in 22 cases of polydrug use and trauma.

Ecstasy use can cause cardiovascular dysfunction, neurological dysfunction, acute renal failure, subacute liver failure, and suicide. The most predominant toxicity pattern is hyperpyrexia/hyperthermia leading to disseminated intravascular coagulation, rhabdomyolysis, acute liver and renal failure, and hyponatraemic encephalopathy.

Like other drugs of abuse, MDMA is more frequently used in men than in women. However, women more frequently seek emergency treatment and reported more adverse acute effects compared to men, probably due to stronger acute and subacute MDMA effects experienced.

Several potential neuroendocrine gender differences have been investigated in human experimental studies with the aim of resolving the question of why female ecstasy intoxications typically present with hyponatremia. These differences include higher plasmatic copetine concentrations, more susceptibility to MDMA effects, and polymorphism differences in CYP2D6 and COMT. The concomitant use of ecstasy with other serotonergic substances can increase the risk of developing a serotonergic syndrome, and the use of CYP2D6 inhibitor drugs can exacerbate the potentially life-threatening toxic effects of MDMA. Women may be more susceptible to MDMA than men.

MDMA administration in healthy individuals results in a temporarily reduced sensitivity to threat-related stimuli, a decrease of fear and anxiety, and increased plasmatic concentrations of oxytocin, which contribute to enhanced acute pro-social effects.

Psychiatrists have used MDMA in combination with psychotherapy to treat post-traumatic stress disorder (PTSD), social anxiety in autistic adults, and anxiety associated with life-threatening illness.

MDMA-assisted psychotherapy in the treatment of resistant PTSD has been demonstrated in three double-blind, randomized, placebo-controlled Phase II clinical trials. These trials had distinctive features with respect to MDMA human pharmacology studies and other exposure-based therapies.

MDMA was administered as a single oral dose or two consecutive oral doses together with psychotherapist interventions to treat PTSD in women. The evidence suggests some benefits from the use of MDMA-assisted psychotherapies, mainly in female patients. Phase II studies are currently being conducted to determine the true effects of MDMA-assisted psychotherapy under PTSD conditions. However, key interindividual determinants as sex-gender, race-ethnicity, age, and potential drug interactions remain to be investigated.

Although MDMA has been used for recreational purposes and therapeutic purposes for almost 40 years, identification of interindividual determinants that are involved in MDMA acute effects and/or susceptibility to MDMA-related toxicity is still far from completion. There are numerous studies about the acute and chronic effects of MDMA in different animal species, most in rats and scarce in monkeys (baboons). Humans showed lower concentrations and a shorter elimination half-life of MDMA in comparison to rats and baboons. Most studies of the pharmacological and toxicological effects of MDMA have been done in male Sprague-Dawley rats. Female Dark Agouti rats show a significant reduction in MDA levels compared to males.

MDMA may cause long-term neurotoxic damage to 5-HT neurons in rats and monkeys, but not in recreational MDMA human users. The lack of significant results may be due to methodological heterogeneity, low quality of some studies and small sample sizes.

Although there is a considerable number of clinical trials in healthy recreational subjects about the acute effects of MDMA, the results are limited by the small number of subjects in each study and the lack of information about genetics, drug interactions, and plasma blood levels of MDMA. MDMA increases empathy and has prosocial effects. These effects are attributed to MDMA-induced oxytocin release. MDMA is being evaluated for its potential therapeutic use in PTSD. Phase III clinical trials are planned in the near future.

MDMA-assisted psychotherapy can be used to treat PTSD at any age. Future clinical trials should include measures of biomarkers and genetic traits to study the biological basis and differences in response.

Article highlights

MDMA effects are more pronounced in women than in men, and race-ethnicity is a factor in MDMA effects. The genetic polymorphism of metabolic CYP450 isoenzymes is also relevant for MDMA concentrations and acute effects.

MDMA holds promise in the treatment of PTSD, but further research is needed to ensure that MDMA-assisted psychotherapy is useful.

Funding

This paper was supported in part by grants from several organizations, including the Ministry of Health, Social Services and Igualdad.

Declaration of interest

The authors have no relevant affiliations with any organization that might have a financial interest in the subject matter discussed.

Study details

Compounds studied
MDMA

Topics studied
Safety

Study characteristics
Literature Review

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