Mini-Review
How MDMA’s Pharmacology and Pharmacokinetics Drive Desired Effects and Harms
The Journal of Clinical Pharmacology 54(3) 245–252 © 2014, The American College of Clinical Pharmacology DOI: 10.1002/jcph.266
C. Michael White, PharmD., FCP, FCCP†
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.
Keywords MDMA, molly, ecstasy, hyponatremia, hyperpyrexia, rhabdomyolysis
R- and S-enantiomer 3,4-methylenedioxymethamphetamine (MDMA) is a commonly used illicit drug and is the sole or one of the ingredients in ecstasy or molly.1 It was synthesized and patented by Merck in 1912 but not originally intended for human consumption (it was made as a precursor in a new synthesis process for hemostatic substances). It was tested in animal and interrogation enhancement studies by the United States (US) military starting in the 1950s.1 In 1976, MDMA was starting to be used in some psychiatric clinics but in 1985, the Drug Enforcement Agency labeled it a Schedule I drug (no approved medical use, high abuse potential, illegal to possess).2 It has been preliminarily explored to enhance psychotherapy success of post-traumatic stress disorder since that time but due to its drug scheduling, this is difficult to conduct.3 MDMA use is engrained in the electronic dance music scene in Europe and the US. It is commonly consumed on weekends in warm crowded environments and combined with dancing.1 In this manuscript we will review the prevalence of MDMA use and adverse events, the pharmacology underlying desired and adverse physiologic effects, its unique pharmacokinetic and drug interaction profile, and treatment and risk reduction strategies.
Prevalence of Use and Adverse Events In the mid to late 1980s ecstasy was being used as a recreational drug across Europe.1 In 2009, 11 million Europeans (3.3% of European adults) reported use in their
lifetime and 2.5 million used it in the past year.4 While use in the US was limited in the 1980s, use rose precipitously from the mid-1990s to today. In 1997, 400,000 ecstasy tablets were seized by US customs but this figure jumped to well over 9 million tablets in the year 2000.2 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.5 The number of new annual MDMA users increased from 615,000 in 2005 to 869,000 in 2012.5 MDMA use among children 12–17 increased from 1.9% in 1999 to 2.2% in 2008.6 Female children are significantly more likely to take MDMA than males (1.8% vs. 2.6%, P ¼ 0.02 in 2008) and African Americans are significantly less likely than Caucasians or Latinos to use
University of Connecticut and Hartford Hospital, Hartford, CT, USA Submitted for publication 5 December 2013; accepted 8 January 2014. Corresponding Author: C. Michael White, Pharm.D., FCP, FCCP, University of Connecticut and Hartford Hospital, 80 Seymour Street, Hartford, CT 06102– 5037, USA Email: [email protected] † Professor and Chair Pharmacy Practice, University of Connecticut, Co-Director, HOPE Collaborative Group
246 MDMA (0.84% vs. 2.47 and 2.45%, respectively, P < 0.001). Household income is not related to MDMA use among children.6 While MDMA is common agent of abuse, the risk of serious adverse events is lower than other illicit agents.7–9 According to the United Nations, in 2008 the annual prevalence of using drugs of abuse in the US was 10.3% for marijuana, 4.8% for opioid pain relievers, 2.1% for cocaine, 0.9% for MDMA, and 0.2% for heroin.7 The US Substance Abuse and Mental Health Services Administration evaluated emergency room visits due to illicit drugs in 2001 and reported 5,542 emergency department visits due to MDMA, 193,043 due to cocaine, 110,512 due to marijuana, 93,064 due to heroin, and 18,555 due to other amphetamine like products.8 The risk of death from each single use of MDMA has been estimated between 1 in 20,000 and 1 in 50,000.9 The risk of adverse events for a single tablet or powder packet of MDMA is not a precise science due to the inability to assure purity, potency, unadulteration, and stability of products.10 In the 1980s and early 1990s, MDMA tablets were seldom contaminated with other substances of abuse although the dose of MDMA was
The Journal of Clinical Pharmacology / Vol 54 No 3 (2014)
