Drug of the Day

Substrate-mediated SERT/NET/DAT efflux — the pharmacological inverse of cocaine. MDMA rides the transporter inward and runs it in reverse, flooding the synapse with serotonin. SERT K_i = 34 nM. CYP2D6 mechanism-based inhibitor. FDA Breakthrough Therapy for PTSD. Full binding table · 3D SERT crystal structure (PDB 6DZV).

N,N-Dimethyltryptamine — endogenous trace amine and potent 5-HT_2A agonist with near-zero measurable tolerance. 5-HT_2A K_i ≈ 170 nM · σ1 K_i ≈ 14 μM. Smoked onset <30 s; MAO-A rapidly clears oral DMT unless co-administered with harmala alkaloids. Full binding table · 3D 5-HT_2A crystal structure (PDB 6WHA) · harm reduction.

4-HO-DMT — active metabolite of psilocybin. 5-HT_2A K_i ~107 nM. PDB 7WC7.

Diethylamide lid-lock · 5-HT_2A K_i ~1 nM · PDB 6WGT · 8–12 h.

DAT/NET substrate-releaser · DAT K_i ~1,400 nM · PDB 7XNA.

μ-opioid agonist · MOR K_i ~1.1 nM · PDB 8EF5 · naloxone-reversible.

κ-opioid full agonist · KOR K_i ~1.8 nM · zero 5-HT_2A · PDB 4DJH.

µ-opioid full agonist, G_i/o-coupled · MOR K_i ~1.8 nM · naloxone-reversible · active-state MOR, PDB 5C1M.

Monoamine substrate-releaser, reverses transporter flux · DAT release EC₅₀ ~25 nM · TAAR1 feedback · genuine meth co-crystal, PDB 4XP6.

Use-dependent NMDA open-channel blocker · PCP-site K_i ~420 nM · AMPA/BDNF/mTOR antidepressant arm · S-ketamine cryo-EM, PDB 7EU7.

CB₁ partial agonist (low intrinsic efficacy vs synthetic full agonists) · CB₁ K_i ~40 nM · 11-OH-THC active metabolite · CB₁ agonist complex, PDB 5XRA.

α4β2 nicotinic agonist, desensitization drives upregulation · K_i ~1 nM (high-affinity state) · combustion is the killer, not the ligand · PDB 5KXI.

Adenosine A_2A/A₁ antagonist → disinhibition of dopamine/arousal · A_2A K_i ~2.4 µM · CYP1A2 → paraxanthine · genuine caffeine co-crystal, PDB 5MZP.

GABA_A positive allosteric modulator — raises Cl⁻ channel opening frequency · K_i ~14 nM · long active metabolites · fatal with opioids/alcohol · diazepam-bound GABA_A, PDB 6HUP.

5-HT_2A agonist, ~500× weaker than LSD (why doses run 200–400 mg) · 5-HT_2A K_i ~551 nM · 10–12 h · 5-HT_2A active-state complex, PDB 7RAN.

Lipophilic prodrug → 6-MAM/morphine at µ-opioid · MOR K_i ~1.8 nM · naloxone-reversible · fatal with depressants · active-state MOR, PDB 5C1M.

Full µ agonist, CYP2D6 → potent oxymorphone · MOR K_i ~12 nM · reformulation drove the heroin/fentanyl shift · MOR agonist complex, PDB 5C1M.

Full µ agonist + NMDA antagonist · MOR K_i ~13 nM · 15–60 h half-life = accumulation + torsades risk; outlasts naloxone · MOR complex, PDB 5C1M.

Ultra-high-affinity µ partial agonist / KOR antagonist · MOR K_i ~0.2 nM · respiratory ceiling, slow off-rate, precipitated withdrawal risk · MOR complex, PDB 5C1M.

Weak parent (MOR K_i ~1600 nM) → potent M1 metabolite (~3.4 nM) + SERT/NET reuptake block · seizures + serotonin syndrome · MOR complex, PDB 5C1M.

G-protein-biased µ partial agonist (low β-arrestin → lower respiratory risk) · MOR K_i ~7.2 nM · 7-OH metabolite more potent · genuine cryo-EM, PDB 7T2G.

Pure DAT/NET reuptake blocker — mechanistic opposite of amphetamine's efflux · DAT K_i ~34 nM · d-threo eutomer, CES1 metabolism · dDAT S1 surrogate, PDB 4XP4.

