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Methylenedioxymetamfetamine

Methylenedioxymetamfetamine

From drugs of abuse

These are agents like methylenedioxymetamfetamine (MDMA) and para-methoxyamfetamine (PMA) that, despite sharing chemical similarities to amfetamines have significantly different effects on their users. MDMA is the third most popularly-used illicit drug in the U.S.A., after cannabis and cocaine (Australian statistics are more difficult to come by).[1] Every member of this class is illicit in Australia and most other developed countries, except for select research purposes. They are called EEs as they are believed to increase one’s capacity for empathy for another person. Currently, in every developed country on Earth MDMA is illegal to possess and distribute, except for specific research purposes. For instance, in Australia it is a schedule 9 substance.

Mechanism of actionEdit

MDMA and other empathogens-entactogens (EPET) acts predominantly on serotonin, that is, it causes the cascading release of serotonin, not dopamine or noradrenaline, as its chief effect. It achieves this by activating TAAR1 and inhibiting VMAT2. Although I should mention that it does have some, relatively weak, actions on dopamine release.[2]

Short-term effectsEdit

The onset of MDMA’s effects is usually seen within 30-60 minutes of ingestion and last 4-6 hours. The short-term effects of lower doses of MDMA include: an increased sense of energy, high heart rate, dry mouth, jaw clenching, muscular aches, altered sense of time and pleasant sensory perceptions (like changes in how things appear or sound). Higher doses may cause visual hallucinations (seeing things that are not real), agitation, high body temperature (even to the point of irreversible brain damage and death) and panic attacks.[1]:665 It was first synthesised in 1912 by a German chemist. It could cause kidney damage, via rhabdomyolysis.[3]

Long-term consequences of useEdit

There is evidence of neurological deficits (including increased susceptibility to psychiatric and/or behavioural disturbances, along with impaired cognition, etc.) that result from repeated MDMA use, along with the finding that people that have used the drug have lower levels of 5-HIAA and other metabolites of serotonin in their cerebrospinal fluid, potentially indicating that their serotonergic neurons have been damaged by the drug. After a dose of MDMA is taken reserves of 5-HT are depleted in the brain, hence suggesting some of the adverse after-effects of MDMA.[4] There is also some evidence for the potential for irreversible neurological harm to the fetus when MDMA is taken by the mother during pregnancy. It is this irreversible brain damage is due to the fact that MDMA causes a lot of oxidative stress in the brain, which is the production of free radicals that react with proteins and DNA, causing damage. Consequently, it is theoretically possible that taking antioxidants like vitamin C might mitigate this potential damage. In mice, Δ9-tetrahydrocannabinol (THC) partially protected against MDMA-induced neurotoxicity, 5-HT depletion and hyperthermia, although it is worth noting this is in rats and hence whether or not this can be generalised to humans is a matter of debate.[5]

Therapeutic useEdit

There is currently just one area of active research that is incorporating MDMA – the treatment of treatment-resistant cases of post-traumatic stress disorder (PTSD). See MDMA is known to reduce fear, which is often a big problem during “exposure therapy” which is basically where psychologists force PTSD sufferers to relive their PTSD-invoking event(s) such as a battle scenario or a sexual assault. As it artificially relieves these fears it better enables people to complete these sessions and get the best possible result.[1]:665[6][7]

Users often report feeling drained, depressed and/or anxious after MDMA’s effects have worn off and they often say it is because they are “zapped” of serotonin as it was overly-released during MDMA use.[1] It is particularly common in the club scene.[1]

PharmacokineticsEdit

It is metabolized predominantly by CYP2D6, an enzyme found in the liver that is under- or over- active in a relatively high proportion of the population (>10%). People with an over-supply of CYP2D6 in their livers will likely experience less of an effect out of MDMA, whereas a deficiency of CYP2D6 will likely lead to an increased potential for serious adverse effects from MDMA use. Its major ill effects include: seizures, hyperthermia, coagulopathies (especially DIC), arrhythmias, heart failure, stroke, cerebral oedema, dehydration, hyponatraemia and kidney and/or liver failure.[8]

The risks (especially cardiovascular and temperature-related complications) associated with MDMA are significantly increased by concomitant use of caffeine.[9]