variable. 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. From the late 1990s to today, 80–90% of the tablets sold as MDMA contain MDMA although the doses in tablets are highly variable. In assessments of single MDMA doses (packets of powder, tablets), most products contained 73–89 mg of MDMA but the range went from 20 mg up to 152 mg MDMA. Without disclosure of how much MDMA exists in the products, it is easy to make wrong assumptions as to the ingested amount. Ingested MDMA dosage is a prime factor in determining the risk of adverse events.1,4,10
Pharmacologic Rationale for Physiologic Responses MDMA is structurally related to amphetamines and hallucinogenic compounds such as mescaline and catinone.1 Figure 1 is an analytic framework that ties together intermediate and final health outcomes associated with MDMA use and the underlying mechanism of action.1,2,4,9,11–27
Figure 1. Pharmacology underlying benefits and risks of MDMA.1,4,9,11–27 This analytic framework figure initiates with MDMA ingestion and metabolite formation and follows through the desired and adverse effects of MDMA. Unshaded boxes represent pharmacologic or intermediate health effects, lightly shaded boxes are the desired effects, and dark shaded boxes are adverse final health outcomes. 5-HT, serotonin; ADH, antidiuretic hormone; BP, blood pressure; DIC, disseminated intravascular coagulopathy; HR, heart rate; MDMA, 3,4-methylenedioxymethamphetamine; MDA, 3,4-methylenedioxyamphetamine; HHMA, 3,4-dihydroxymethamphetamine; HHA, 3,4-dihydroxyamphetamine; HMMA, 4-hydroxy-3methoxymethamphetamine; HMA, 4-hydroxy-3-methoxyamphetamine; HPAG, Hypothalamic, pituitary, adrenal, gonadal; QTc, Corrected QT interval; STD, sexually transmitted disease.
White
Desirable Effects of MDMA MDMA interacts with monoamine transporters to stimulate non-exocytotic release of serotonin, dopamine, and norepinephrine in the brain.1 The 3,4-methylenedioxy aspect of MDMA causes 10-fold greater serotonin release and 6-fold lesser effects on dopamine than methamphetamine.1 This causes an elevation of mood and increased energy while also causing the secretion of numerous hormones including cortisol, oxytocin, and antidiuretic hormone.1,4,11–18 Presumably, MDMA-induced cortisol elevations enhance the feeling of increased energy and lack of fatigue.13 Cortisol concentrations significantly increase by 100–150% from baseline levels with MDMA ingestions of 0.5 and 1.5 mg/kg of body weight in the absence of physical exertion.13 When combined with hot temperatures and physical exertion while dancing, cortisol concentrations significantly increase by 800% and maximal increases usually occur around 2–4 hours after ingestion.14,15 MDMA increases the desire to interact and bond with other people due to an outflow of oxytocin.16 In one study of 15 subjects, the administration of 100 mg of MDMAinduced an increase in oxytocin from 0.8 (SEM 0.3) pmol/L at baseline to a maximum of 34.3 (SEM 7.2) pmol/L at 110 minutes post-ingestion and then decreased to 4.0 (SEM 0.8) pmol/L by 300 minutes post-ingestion. Patient amicability was correlated with oxytocin concentrations over the 300 minutes.17 Oxytocin release is predominantly due to direct and indirect 5-HT 1 A stimulation in the hypothalamus and the outflow is greater in high ambient temperatures like exist at raves (high energy, all-night dances that feature hard pounding techno-music and flashing laser lights) and nightclubs.18 The hallucinogenic effects of MDMA are due to direct 5-HT (serotonin) 2 A receptor stimulation, likely through the 3,4-methylenedioxy ring.1 People on MDMA report being able to feel the music and better appreciate light show sensations. Negative Effects of MDMA The main adverse events associated with MDMA are clear extensions of the desirable effects of MDMA (Figure 1).1,4,11–18 While most people derive a raised mood, increased energy, and pleasant visual hallucinations from MDMA; anxiety and panic attacks have been reported.1,4,9 The panic attacks usually resolve within a few hours but in rare case they have persisted for several months.9 Hyperpyrexia resulting in rhabdomyolysis or heat stroke has occurred due to serotonin syndrome or enhanced physical activity without recognizing clinical clues of overexertion, warm temperatures in the clubs, and dehydration.1,4,9 Rhabdomyolysis can be profound with peak creatinine kinase levels around 30,000 or even up
