182 - Psychedelics & Recreational Drugs

The NEJM study showed psilocybin at 25 mg was equivalent to escitalopram on the QIDS primary measure at 6 weeks, but numerically superior on every secondary measure including well-being, emotional blunting, and sexual dysfunction. Attia: 'if there is a way to give somebody 25 milligrams of psilocybin and get the same anti-depressive benefits but without these other side effects, this is very exciting.' Integration psychotherapy after the session is essential — the plasticity window created by DMN disruption needs skilled guidance.

Nutt describes LSD's scheduling as 'the worst censorship of research in the history of the world.' Bobby Kennedy personally contested the ban. Norwegian meta-analysis of pre-ban alcoholism RCTs found effect size 1.0. At 10 mcg, many people can already feel something; 25 mcg is perceptible but not fully psychedelic; 100–125 mcg produces the full trip used in the American model.

MDMA was synthesized in 1904, rediscovered by Shulgin in the 1960s, used legally as 'Empathy' by West Coast therapists for ~10 years before a Texas dealer renamed it 'Ecstasy' and sold it commercially. The rename created the moral panic that drove scheduling. Nutt's 1990s work showed the actual harms were environmental, not pharmacological: mandating free water and chill-out rooms in UK clubs essentially eliminated ecstasy deaths.

Nutt draws a sharp contrast with psilocybin: ketamine antidepressant effects last 2–3 days per dose and require ongoing administration; psilocybin effects from two sessions lasted 6+ weeks. Esketamine was patented because racemic ketamine could not be patented (it was used as a Vietnam War battlefield analgesic). The nasal route is more practical for psychiatric use than IV.

The 'altered traits' language comes from the book Altered Traits by Goleman and Davidson. Attia: 'I don't think cocaine can do that so therefore it has two strikes — it has a physical risk that is non-trivial and it's not going to make your life better when you're not taking it.' Psilocybin's case: 'if it just altered your state you probably wouldn't take it because it's really not that pleasurable but the real benefit is the potential to alter a trait whether it be depression smoking cessation or something else.'

Nutt's group is developing noribogaine with a company to determine whether it is a classic psychedelic via brain imaging. Ibogaine is widely used in Mexico and Vietnam clinics. The risk-benefit argument: 1/1,000 cardiac risk vs. ~300/1,000 mortality from untreated opioid addiction. Attia: 'one in a thousand is an enormous risk but if you're weighing it against a person remaining addicted to opioids what's the natural history of that — 300 out of a thousand yes about that.'

The nine user-harm scales include acute toxicity, chronic toxicity, addiction potential, and several others. The seven societal-harm scales include international damage (e.g., herbicide spraying of coca crops), economic harm, family harm, and health-system costs. Weighting these appropriately produces a transparent numeric ranking. In every jurisdiction tested, the top-3 individual-harm drugs are opioids, crack/crystal meth, and cocaine. Tobacco ranks 6th–7th because, while it kills more people in absolute terms, it kills them later and causes negligible acute societal harm. Alcohol scores highest socially because its prevalence (80% of UK/US adults drink) means its acute toxicity cascades widely: drunk driving, domestic violence, accidental deaths.

The study was deliberately blinded by telling all participants they would receive psilocybin — half got 25 mg (active), half got 1 mg (placebo dose) — while both groups also received a daily pill (either escitalopram or placebo). The journal required QIDS as the primary outcome; the researchers had also pre-specified well-being. When QIDS showed no statistical difference, journal convention forbade reporting the secondary outcome as positive. Nutt argues the study accomplished its political goal: being the first psychedelic study in NEJM signals to regulators worldwide that psilocybin is a medicine. The mechanistic distinction is that SSRIs work via serotonin 1A receptors in the limbic system, effectively plastering over the stress response; psilocybin acts via serotonin 2A receptors in the cortex, disrupting the rigid negative-thinking loops embedded in the default mode network.

Bill Wilson, founder of Alcoholics Anonymous, personally escaped his alcoholism through a psychedelic experience before LSD existed, and later used legal LSD and was instrumental in setting up six clinical trials for LSD in alcoholism. A 2012 Norwegian meta-analysis of those old trials found an effect size of 1.0 — twice that of any subsequent alcoholism treatment ever developed. The mechanism of LSD's ban: Tim Leary's counterculture movement was changing voting patterns against the Vietnam War; the Nixon administration found 'social harms' easier to invoke than physical harms, and the tabloid press was recruited to manufacture outrage stories. The scientific community had no procedural defense against social-harm claims.

MDMA was originally synthesized in 1904, rediscovered by Sasha Shulgin in the 1960s, and used legally as 'Empathy' by West Coast therapists for couples counseling and PTSD through the 1970s–1980s. It was renamed 'Ecstasy' when a Texas dealer realized the marketing potential and sold it commercially. The rename created the moral panic that drove the ban — newspapers could not ban 'Empathy' but could ban 'Ecstasy.' The actual harms Nutt's team found in the 1990s were environmental (dehydration from dancing, hyperthermia from inadequate cooling), not pharmacological. Mandating free water and chill-out rooms in UK clubs effectively eliminated ecstasy deaths in that era.

The mechanism of psychedelic tolerance is unclear but involves downstream receptor desensitization in the serotonin 2A pathway that reverses over 1–2 weeks. This is categorically different from opioid tolerance, where dose escalation can indefinitely overcome tolerance at the cost of increasingly severe physical dependence. Ketamine is also escalatable — recreational ketamine users progress from clinical doses (~500 mg) to 5 grams per day, at which point they develop bladder atrophy (requiring resection) and a chronic cognitive state mimicking schizophrenia. Psychedelics have no such escalation ceiling to exploit.

In depression, elements of the DMN become malignantly over-engaged in negative rumination. In addiction, the DMN encodes the drug itself as a core self-object. Disrupting the DMN via psychedelics creates a brief window of plasticity where new patterns can be encoded. Ibogaine likely acts via the same principle. The DMN also coordinates retrospective/prospective thinking: damage to its frontal node changes personality; damage to its posterior node causes severe disorientation — explaining why psychedelics feel like ego dissolution.