MDMA

links: Drugs reference:

• Disposition of methylenedioxymethamphetamine and three metabolites in the brains of different rat strains and their possible roles in acute serotonin depletion 11-7-2021

MDMA #

• Reverses the direction of SERT, DAT, and NET. TAAR1 agonist. Weak MAO-I.
• Tryptophan Hydroxylase inhibitor!
• A big potential MOA for its toxicity is binding to - perhaps reversing VMAT2! Meaning, unloading vesicles inside of the neuron, whereby the monoamines leave via the reversed transporters, since I guess we don’t need vesicular transport where we’re going.
• MAO-B Mediates Ecstasy-Induced Neurotoxic Effects to Adolescent Rat Brain Mitochondria
  • Figure 4: enter Selegiline (2mg/kg = HED 22)
• Its Serotonin release is 5x that of dopamine in the frontal cortex R
• Hypothalamic-pituitary-adrenal axis responses to stress in subjects with 3,4-methylenedioxy-methamphetamine (’ecstasy’) use history: correlation with dopamine receptor sensitivity
• MDMA, cortisol, and heightened stress in recreational ecstasy users
  • In the laboratory, acute ecstasy/MDMA use can increase cortisol levels by 100-200%, whereas ecstasy/MDMA-using dance clubbers experience an 800% increase in cortisol levels, because of the combined effects of the stimulant drug and dancing
    • I mean, what’s the control for an equivalent level of activity?
• Blockade of nitric oxide signalling promotes resilience to the effects of social defeat stress on the conditioned rewarding properties of MDMA in mice
• Debunking the myth of ‘Blue Mondays’: No evidence of affect drop after taking clinical MDMA
• Involvement of nicotinic receptors in methamphetamine- and MDMA-induced neurotoxicity: pharmacological implications
  • α7 nAChR agonism exacerbates toxicity.
• Molecular and Cellular Mechanisms of Ecstasy-Induced Neurotoxicity: An Overview
  • S(+)-MDMA is psychostimulant, and R(-) is hallucinogenic.
  • 
    • Perhaps CYP2D6 is merely the preference, as CYP2B6 and CYP1A2 are able to substitute for it and demethyl(ene)ate.
    • So, HHMA is less toxic I believe. MDA is toxic, even moreso than MDMA! HHA (aka alpha-methyldopamine) is also neurotoxic.
      • Apparently MDA is quite minor in quantity compared to HHMA.
      • HHMA and HMMA don’t cross the blood brain barrier.
    • 3,4-Methylenedioxymethamphetamine induces monoamine release, but not toxicity, when administered centrally at a concentration occurring following a peripherally injected neurotoxic dose, so onto the liver: lower CYP2D6 would divert metabolism more cowards CYP3A4: CYP2D6 deficiency, a factor in ecstasy related deaths?
  • 5-HT2A antagonists significantly prevented MDMA-indyced hyperthermia.
• Molecular and Cellular Mechanisms of Ecstasy-Induced Neurotoxicity: An Overview
  • CYP2D6*4 associated with a lack of prolactin release seen in extensive metabolizers, and an increase in hyperthermia.
  • Thyroparathyroidectomized rats did not become hyperthermic and in fact displayed a significant hypothermia. UCP3 has an important role in the muscular thermogenesis from MDMA; female rats are less susceptible to hypothermia as they express less skeletal muscle UCP3.
  • Serotonin syndrome/5-HT behavioral syndrome: enhanced locomotor activity, reciprocal forepaw treading, head weaving, piloerection,m hind limb abduction, poptosis, ataxia, penile erection, ejaculation, salivation, defecation, subsequent dose-dependent convulsions, and possible death.
• Evidence for a role of energy dysregulation in the MDMA-induced depletion of brain 5-HT
  • Depletes striatal ATP. So, ameliorate with niacinamide, and therefore maybe other B vitamins. CoQ10.
• Role of brain nitric oxide in (±)3,4-methylenedioxymethamphetamine (MDMA)-induced neurotoxicity in rats
  • l-NOARG pretreatment caused significant inhibition of brain NOS activity but did not affect the acute 5-HT and (DA) changes or the hyperthermia induced by MDMA. Partially protected against mf 40 mg/kg long-term 5-HT depletion though.
• MDMA-induced neurotoxicity: long-term effects on 5-HT biosynthesis and the influence of ambient temperature
  • (140mg HED)
• Beyond ecstasy: Alternative entactogens to 3,4-methylenedioxymethamphetamine with potential applications in psychotherapy
• Causes ’emotional tracers’ in the QRI model. https://twitter.com/algekalipso/status/1740883429808554291 People with Asperger’s/ASD say it allows ’translation’ of thoughts→emotions→words. And it sounds like he’s talking about global hypoconnectivity: Without a certain threshold of emotional depth, it’s as if parts of your being don’t have the ability to spread what they know or have noticed to the rest of your parts. There’s a missing vibrational currency that allows such a sync up.

Neurotoxicity #

• [Neurotoxicity of MDMA: Main effects and mechanisms]
• [Methylenedioxyamphetamine (MDA) and methylenedioxymethamphetamine (MDMA) cause selective ablation of serotonergic axon terminals in forebrain: immunocytochemical evidence for neurotoxicity]
• [Demonstration and localization of neuronal degeneration in the rat forebrain following a single exposure to MDMA]
• [MDMA-induced neurotoxicity: long-term effects on 5-HT biosynthesis and the influence of ambient temperature]
• [Altered Serotonin Innervation Patterns in the Forebrain of Monkeys Treated with (±)3,4-Methylenedioxymethamphetamine Seven Years Previously: Factors Influencing Abnormal Recovery]
• [Studies of (±)-3,4-Methylenedioxymethamphetamine (MDMA) Metabolism and Disposition in Rats and Mice: Relationship to Neuroprotection and Neurotoxicity Profile](Studies of (±)-3,4-Methylenedioxymethamphetamine (MDMA) Metabolism and Disposition in Rats and Mice: Relationship to Neuroprotection and Neurotoxicity Profile)

Dose #

• 
• Most sources say 120 max at ~1.5 mg/kg.
• There is a rationale in taking a second smaller dose of half the initial dose, 2 hours after the initial one, or whenever the peak is.
• 3-6 hour duration.
• https://elevationchemicals.com/product/marquis-reagent-testing-kit/?sca_ref=461.8R2CEt6Fzn
• Antioxidants like Vitamin E, vitamin C.