247 to 100,000 m/L.9 There have been numerous placebo controlled studies evaluating body temperature conducted in the controlled settings without exercise. The totality of the evidence suggests a dose related increase in body temperature with doses of 0.25–1.0, 1.5–1.7, and 2.0 mg/kg inducing temperature changes of 0.1 to þ0.3 °C, þ0.3 to þ0.5 °C, and þ0.4 to þ2.0 °C, respectively.19 In serotonin syndrome, several signs and symptoms coalesce including confusion, diaphoresis, muscle rigidity, shivering, tremor, heightened deep tendon reflexes, and myoclonus. Hyponatremia can occur from free water uptake in the collecting tubules secondary to the ADH effects and from over consumption of water to prevent dehydration and overheating. Dilutional hyponatremia can induce mental status changes and as a result of cerebral edema, can induce seizures and coma.1,4,9 As an extension of the desired bonding and enhanced socialization effects of MDMA, people may make choices about whether to engage in sex or to take other substances of abuse that they would not have otherwise.20 This can open them up for a host of adverse effects like developing sexually transmitted diseases or prolonged feelings of guilt over those choices. In Ontario Canada, investigators determined whether people suspecting they were sexually assaulted were covertly drugged.21 Drugs found on toxicological screening that were not known to have been consumed occurred in 64.4% of the 135 cases [MDMA (9.2%), cannabis (40.2%), cocaine (32.2%), amphetamines (13.8%), ketamine (2.3%), and GHB (1.1%)]. Male DNA was found vaginally or anally in 46.9% of cases where unexpected drugs were found which shows the increased risk of unprotected sexual contact after drugging.21 There is a tendency for short term memory loss with MDMA use as a result of elevations in cortisol and oxytocin concentrations and distractions arising from the psychedelic effects of the drug.1,4,9,20 Oxytocin increases facial recognition ability and interpersonal memories but suppresses retention of other memories.16,18 In addition, the neurotoxic effects of MDMA’s active metabolites HHA and HHMA can negatively impact neuronal function over the short and long term.1,4,9 HHA and HHMA active metabolites can induce liver injury as well.4 Liver injury via this mechanism is reminiscent of acute cholestatic hepatitis.9 The presence of eosinophils and histocytes as well as evidence of recurrence upon subsequent MDMA exposure supports a hypersensitivity reaction etiology. Patients commonly present with jaundice, abdominal pain, and raised liver transaminases. Hepatic injury can also occur secondary to hyperpyrexia with centrilobular necrosis and microvascular steatosis. In an evaluation conducted in 1998, MDMA use caused 36% of all non-viral liver failure in patients
How MDMA’s Pharmacology and Pharmacokinetics Drive Desired Effects and Harms
The Journal of Clinical Pharmacology 54(3) 245–252 © 2014, The American College of Clinical Pharmacology DOI: 10.1002/jcph.266
C. Michael White, PharmD., FCP, FCCP†
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.
Keywords MDMA, molly, ecstasy, hyponatremia, hyperpyrexia, rhabdomyolysis
R- and S-enantiomer 3,4-methylenedioxymethamphetamine (MDMA) is a commonly used illicit drug and is the sole or one of the ingredients in ecstasy or molly.1 It was synthesized and patented by Merck in 1912 but not originally intended for human consumption (it was made as a precursor in a new synthesis process for hemostatic substances). It was tested in animal and interrogation enhancement studies by the United States (US) military starting in the 1950s.1 In 1976, MDMA was starting to be used in some psychiatric clinics but in 1985, the Drug Enforcement Agency labeled it a Schedule I drug (no approved medical use, high abuse potential, illegal to possess).2 It has been preliminarily explored to enhance psychotherapy success of post-traumatic stress disorder since that time but due to its drug scheduling, this is difficult to conduct.3 MDMA use is engrained in the electronic dance music scene in Europe and the US. It is commonly consumed on weekends in warm crowded environments and combined with dancing.1 In this manuscript we will review the prevalence of MDMA use and adverse events, the pharmacology underlying desired and adverse physiologic effects, its unique pharmacokinetic and drug interaction profile, and treatment and risk reduction strategies.