DAT/NET-selective reuptake blocker up to ~50× cocaine potency · DAT IC₅₀ ~2.1 nM · compulsive redosing, hyperthermia, agitated delirium · dDAT surrogate, PDB 4XP1.

Non-selective monoamine releaser, MDMA-like DA:5-HT balance · DAT release EC₅₀ ~49 nM · short euphoria → redosing/vasoconstriction · dDAT releaser surrogate, PDB 4XP6.

4-bromo phenethylamine, 5-HT_2A partial agonist · K_i ~34 nM · steep dose-response (a few mg matters), often mis-sold · 5-HT_2A–Gq complex, PDB 7RAN.

Sub-nM 5-HT_2A agonist · K_i ~2.2 nM · sold on blotter as "LSD" but causes vasoconstriction, seizures, deaths — test your blotter · 5-HT_2A + 25CN-NBOH, PDB 6WHA.

α-methyl blocks MAO → very long duration (the 1967 "STP" scare) · potent 5-HT_2A partial agonist · slow onset = stacking trap · 5-HT_2A + 25CN-NBOH, PDB 6WHA.

Inactive prodrug → dephosphorylated to psilocin (the #004 payload) · psilocin 5-HT_2A K_i ~107 nM · depression trials · 5-HT_2A + psilocin, PDB 7WC5.

5-HT_1A-dominant (unlike DMT) · 5-HT_1A K_i ~28 nM · intense short "release" · fatal with MAOIs/harmalas · active 5-HT_1A–Gi complex, PDB 7E2Y.

Allosteric SERT inhibitor (+ NMDA/κ/σ) · SERT IC₅₀ ~0.59 µM · interrupts opioid withdrawal — but hERG/QT → torsades → sudden death · genuine SERT–ibogaine cryo-EM, PDB 6DZV.

Names the NMDA "PCP site" — use-dependent open-channel blocker ~15–20× ketamine potency · K_i ~23 nM · longer channel residence · genuine PCP-bound NMDAR, PDB 7SAB.

High-potency, short-half-life benzodiazepine — potent panic relief, steep interdose withdrawal and strong dependence. Fatal with opioids/alcohol; taper, never stop cold. · BZD-site Ki ~3.3 nM · PDB 6HUO.

Long-half-life benzodiazepine (anticonvulsant, panic). Same GABA-A BZD-site PAM mechanism as diazepam; smoother curve than alprazolam but the same dependence and depressant-synergy danger. · BZD-site Ki ~0.85 nM · PDB 6HUP.

α1-selective GABA-A modulator — hypnotic with less anxiolytic action, but real complex-sleep behaviours (sleep-driving), next-day impairment and rebound. Fatal with other depressants. · α₁ Ki ~27 nM · PDB 8DD2.

Low-affinity, many-site depressant: potentiates GABA-A, blocks NMDA, hits glycine/nAChR/GIRK. No pocket co-crystal — it acts at diffuse sites. Zero-order kinetics; kindling withdrawal → delirium tremens; fatal with opioids/benzos. · NMDA IC₅₀ ~30–60 mM · PDB 7EU7.

Endogenous metabolite and narcolepsy drug with a brutally steep dose-response — recreational to unconscious over a narrow range. GABA-B + high-affinity GHB site. Severe benzo/baclofen-refractory withdrawal; fatal with alcohol/depressants. · GHB-site Ki ~4 µM · PDB 7C7Q.

A baclofen/gabapentinoid hybrid sold as a supplement: GABA-B agonist plus α2δ calcium-channel binding. Anxiolytic/nootropic, but dose creep, strong tolerance and a genuinely severe withdrawal syndrome. Don't stack with depressants. · GABA-B Ki ~177 µM · PDB 7C7Q.

The classic barbiturate: increases GABA-A channel OPEN DURATION and directly gates at high dose — so unlike benzos there is no overdose ceiling. Potent CYP inducer, withdrawal seizures; fatal with opioids/alcohol. · Nav IC₅₀ ~10 µM · PDB 6X3W.

Binds the α2δ-1 auxiliary subunit of voltage-gated calcium channels — reducing excitatory transmitter release. NOT a GABA-receptor ligand. Neuropathic pain/anxiety use, but euphoria and misuse (esp. with opioids raises overdose risk); dependence and withdrawal. · α₂δ-1 Ki ~19 nM · PDB 7VFS.