Para-methoxymethamfetamine (PMA)Edit

PMA, also known as 4-methoxymethamfetamine is unique among amfetamine-type stimulants in that it generally produces minimal psychoactive effects, but rather causes increases in body temperature, which can get to fatal levels if used to excess. Tragically PMA was associated with a few deaths in the U.S. and Canada, as its sulfate and hydrochloride salts, respectively, when recreational drug users came across research that indicated that in rats PMA produced more profound effects than MDMA.[10] It is worth noting, that as with thalidomide, animal studies were inaccurate models of humans; in humans its effects are virtually non-existent until you overdose. Most of these deaths were due to this increase in body temperature typical of the drug. It can also cause a rise in blood pressure. It is often sold alongside MDMA, including in tablets that are sold as MDMA.[11]

Reference listEdit

  1. 1.0 1.1 1.2 1.3 1.4 Brunton, LL; Chabner, BA; Knollmann, BC, eds. (2010). Goodman & Gilman's Pharmacological Basis of Therapeutics. (12th ed.). New York, USA: McGraw-Hill Professional. ISBN 978-0-07-162442-8.
  2. Parrott, AC (July 2013). "Human psychobiology of MDMA or 'Ecstasy': an overview of 25 years of empirical research.". Human psychopharmacology 28 (4): 289–307. doi:10.1002/hup.2318. PMID 23881877.
  3. Campbell, GA; Rosner, MH (November 2008). "The agony of ecstasy: MDMA (3,4-methylenedioxymethamphetamine) and the kidney.". Clinical Journal of the American Society of Nephrology 3 (6): 1852–60. doi:10.2215/CJN.02080508. PMID 18684895.
  4. Benningfield, MM; Cowan, RL (January 2013). "Brain serotonin function in MDMA (ecstasy) users: evidence for persisting neurotoxicity.". Neuropsychopharmacology 38 (1): 253–5. doi:10.1038/npp.2012.178. PMC 3671996. PMID 23147495.
  5. Morley, KC; Li, KM; Hunt, GE; Mallet, PE; McGregor, IS (June 2004). "Cannabinoids prevent the acute hyperthermia and partially protect against the 5-HT depleting effects of MDMA ("Ecstasy") in rats.". Neuropharmacology 46 (7): 954–65. doi:10.1016/j.neuropharm.2004.01.002. PMID 15081792.
  6. Stein, DJ; Ipser, JC; Seedat, S (January 2006). "Pharmacotherapy for post traumatic stress disorder (PTSD).". The Cochrane Database of Systematic Reviews (1): CD002795. doi:10.1002/14651858.CD002795.pub2. PMID 16437445.
  7. White, CM (April 2014). "3,4-Methylenedioxymethamphetamine's (MDMA's) Impact on Posttraumatic Stress Disorder.". The Annals of Pharmacotherapy 48 (7): 908–915. doi:10.1177/1060028014532236. PMID 24740469.
  8. Brayfield, A, ed. (10 October 2011). "Methylenedioxymethamfetamine". Martindale: The Complete Drug Reference. London, UK: Pharmaceutical Press. Retrieved 25 July 2014.
  9. Vanattou-Saïfoudine, N; McNamara, R; Harkin, A (November 2012). "Caffeine provokes adverse interactions with 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') and related psychostimulants: mechanisms and mediators.". British Journal of Pharmacology 167 (5): 946–59. doi:10.1111/j.1476-5381.2012.02065.x. PMC 3492978. PMID 22671762.
  10. Refstad, S (November 2003). "Paramethoxyamphetamine (PMA) poisoning; a 'party drug' with lethal effects.". Acta Anaesthesiologica Scandinavica 47 (10): 1298–9. doi:10.1046/j.1399-6576.2003.00245.x. PMID 14616331.
  11. Kraner, JC; McCoy, DJ; Evans, MA; Evans, LE; Sweeney, BJ (October 2001). "Fatalities caused by the MDMA-related drug paramethoxyamphetamine (PMA).". Journal of Analytical Toxicology 25 (7): 645–8. doi:10.1093/jat/25.7.645. PMID 11599617.

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