Prevalence of Use and Adverse Events In the mid to late 1980s ecstasy was being used as a recreational drug across Europe.1 In 2009, 11 million Europeans (3.3% of European adults) reported use in their
lifetime and 2.5 million used it in the past year.4 While use in the US was limited in the 1980s, use rose precipitously from the mid-1990s to today. In 1997, 400,000 ecstasy tablets were seized by US customs but this figure jumped to well over 9 million tablets in the year 2000.2 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.5 The number of new annual MDMA users increased from 615,000 in 2005 to 869,000 in 2012.5 MDMA use among children 12–17 increased from 1.9% in 1999 to 2.2% in 2008.6 Female children are significantly more likely to take MDMA than males (1.8% vs. 2.6%, P ¼ 0.02 in 2008) and African Americans are significantly less likely than Caucasians or Latinos to use
University of Connecticut and Hartford Hospital, Hartford, CT, USA Submitted for publication 5 December 2013; accepted 8 January 2014. Corresponding Author: C. Michael White, Pharm.D., FCP, FCCP, University of Connecticut and Hartford Hospital, 80 Seymour Street, Hartford, CT 06102– 5037, USA Email: [email protected] † Professor and Chair Pharmacy Practice, University of Connecticut, Co-Director, HOPE Collaborative Group
246 MDMA (0.84% vs. 2.47 and 2.45%, respectively, P < 0.001). Household income is not related to MDMA use among children.6 While MDMA is common agent of abuse, the risk of serious adverse events is lower than other illicit agents.7–9 According to the United Nations, in 2008 the annual prevalence of using drugs of abuse in the US was 10.3% for marijuana, 4.8% for opioid pain relievers, 2.1% for cocaine, 0.9% for MDMA, and 0.2% for heroin.7 The US Substance Abuse and Mental Health Services Administration evaluated emergency room visits due to illicit drugs in 2001 and reported 5,542 emergency department visits due to MDMA, 193,043 due to cocaine, 110,512 due to marijuana, 93,064 due to heroin, and 18,555 due to other amphetamine like products.8 The risk of death from each single use of MDMA has been estimated between 1 in 20,000 and 1 in 50,000.9 The risk of adverse events for a single tablet or powder packet of MDMA is not a precise science due to the inability to assure purity, potency, unadulteration, and stability of products.10 In the 1980s and early 1990s, MDMA tablets were seldom contaminated with other substances of abuse although the dose of MDMA was
The Journal of Clinical Pharmacology / Vol 54 No 3 (2014)
variable. 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. From the late 1990s to today, 80–90% of the tablets sold as MDMA contain MDMA although the doses in tablets are highly variable. In assessments of single MDMA doses (packets of powder, tablets), most products contained 73–89 mg of MDMA but the range went from 20 mg up to 152 mg MDMA. Without disclosure of how much MDMA exists in the products, it is easy to make wrong assumptions as to the ingested amount. Ingested MDMA dosage is a prime factor in determining the risk of adverse events.1,4,10
Pharmacologic Rationale for Physiologic Responses MDMA is structurally related to amphetamines and hallucinogenic compounds such as mescaline and catinone.1 Figure 1 is an analytic framework that ties together intermediate and final health outcomes associated with MDMA use and the underlying mechanism of action.1,2,4,9,11–27
Figure 1. Pharmacology underlying benefits and risks of MDMA.1,4,9,11–27 This analytic framework figure initiates with MDMA ingestion and metabolite formation and follows through the desired and adverse effects of MDMA. Unshaded boxes represent pharmacologic or intermediate health effects, lightly shaded boxes are the desired effects, and dark shaded boxes are adverse final health outcomes. 5-HT, serotonin; ADH, antidiuretic hormone; BP, blood pressure; DIC, disseminated intravascular coagulopathy; HR, heart rate; MDMA, 3,4-methylenedioxymethamphetamine; MDA, 3,4-methylenedioxyamphetamine; HHMA, 3,4-dihydroxymethamphetamine; HHA, 3,4-dihydroxyamphetamine; HMMA, 4-hydroxy-3methoxymethamphetamine; HMA, 4-hydroxy-3-methoxyamphetamine; HPAG, Hypothalamic, pituitary, adrenal, gonadal; QTc, Corrected QT interval; STD, sexually transmitted disease.
