A brief comparison of GHB and MDMA may be instructive because one therapeutic challenge ahead will be to design agents that reverse SSRI-like flattening of affect without inducing mawkish sentimentalism (cf. ethyl alcohol). In contrast to mainstream psychiatric drug therapies, both GHB and MDMA deliver a rare emotional intensity of experience, albeit an intensity different both in texture and molecular mechanism. GHB is known by clubbers if not structural chemists as “liquid ecstasy”. GHB and MDMA are indeed sometimes mixed at raves; but the two drugs are chemically unrelated. GHB is an endogenous neuromodulator derived from GABA, the main inhibitory neurotransmitter of the brain. A naturally-occurring fatty acid derivative, GHB is a metabolite of normal human metabolism. GHB has its own G protein-coupled presynaptic receptor in the brain. Sold as a medicine, GHB is licensed as an oral solution under the brand name Xyrem for the treatment of cataplexy associated with narcolepsy. Unlike MDMA, GHB stimulates tissue serotonin turnover. GHB increases both the transport of tryptophan to the brain and its uptake by serotonergic cells. Taking GHB stimulates growth hormone secretion; hence its popularity with bodybuilders. GHB offers cellular protection against cerebral hypoxia, and deep sleep without inducing a hangover. GHB also stimulates tyrosine hydroxylase. Tyrosine hydroxylase converts L-tyrosine to L-dopa, subsequently metabolised to dopamine. Unlike MDMA, the acute effects of GHB involve first inhibiting the dopamine system, followed the next day by a refreshing dopamine rebound. GHB induces mild euphoria in many users. In general, the neurotransmitter GABA acts to reduce the firing of the dopaminergic neurons in the tegmentum and substantia nigra. The sedative/hypnotic effect of GHB is mediated by its stimulation of GABA(B) receptors, though GHB also modulates the GABA(A) receptor complex too. The main effect of GABA(B) agonism is normally muscle relaxation, though interestingly, pretreatment with the GABA(B) agonist baclofen also prevents an MDMA-induced rise in core body temperature. Whatever the exact GABA(A), GABA(B), and GHB-specific mechanisms by which GHB works, when taken at optimal dosage GHB typically acts as a “sociabiliser”. This is a term popularised by the late Claude Rifat (Claude de Contrecoeur), author of GHB: The First Authentic Antidepressant (1999). Rifat was GHB’s most celebrated advocate and an outspoken critic of Anglo-American psychiatry. Similar therapeutic claims have been made for GHB as for MDMA, despite their pharmacological differences. GHB swiftly banishes depression and replaces low mood with an exhilarating feeling of joy; GHB has anxiolytic properties; it’s useful against panic attacks; it suppresses suicidal ideation; it inhibits hostility, paranoia and aggression; it enhances the recall of long-forgotten memories and dreams; and it promotes enhanced feelings of love. Like MDMA, and on slightly firmer grounds, GHB has been touted as an aphrodisiac: GHB heightens and prolongs the experience of orgasm. GHB disinhibits the user, and deeply relaxes his or her body. Inevitably, GHB has been demonised as a date-rape drug [“I was at this party, and this guy gave me a drink. Next thing I know, it’s morning and I’m in someone’s bed. I’ve no idea what happened in between…”]. GHB has a steep dose-response curve. Higher doses will cause anterograde amnesia i.e. users forget what they did under the influence of the drug. It’s dangerous to combine GHB with other depressants. So despite GHB’s therapeutic and pro-social potential, GHB is probably unsafe to commend to clubbers. This is because a significant percentage of the population will combine any drug whatsoever with alcohol regardless of the consequences to health. If used wisely, sparingly, and in a different cultural milieu, then GHB could be a valuable addition to the bathroom pharmacopoeia. But even then, it’s still flawed. GHB may intensify emotion and affection, but not introspective depth or intellectual acuity. Unlike taking too much MDMA, overdoing GHB makes the user fall profoundly asleep. If our consciousness is to be durably enhanced, then sedative-hypnotics have only a limited role to play in the transition ahead.

– Extract from “Utopian Pharmacology: Mental Health in the Third Millennium
MDMA and Beyond” by David Pearce (notice the great domain name:

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