Cough-syrup morphinan that becomes a dissociative at plateau doses via NMDA open-channel block (+ sigma-1). CYP2D6 → dextrorphan. Serotonin syndrome with SSRIs/MAOIs; the real danger is combination products (acetaminophen/antihistamines). Also at /dextromethorphan/. · DXM NMDA Ki ~1.7 µM · PDB 7EU7.

Laughing gas: an NMDA-antagonist anesthetic with seconds-long duration and no defined orthosteric site (shown on NMDAR, honestly labeled). The real harm is chronic use — irreversible B12 inactivation → neuropathy/SACD — and hypoxia; always mix with oxygen. · MAC ~104% · PDB 4PE5.

The therapeutic dissociative: low-affinity, fast-off, strongly voltage-dependent NMDA open-channel block — it filters pathological tonic Ca influx while sparing phasic synaptic signalling. That kinetic difference is why it treats Alzheimer's while ketamine/PCP dissociate. · NMDA Ki ~540 nM · PDB 7SAD.

Prozac: SERT reuptake inhibitor with a weeks-long washout via active norfluoxetine — so low discontinuation syndrome. CYP2D6 inhibitor, activating. Serotonin syndrome is the hard line: fatal with MAOIs. · SERT Ki ~1 nM · PDB 4MM8.

Zoloft: sub-nanomolar SERT block with an unusual (for an SSRI) DAT affinity. First-line, relatively pregnancy-safe; GI-heavy. Serotonin syndrome with MAOIs; QT at high dose. Real sertraline co-crystal (6AWO). · SERT Ki ~0.08 nM · PDB 6AWO.

The (S)-enantiomer of citalopram and the most SERT-selective SSRI, occupying both the orthosteric S1 and allosteric S2 sites (real co-crystal 5I73). Dose-capped for QT. Serotonin syndrome with MAOIs. · SERT Ki ~1 nM · PDB 5I73.

Paxil: the most potent SSRI at SERT, with anticholinergic action and strong self-CYP2D6 inhibition (nonlinear kinetics). Short half-life + potency = the worst discontinuation syndrome. Real paroxetine co-crystal (5I6X). · SERT Ki ~0.07 nM · PDB 5I6X.

Effexor: dose-dependent SNRI — serotonergic low, noradrenergic added higher. Notorious short-half-life discontinuation ('brain zaps'), dose-dependent hypertension, higher overdose toxicity than SSRIs. Serotonin syndrome with MAOIs. · SERT Ki ~39 nM · PDB 5I6X.

Wellbutrin/Zyban: dopamine/noradrenaline reuptake inhibitor (workhorse metabolite hydroxybupropion) plus nicotinic antagonism for smoking cessation. Weight-neutral, activating, no sexual dysfunction — but dose-dependent seizure risk (contraindicated in eating disorders). · DAT Ki ~441 nM · PDB 4M48.

A tricyclic: SERT/NET reuptake block plus potent H1, muscarinic, α1 and cardiac Na-channel blockade. Low-dose for pain/migraine/sleep. Narrow therapeutic index — overdose is lethal via QRS-widening Na-channel block (bicarbonate antidote). Fatal with MAOIs. · SERT Ki ~0.9 nM · PDB 4M48.

Irreversible non-selective MAOI (hydrazine) — a ~2-week washout to resynthesize enzyme. The tyramine 'cheese reaction' → hypertensive crisis, and serotonin syndrome with any serotonergic. The most interaction-dangerous antidepressant. · MAO-A IC₅₀ ~30 nM · PDB 2BYB.

The archetypal typical antipsychotic: high-affinity D2 antagonist (real haloperidol co-crystal 6LUQ). Potent D2 blockade → strong EPS/tardive dyskinesia, hyperprolactinemia, NMS and QT. Not a PRN sedative. · D₂ Ki ~1.4 nM · PDB 6LUQ.

Atypical by its 5-HT2A>D2 ratio (real D2–risperidone co-crystal 6CM4). Loses atypicality — gains EPS — at higher dose; potent hyperprolactinemia; active metabolite paliperidone. Metabolic and orthostatic effects; NMS. · 5-HT₂A Ki ~0.2 nM · PDB 6CM4.

Broad multi-receptor antipsychotic (D2/5-HT2A/H1/M/5-HT2C). Effective, but the worst metabolic syndrome — H1/5-HT2C-driven weight gain, diabetes, dyslipidemia. Sedating; NMS; the IM olanzapine+benzodiazepine warning. · 5-HT₂A Ki ~2 nM · PDB 6CM4.