White
Desirable Effects of MDMA MDMA interacts with monoamine transporters to stimulate non-exocytotic release of serotonin, dopamine, and norepinephrine in the brain.1 The 3,4-methylenedioxy aspect of MDMA causes 10-fold greater serotonin release and 6-fold lesser effects on dopamine than methamphetamine.1 This causes an elevation of mood and increased energy while also causing the secretion of numerous hormones including cortisol, oxytocin, and antidiuretic hormone.1,4,11–18 Presumably, MDMA-induced cortisol elevations enhance the feeling of increased energy and lack of fatigue.13 Cortisol concentrations significantly increase by 100–150% from baseline levels with MDMA ingestions of 0.5 and 1.5 mg/kg of body weight in the absence of physical exertion.13 When combined with hot temperatures and physical exertion while dancing, cortisol concentrations significantly increase by 800% and maximal increases usually occur around 2–4 hours after ingestion.14,15 MDMA increases the desire to interact and bond with other people due to an outflow of oxytocin.16 In one study of 15 subjects, the administration of 100 mg of MDMAinduced an increase in oxytocin from 0.8 (SEM 0.3) pmol/L at baseline to a maximum of 34.3 (SEM 7.2) pmol/L at 110 minutes post-ingestion and then decreased to 4.0 (SEM 0.8) pmol/L by 300 minutes post-ingestion. Patient amicability was correlated with oxytocin concentrations over the 300 minutes.17 Oxytocin release is predominantly due to direct and indirect 5-HT 1 A stimulation in the hypothalamus and the outflow is greater in high ambient temperatures like exist at raves (high energy, all-night dances that feature hard pounding techno-music and flashing laser lights) and nightclubs.18 The hallucinogenic effects of MDMA are due to direct 5-HT (serotonin) 2 A receptor stimulation, likely through the 3,4-methylenedioxy ring.1 People on MDMA report being able to feel the music and better appreciate light show sensations. Negative Effects of MDMA The main adverse events associated with MDMA are clear extensions of the desirable effects of MDMA (Figure 1).1,4,11–18 While most people derive a raised mood, increased energy, and pleasant visual hallucinations from MDMA; anxiety and panic attacks have been reported.1,4,9 The panic attacks usually resolve within a few hours but in rare case they have persisted for several months.9 Hyperpyrexia resulting in rhabdomyolysis or heat stroke has occurred due to serotonin syndrome or enhanced physical activity without recognizing clinical clues of overexertion, warm temperatures in the clubs, and dehydration.1,4,9 Rhabdomyolysis can be profound with peak creatinine kinase levels around 30,000 or even up
247 to 100,000 m/L.9 There have been numerous placebo controlled studies evaluating body temperature conducted in the controlled settings without exercise. The totality of the evidence suggests a dose related increase in body temperature with doses of 0.25–1.0, 1.5–1.7, and 2.0 mg/kg inducing temperature changes of 0.1 to þ0.3 °C, þ0.3 to þ0.5 °C, and þ0.4 to þ2.0 °C, respectively.19 In serotonin syndrome, several signs and symptoms coalesce including confusion, diaphoresis, muscle rigidity, shivering, tremor, heightened deep tendon reflexes, and myoclonus. Hyponatremia can occur from free water uptake in the collecting tubules secondary to the ADH effects and from over consumption of water to prevent dehydration and overheating. Dilutional hyponatremia can induce mental status changes and as a result of cerebral edema, can induce seizures and coma.1,4,9 As an extension of the desired bonding and enhanced socialization effects of MDMA, people may make choices about whether to engage in sex or to take other substances of abuse that they would not have otherwise.20 This can open them up for a host of adverse effects like developing sexually transmitted diseases or prolonged feelings of guilt over those choices. In Ontario Canada, investigators determined whether people suspecting they were sexually assaulted were covertly drugged.21 Drugs found on toxicological screening that were not known to have been consumed occurred in 64.4% of the 135 cases [MDMA (9.2%), cannabis (40.2%), cocaine (32.2%), amphetamines (13.8%), ketamine (2.3%), and GHB (1.1%)]. Male DNA was found vaginally or anally in 46.9% of cases where unexpected drugs were found which shows the increased risk of unprotected sexual contact after drugging.21 There is a tendency for short term memory loss with MDMA use as a result of elevations in cortisol and oxytocin concentrations and distractions arising from the psychedelic effects of the drug.1,4,9,20 Oxytocin increases facial recognition ability and interpersonal memories but suppresses retention of other memories.16,18 In addition, the neurotoxic effects of MDMA’s active metabolites HHA and HHMA can negatively impact neuronal function over the short and long term.1,4,9 HHA and HHMA active metabolites can induce liver injury as well.4 Liver injury via this mechanism is reminiscent of acute cholestatic hepatitis.9 The presence of eosinophils and histocytes as well as evidence of recurrence upon subsequent MDMA exposure supports a hypersensitivity reaction etiology. Patients commonly present with jaundice, abdominal pain, and raised liver transaminases. Hepatic injury can also occur secondary to hyperpyrexia with centrilobular necrosis and microvascular steatosis. In an evaluation conducted in 1998, MDMA use caused 36% of all non-viral liver failure in patients
