amphetamines and related psychostimulant substances

see also:

• sympathomimetics;
• drug dependency;
• Mx of toxicity from amphetamines and related substances
• intravenous drug users (IVDU) or injection drug use (IDU)

• Chinese use stimulant ephedra (ma huang) containing the alkaloids ephedrine & pseudoephedrine for over 5000yrs to Rx asthma & URTI.
• amphetamine 1st synthesised in Germany in 1887 but not used clinically until 1920's following reduced availability of ephedrine to Rx asthma.
• discovery of dextroamphetamine and metamphetamine / meth / ice soon followed.
• nasal decongestant containing amphetamine marketed in 1932, but widespread abuse led to FDA banning amphetamine inhalers in 1959.
• amphetamines were widely used as stimulants during World War II for a variety of conditions including hypotension & obesity.
• passage of Controlled Substance Act in US in 1970 reduced rates of amphetamine abuse.
• 'designer' amphetamines created in 1980's for illicit recreational use including the more serotoninergic MDMA (Ecstasy).
• resurgence of metamphetamine abuse due to production of high purity formulation known as 'ice'.
• the rave scene of the 1990's brought widespread use of MDMA and ice to Europe, North America, and Australasia.
  • in Australia, use of amphetamines is ~2.9% of 15-64 yr olds, with lifetime use ~7.7% amongst men and ~4.9% amongst women (although lifetime rates in NZ in 2004 were reported at 9%)
• production of similar piperazine family drugs such as BZP (became a restricted substance in 2008) followed.
  • although BZP and TFMPP are not strictly amphetamines, BZP has actions similar to amphetamine while TFMPP is more similar to MDMA.
• 4-Bromo-2,5-dimethoxyamphetamine (2CB, MFT, “Nexus”) is a rave drug which produces relaxation, euphoria and altered perception but also severe arterial spasm which has resulted in report on one limb requiring amputation.
• medicinal amphetamines may be abused:
  • methylphenidate used in Rx of ADHD
  • phentermine used in Rx of obesity

• amphetamines are derived from the CNS stimulants, phenylethylamines, and have structural similarities to adrenaline.
• metamphetamine is easily made (although risk of explosions in home labs) through reduction of ephedrine or pseudoephedrine (hence limited OTC availability of these).
• they are lipophilic weak bases with large Vd & not readily metabolised by MAO or COMT, thus have long durations of actions.
• eliminated by hepatic biotransformation & urine pH-dependent renal excretion.
• amphetamines and trace amines bind to the trace amine-associated receptor 1 (TAAR1), an intracellular amine-activated Gs-coupled and Gq-coupled G protein-coupled receptor (GPCR)
  • TAAR1 plays a significant role in regulating neurotransmission in dopamine, norepinephrine, and serotonin neurons in the CNS, and also affects immune system and neuroimmune system function through different mechanisms
  • it increases cAMP in the presynaptic cell via Gαs G-protein activation of adenylyl cyclase
  • monoamine autoreceptors (e.g., D2 short, presynaptic α2, and presynaptic 5-HT1A) have the opposite effect of TAAR1, and together these receptors provide a regulatory system for monoamines
    • amphetamine and trace amines possess high binding affinities for TAAR1, but not for monoamine autoreceptors
    • monoamine oxidase inhibitors (MAOIs) increase the concentration of trace amines
  • primary endogenous ligands of TAAR1 ranked by potency are tyramine > β-phenethylamine > dopamine = octopamine
  • low CNS phenylethylamine (PEA) levels and under-activation of TAAR1 appears to be associated with major depressive illnesses and also ADHD.
  • high CNS PEA levels and over-activation of TAAR1 due to decreased PEA metabolism has been linked to schizophrenia
  • differences in TAAR1 allele frequencies may contribute to fibromyalgia
• amphetamines are taken up into neuronal cells via neuronal monoamine reuptake transporters, and also act as a substrate for these transporters, resulting in transporter-mediated neurotransmitter release.
• desired actions of amphetamine & metamphetamine (Speed/Ice) amongst those who use them recreationally are:
  • euphoria, hyper-stimulation, increased stamina and sex drive and disinhibition, decreased appetite.
• desired actions of MDMA (Ecstasy) which has more serotoninergic actions, amongst those who use them recreationally are:
  • euphoria, inner peace, social facilitation, heightened sexuality and disinhibition, mild hallucinogen effects
• acute toxicity is produced by excessive extracellular noradrenaline / norepinephrine, dopamine and Serotonin physiology resulting in an alpha-adrenergic and beta-adrenergic sympathomimetic toxidrome.

