IUPAC: [(1S,2S,4R,5S,7S)-9-methyl-3-oxa-9-azatricyclo[3.3.1.0²,⁴]nonan-7-yl] (2S)-3-hydroxy-2-phenylpropanoate · C₁₇H₂₁NO₄ · MW 303.35 g/mol · CAS 51-34-3 (free base)
Scopolamine (hyoscine). A tropane alkaloid produced by nightshades — Datura stramonium (jimsonweed), Brugmansia (angel's trumpet), Hyoscyamus niger (henbane), Atropa belladonna. Not a psychedelic and not a dissociative: a true deliriant — a non-selective muscarinic acetylcholine receptor antagonist that erases the cholinergic tone the brain uses to encode memory and stay oriented. Context names: hyoscine, "Devil's Breath" (burundanga), Transderm Scōp.
Scopolamine is a competitive, reversible antagonist at all five muscarinic acetylcholine receptor subtypes (M1–M5). It is the pharmacological inverse of the drugs this series usually covers: where classical psychedelics agonize 5-HT2A and dissociatives block the NMDA channel, scopolamine simply occupies the orthosteric acetylcholine pocket of a G-protein-coupled receptor and silences it. There is no positive signal generated — only the subtraction of endogenous cholinergic tone. That subtraction, when it reaches the cortex and hippocampus, is what produces delirium and dense anterograde amnesia.
As a lipophilic tertiary amine, scopolamine readily crosses the blood-brain barrier — the property that separates it from its quaternary cousins (methscopolamine, butylscopolamine/Buscopan), which are charged, peripherally restricted, and produce no CNS syndrome. The muscarinic receptors are class A GPCRs: M1/M3/M5 couple to Gq/PLC (excitatory), while M2/M4 couple to Gi/o (inhibitory). Blocking them non-selectively deranges autonomic and cortical circuits simultaneously.
Antagonism of M1 (Gq-coupled, Ki ≈ 7.5 nM human) on cortical and hippocampal neurons collapses cholinergic drive from the basal forebrain, disrupting theta rhythm and long-term potentiation. This is the direct substrate of the amnesia and delirium — scopolamine is the classical pharmacological model of the cholinergic memory deficit.
M2 (Gi-coupled) is the vagal brake on the sinoatrial node. Blockade removes parasympathetic tone → sinus tachycardia. (Paradoxically, very low transdermal doses can briefly slow the heart via central/presynaptic effects before the peripheral block dominates.)
M3 (Gq) drives exocrine secretion, pupillary constriction, bladder/gut motility. Antagonism gives the peripheral toxidrome: dry mouth, mydriasis + cycloplegia, ileus, urinary retention, anhidrosis. The antisialagogue (drying) and antiemetic effects are therapeutic exploits of this same block.
M4 (Ki ≈ 37 nM) modulates striatal output; M5 (Ki ≈ 18 nM) gates midbrain dopamine release. Their blockade contributes to motor restlessness, disinhibited dopaminergic signaling, and the agitated, combative quality of the deliriant state.
Muscarinic transmission relays vestibular signals to the medullary vomiting center and area postrema. Central M-blockade interrupts that relay — the mechanism behind scopolamine's genuine, evidence-based efficacy in motion sickness and post-operative nausea.
A single low IV dose (4 µg/kg) produces rapid, transient antidepressant effects in controlled trials — attributed to transient M1 blockade triggering downstream glutamatergic/mTOR plasticity, mechanistically parallel to ketamine. Distinct from, and far below, deliriant doses.
Scopolamine's pharmacology is almost entirely a story of route and rate. Oral bioavailability is low and erratic (~13–27%) due to heavy first-pass metabolism, so plant ingestion (Datura tea, seeds) produces wildly unpredictable exposure. The medical formulation solves this with a transdermal patch (Transderm Scōp) that meters roughly 1 mg over 3 days — a controlled trickle that gives antiemetic benefit while staying well below the delirium threshold. Insufflated or injected as a criminal payload, the same molecule hits fast and hard.
Metabolism cascade: the tropane ester is the labile bond. Serum and hepatic carboxylesterases hydrolyze scopolamine into two inactive fragments — the amino-alcohol scopine and tropic acid — with parallel oxidative and glucuronide/sulfate conjugation. Almost nothing pharmacologically active survives to the urine.
Because clearance depends on esterase and CYP3A4 capacity, exposure is highly variable between individuals — children, the elderly, and people with reduced hepatic function accumulate drug and tip into toxicity at doses others tolerate. This is compounded catastrophically when the "dose" is a plant: alkaloid content in Datura varies by species, part, season, and specimen by more than an order of magnitude, so there is no reliable way to titrate.