Seroquel: loose, fast-dissociating D2 antagonist with very high H1 affinity; metabolite norquetiapine adds NET inhibition. Dose-tiered — low = sedative, mid = antidepressant, high = antipsychotic. Massively over-prescribed off-label for sleep. Metabolic, orthostasis, QT. · D₂ Ki ~180 nM · PDB 6CM4.

The 'dopamine stabilizer': D2 PARTIAL agonist (+ 5-HT2A antagonist, 5-HT1A partial agonist), so lower EPS/prolactin — but can destabilize if switched from an antagonist. Long half-life, akathisia signature, and the impulse-control (gambling/hypersexuality) warning. · D₂ Ki ~0.34 nM · PDB 7E2Z.

Uniquely effective in treatment-resistant schizophrenia via a promiscuous profile (D4>D2 low-occupancy, 5-HT2A, muscarinic, H1). Last-line because of agranulocytosis (mandatory ANC monitoring), myocarditis, seizures, and fatal ileus. Never miss bloodwork. · D₄ Ki ~16 nM · PDB 8JXV.

A monovalent cation, not a receptor drug: inhibits GSK-3β and inositol monophosphatase by displacing catalytic Mg²⁺ (shown on GSK-3β; Li⁺ isn't an organic ligand). Gold-standard anti-suicidal efficacy but a narrow therapeutic index — NSAIDs/thiazides/ACE and dehydration push it toxic. · Serum 0.6–1.2 mM · PDB 1PYX.

Phenyltriazine that stabilizes the inactivated state of voltage-gated Na channels → less glutamate release (real lamotrigine–Nav1.7 co-crystal 8THH). Best for bipolar depression. Mandatory slow titration: too fast, or combined with valproate, risks Stevens-Johnson/TEN. · Nav IC₅₀ ~10 µM · PDB 8THH.

Non-intoxicating because it is NOT a CB1 agonist — it's a negative allosteric modulator, plus 5-HT1A/TRPV1/GPR55 activity. Epidiolex (epilepsy) is FDA-approved. Main real risk is CYP-mediated drug interactions and unregulated-product purity. · CB₁ ~4.4 µM · PDB 5U09.

The original 'Spice/K2' cannabinoid and the mechanistic reason it's dangerous: a CB1 FULL agonist with no ceiling (unlike THC's partial agonism), so seizures, psychosis, tachyarrhythmia, AKI and deaths. Uneven spraying = no safe dose. 'It's just fake weed' is lethal. · CB₁ Ki ~9 nM · PDB 5XR8.

The endogenous cannabinoid ('ananda' = bliss): an on-demand retrograde CB1 partial agonist, rapidly destroyed by FAAH (why it's fleeting, and why FAAH inhibitors are a drug class). Linked to runner's high. An educational endogenous-ligand entry. · CB₁ Ki ~72 nM · PDB 6N4B.

The active principle of Amanita muscaria: a potent DIRECT (orthosteric) GABA-A agonist — unlike benzodiazepine modulators. Formed from ibotenic acid on drying. Sedative/oneiric, non-serotonergic; harm is ibotenic delirium, dose variability and deadly Amanita mis-ID. · GABA-A Ki ~5 nM · PDB 9G5Q.

The β-carboline that makes oral DMT work: a reversible MAO-A inhibitor (real MAO-A–harmine co-crystal 2Z5X) plus DYRK1A inhibition. Reversibility is safer than irreversible MAOIs but still creates the MAOI danger set — serotonin syndrome with SSRIs is the real ayahuasca risk. · MAO-A Ki ~5 nM · PDB 2Z5X.

An α2-adrenergic antagonist — blocking the autoreceptor brake raises noradrenergic outflow. Historically an aphrodisiac, now a fat-loss supplement and an anxiety/panic research probe. Hypertension, tachycardia, panic; dangerous with stimulants and MAOIs. · α₂A Ki ~0.4 nM · PDB 6KUW.

A non-selective muscarinic antagonist and genuine deliriant (Datura/'Devil's Breath') — dysphoric, amnestic, nothing like a recreational trip. Medical use as a motion-sickness patch. Overdose is the anticholinergic toxidrome; Datura dosing is lethal-unpredictable (physostigmine antidote). · M₁ Ki ~7.5 nM · PDB 5CXV.