• Amp, Bennies, Black beauties, Browns, Cranks, Fives, Goey, Hearts, Louee, Speed, Uppers, Whiz
• mainly sympathomimetic actions with greater peripheral effects than metamphetamine
• basic drug with pKa of 9.9, thus alkaline urine reduces excretion and increases half-life to ~20 hours, while acidic urine reduces half life to 5-6 hours
• generally taken orally but can be inhaled vaporised, or snorted as a fine powder, or injected
• iv injection produces marked euphoria, clear thinking but inefficient, often reptitious vigorous activity
• effects may include:
  • tachycardia, severe anxiety, paranoia, hallucinations (“snow lights”),insomnia, weight loss, SOB, chest pain, hypertension, acute myocardial infarction (AMI/STEMI/NSTEMI), hepatotoxicity, seizures, circulatory collapse
• users often take “downers” (eg. alcohol, marijuana, benzodiazepines, barbiturates, or opiates and opioids) to offset overstimulation effects
• there is a rapid fall off in effects which enhances intense craving for the drug which rapidly leads to addiction
• withdrawal (“crashing”) leads to long periods of sleep, hunger, extreme lethargy, depression, suicidality and anhedonia

• commonly used in Mx of ADHD since the 1990's

• introduced in Aust in 2013 as Vyvanse for Mx of ADHD
• prodrug of dexamphetamine

• mainly sympathomimetic actions, most potent cardiovascular effects of all amphetamines, greater CNS effects than amphetamine
• results in a far higher brain dopamine level than other commonly abused substances
• crystal meth is becoming the major pyschosocially destructive substance abuse epidemic
• see metamphetamine / meth / ice

• 3,4-methylenedioxymetamphetamine
• Adam, Bart Simpson, Clarity, Disco biscuits, Essence, E, Ecstasy, Love drug, Red and black, White dove, X, XTC
• usually colourful tablets at 50-200mg per dose
• most tablets sold in Australia are not actually MDMA but metamphetamine which is simpler to make, and often include contaminants such as cocaine, heroin, ketamine, codeine, paracetamol, ephedrine, pseudoephedrine, caffeine, benzodiazepines, antihistamines and LSD.
• a more recent development is use of MDMA in powder form (“Molly”) as users perceive that it is more likely to be MDMA
• users of MDMA in the dance scene are advised to take frequent rest breaks and sip water regularly to rehydrate
• unwanted effects include jaw clenching, teeth grinding, anxiety, paranoia, confusion, hallucinations, bizarre behaviour, and possibly psychosis.
• overdose can result in hypertension, tachycardia and hyperthermia, and may be fatal.

• Peace, Serenity, Tranquillity

• 2CB, MFT, Nexus
• extremely potent hallucinogen producing marked psychoactive effects, euphoria, altered perception
• used impregnated in paper as with LSD

• Bliss, BNZ, Bolts, Charge, Exodus, Frenzy, Goodstuff, Grins, Herbal Ecstasy, Herbal party pills, Jumps, Kandy, Legal ecstasy, Legal E, Legal X, Nemesis, Red Hearts, Silver bullet.
• BZP inhibitis reuptake of dopamine & serotonin & stimulates peripheral alpha-2 receptors but exhibits lower potency than amphetamine.
  • seizures, vomiting, collapse, agitation, anxiety & confusion are common in toxicity.
• TFMPP is more serotoninergic and produces affects similar to MDMA

• flakka, gravel, bath salts
• a synthetic cathinone and is related to MDPV (both of which are pyrovalerones)
• cathinone is the naturally occurring β-ketone amphetamine analogue found in the Catha edulis (the Khat plant)
• pyrovalerone-cathinones are potent and selective dopamine and noradrenaline uptake blockers, but are not effective releasers of monoamines
• hallucinatory effects are consistent with other serotonergic drugs such as MDMA or LSD
• can be ingested, injected, insufflated, taken sublingually, and vaporized and inhaled
• iv injection is the major risk for lethality
• have a high abuse and addiction potential
• euphoria and increased libido effects last 2-7hrs but “undesirable” effects can last hours to days
• toxicity includes:
  • bizarre behavior which is often aggressive and violent, hallucinations, psychosis
  • excessive sympathetic stimulation
  • serotonin syndrome
  • coma, seizures, rhabdomyolysis, acute kidney injury (AKI) / acute renal failure (ARF)

• eg. 25I-NBOMe, 25B-NBOMe, 25C-NBOMe, “Blue Batman”, “N-Bomb”
• new psychedelic drugs, 1st brought to Australia in 2012
• similar to LSD but act at a very low dose, in micrograms instead of milligrams
• typical doses cause hallucinations and euphoria and can last for more than 12 hours.
• harmful side affects include delirium, aggressive behaviour, self-harm, and paranoia, and risk of death (eg. believing one can fly or swim)