The single most important honesty point on this page: the scopolamine "trip" is not recreational, not insightful, and not enjoyable. Unlike the euphoric-serotonergic or the profound-dissociative states, a full deliriant dose is characterized by true delirium — hallucinations indistinguishable from reality, conversations with people who are not there, total loss of the thread of self, and a dense amnesia that deletes the entire episode. Users almost universally describe it as dark and dysphoric; the folk warning "you don't take Datura twice" is well earned. What follows are the circuit consequences of subtracting cholinergic tone across the neuraxis.
Loss of basal-forebrain cholinergic drive to cortex and hippocampus disrupts attention, working memory, and the encoding of new memories. This is why scopolamine is the standard laboratory model of the cholinergic amnestic deficit. Subjectively: disorientation, incoherent thought, vivid waking hallucinations (often mundane and unpleasant — spiders, insects, dead relatives, phantom cigarettes), and near-total blackout for the event.
Simultaneously, the body enters the classic anticholinergic toxidrome — "blind as a bat" (mydriasis, cycloplegia), "dry as a bone" (no saliva, sweat, or tears), "red as a beet" (cutaneous vasodilation), "hot as a hare" (hyperthermia from lost sweating), "mad as a hatter" (delirium), and "full as a flask" (urinary retention), with tachycardia and ileus. Hyperthermia and the delirium are the dangerous parts.
At sub-deliriant doses scopolamine is a genuinely useful drug. The transdermal patch is first-line for motion sickness and post-operative nausea (central vestibular M-blockade). As an antisialagogue it dries secretions before anaesthesia and in palliative care it reduces the "death rattle." Ophthalmic scopolamine produces cycloplegia/mydriasis. These uses live entirely below the CNS delirium threshold and are the reason the molecule is in the pharmacopeia at all.
In Colombia scopolamine (burundanga) has a notorious criminal reputation: victims dosed covertly become compliant, suggestible, and amnestic — reportedly emptying bank accounts or handing over property, then remembering nothing. The pharmacology is real (amnesia + disinhibition are genuine effects); the sensational "blow it in your face and zombify you instantly" media version overstates a fine powder's transdermal/inhaled potency. The actionable truth: it is a real covert-drugging agent and a real poison, not a magic spell.
Situating scopolamine in this series: it is neither the ego-dissolving 5-HT2A psychedelia of LSD/psilocybin nor the detached hole of ketamine. It is the third door — the deliriant — where the "experience" is confusion, involuntary hallucination, and erasure. Almost no one who has had a full dose seeks it out again.
Muscarinic antagonists are a clean test case for the conformational-entropy view of binding that FlexAID∆S scores explicitly. The orthosteric pocket of the muscarinic receptor sits deep in the 7TM bundle, capped by a "tyrosine lid" (a hydrogen-bonded cage of aromatic tyrosines above the ligand). When the tropane ester of scopolamine — or the near-identical scopine ester tiotropium seen in the crystal — wedges into that pocket, it rigidifies both the ligand and the lid.
In FlexAID∆S terms, this is the difference between a favorable ΔG that does work (agonist → active-state collapse) and one that prevents work (antagonist → locked inactive ensemble). The exceptional pre-organization of the tropane scaffold — the same feature that makes it a natural-product privileged motif — is what lets scopolamine occupy M1 with sub-10 nM affinity while contributing almost nothing but pocket-shape complementarity.
Clinical and non-moralistic. Scopolamine and Datura/Brugmansia are genuinely dangerous — this is not a "bad trip" drug, it is a poison with a narrow, unpredictable margin. People die from plant deliriants, mostly from dose unpredictability and from injuries sustained during delirium.
0HK), X-ray 2.7 Å, Thal et al.,
Nature 2016. No scopolamine co-crystal exists; tiotropium is a
scopine (oxa-tropane) ester — a close structural analog of scopolamine occupying the same orthosteric ACh pocket. Shown as an
honest, best-available antagonist-bound muscarinic complex.
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| Target | Affinity | Rel. | Mechanism |
|---|---|---|---|
|
M3
mAChR M3 (CHRM3)
|
Ki = 6.5 nM
human · [³H]NMS
|
Antagonist | |
|
M1
mAChR M1 (CHRM1)
|
Ki = 7.5 nM
|
Antagonist | |
|
M2
mAChR M2 (CHRM2)
|
Ki = 9.5 nM
|
Antagonist | |
|
M5
mAChR M5 (CHRM5)
|
Ki = 17.6 nM
|
Antagonist | |
|
M4
mAChR M4 (CHRM4)
|
Ki = 36.9 nM
|
Antagonist | |
|
σ1R
Sigma-1 receptor
|
Inactive
|
No activity |