A sedating H1 antihistamine that at high dose becomes an antimuscarinic deliriant and a cardiac Na-channel blocker. The 'high' is miserable and dangerous (hat-man hallucinations). Overdose = anticholinergic toxidrome + seizures + QRS-widening cardiotoxicity; the 'Benadryl challenge' has killed. · H₁ Ki ~16 nM · PDB 3RZE.

Chantix: an α4β2 nicotinic PARTIAL agonist (real varenicline–α4β2 co-crystal 6UR8) — enough dopamine to blunt craving while blocking nicotine's full reward. Best-in-class cessation efficacy; nausea and vivid dreams; the neuropsychiatric warning was later de-escalated (EAGLES). · α₄β₂ Ki ~0.1 nM · PDB 6UR8.

A non-sedating, non-dependent anxiolytic: 5-HT1A partial agonist (+ D2 antagonism) unlike benzodiazepines. Weeks to work, no abuse liability, no benzo cross-tolerance (so it can't cover benzo withdrawal). GAD and SSRI augmentation; serotonin syndrome with MAOIs; grapefruit/CYP3A4. · 5-HT₁A Ki ~15 nM · PDB 7E2Y.

The long-acting antagonist cousin of naloxone: blocks µ-opioid reward (and via endogenous-opioid blockade, treats alcohol use disorder too). Must be opioid-free to start (precipitated withdrawal). Lost tolerance means overdose risk if someone relapses after a depot wanes. · MOR Ki ~0.2 nM · PDB 4DKL.

The plant/product companion to mitragynine #022: leaf vs extracts vs 7-OH shots, biphasic stimulant-low/opioid-high profile, krypton adulteration, real dependence. Same µOR–Gi cryo-EM. · MOR Ki ~7.2 nM (mitragynine) · PDB 7T2G.

Vyvanse: inactive until red-cell aminopeptidases release d-amphetamine. Same DAT/NET substrate-releaser payload as #006, rate-limited conversion, lower insufflation/IV likeability. · payload = d-amphetamine · PDB 7XNA.

Wakefulness-promoting atypical DAT blocker (~50% occupancy), not a releaser. Rare SJS/TEN; CYP3A4 induction can fail steroidal contraceptives. · Schedule IV · PDB 4XP4 (DAT S1 surrogate).

Full µ agonist several-fold morphine; high IV solubility; H3-glucuronide neuroexcitation in renal failure. Naloxone-reversible. Equianalgesic conversion errors kill. · MOR Ki ~0.4–1.8 nM · PDB 5C1M.

Weak parent until CYP2D6 makes morphine. Poor metabolizers get no analgesia; ultrarapid metabolizers have died on labeled pediatric doses. · payload MOR Ki ~1.8 nM · PDB 5C1M.

Emergency reversal, not maintenance (that's naltrexone #070). t½ 30–80 min — fentanyl can outlast it; redose and stay. · MOR Ki ~1 nM · PDB 4DKL.

Diprivan: genuine GABA-A + propofol cryo-EM. No analgesia, no benzo ceiling, no flumazenil reversal. Unmonitored use is apnea. PRIS on high-dose infusions. · PDB 6X3T (real ligand).

Balanced SNRI at therapeutic doses (unlike venlafaxine's SERT-first climb), plus neuropathic-pain labels. Hepatotoxicity warning, MAOI hard stop, nasty taper. · SERT Ki ~0.8 nM · PDB 5I6X.

Multi-mechanism anticonvulsant. Boxed teratogen (neural tube + neurodevelopment), hepatotoxicity, pancreatitis, hyperammonemia. Doubles lamotrigine. · PDB 8THH (Na_v surrogate).

α2δ-1 ligand despite the name — zero GABA-receptor activity. Saturable absorption, renal clearance, opioid-combo overdose risk. Companion to pregabalin #040. · PDB 7VFS (apo α2δ-1).

Circadian hormone, not a GABA hypnotic. Best as a timed phase-shift tool; US OTC doses/purity are unregulated. · MT1/MT2 sub-nM · PDB 6ME3 (analog).

Reversible acetylcholinesterase inhibitor for Alzheimer's — modest cognition, GI and vagal bradycardia, cancelled by anticholinergics. Genuine co-crystal. · AChE IC50 ~6–20 nM · PDB 6O4W.