Scopolamine

Clinical data
Trade names	Transderm Scop, others
Other names	Hyoscine[1]
AHFS/Drugs.com	Monograph
MedlinePlus	a682509
License data	US DailyMed: Scopolamine
Pregnancy category	AU: B2[2]
Routes of administration	By mouth, transdermal, ophthalmic, subcutaneous, intravenous, sublingual, rectal, buccal, transmucosal, intramuscular
Drug class	Antimuscarinic Deliriant Antiemetic Amnestic
ATC code	A04AD01 (WHO) N05CM05 (WHO), S01FA02 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) / S2[3] UK: POM (Prescription only) / P[4][5] US: ℞-only[6]
Pharmacokinetic data
Bioavailability	20-40%[7]
Metabolism	Liver (CYP3A4)[8]
Elimination half-life	5 hours[7]
Excretion	Kidney
Identifiers
IUPAC name (–)-(S)-3-Hydroxy-2-phenylpropionic acid (1R,2R,4S,5S,7α,9S)-9-methyl-3-oxa-9-azatricyclo[3.3.1.02,4]non-7-yl ester
CAS Number	51-34-3 Y
PubChem CID	3000322
IUPHAR/BPS	330
DrugBank	DB00747 Y
ChemSpider	10194106 Y
UNII	DL48G20X8X as salt: 451IFR0GXB
KEGG	D00138 Y as salt: D02071 Y
ChEBI	CHEBI:16794 Y
ChEMBL	ChEMBL569713 N
PDB ligand	OW0 (PDBe, RCSB PDB)
CompTox Dashboard (EPA)	DTXSID6023573
ECHA InfoCard	100.000.083
Chemical and physical data
Formula	C17H21NO4
Molar mass	303.358 g·mol−1
3D model (JSmol)	Interactive image
SMILES OC[C@H](c1ccccc1)C(=O)O[C@@H]2C[C@H]3N(C)[C@@H](C2)[C@@H]4O[C@H]34
InChI InChI=1S/C17H21NO4/c1-18-13-7-11(8-14(18)16-15(13)22-16)21-17(20)12(9-19)10-5-3-2-4-6-10/h2-6,11-16,19H,7-9H2,1H3/t11-,12-,13-,14+,15-,16+/m1/s1 Y Key:STECJAGHUSJQJN-FWXGHANASA-N Y
NY (what is this?)  (verify)

Scopolamine, also known as hyoscine,^[9] or Devil's Breath,^[10] is a natural or synthetically produced tropane alkaloid and anticholinergic drug that is used as a medication to treat motion sickness^[11] and postoperative nausea and vomiting.^[12][1] It is also sometimes used before surgery to decrease saliva.^[1] When used by injection, effects begin after about 20 minutes and last for up to 8 hours.^[1] It may also be used orally and as a transdermal patch since it has been long known to have transdermal bioavailability.^[1][13]

Scopolamine is in the antimuscarinic family of drugs and works by blocking some of the effects of acetylcholine within the nervous system.^[1]

Scopolamine was first written about in 1881 and started to be used for anesthesia around 1900.^[14][15] Scopolamine is also the main active component produced by certain plants of the nightshade family, which historically have been used as psychoactive drugs, known as deliriants, due to their antimuscarinic-induced hallucinogenic effects in higher doses.^[12] In these contexts, its mind-altering effects have been utilized for recreational and occult purposes.^[16][17][18] The name "scopolamine" is derived from one type of nightshade known as Scopolia, while the name "hyoscine" is derived from another type known as Hyoscyamus niger, or black henbane.^[19][20] It is on the World Health Organization's List of Essential Medicines.^[21]

Scopolamine has a number of formal uses in modern medicine where it is used in its isolated form and in low doses to treat:^[22][23]

• Postoperative nausea and vomiting.
• Motion sickness, including sea sickness, leading to its use by scuba divers (where it is often applied as a transdermal patch behind the ear)^{[24][25][26][27]}
• Gastrointestinal spasms
• Renal or biliary spasms
• Aid in gastrointestinal radiology and endoscopy
• Irritable bowel syndrome
• Clozapine-induced drooling
• Bowel colic
• Eye inflammation^[28]

It is sometimes used as a premedication, especially to reduce respiratory tract secretions in surgery, most commonly by injection.^[22][23] Common side effects include sleepiness, blurred vision, dilated pupils, and dry mouth.^[1] It is not recommended in people with angle-closure glaucoma or bowel obstruction.^[1] Whether its use during pregnancy is safe remains unclear, and use during breastfeeding is still cautioned by health professionals and manufacturers of the drug.^[29]

Scopolamine enters breast milk by secretion. Although no human studies exist to document the safety of scopolamine while nursing, the manufacturer recommends that caution be taken if scopolamine is administered to a breastfeeding woman.^[29]

Adverse effect incidence:^{[6][30][31][32]}

Uncommon (0.1–1% incidence) adverse effects include:

• Dry mouth
• Anhidrosis (reduced ability to sweat to cool off)
• Tachycardia (usually occurs at higher doses and is succeeded by bradycardia)
• Bradycardia
• Urticaria (hives)
• Pruritus (itching)

Rare (<0.1% incidence) adverse effects include:

• Constipation
• Urinary retention
• Hallucinations
• Agitation
• Confusion
• Restlessness
• Seizures

Unknown frequency adverse effects include:

• Anaphylactic shock or reactions
• Dyspnea (shortness of breath)
• Rash
• Erythema
• Other hypersensitivity reactions
• Blurred vision
• Mydriasis (dilated pupils)
• Drowsiness
• Dizziness
• Somnolence
• Death

Physostigmine, a cholinergic drug that readily crosses the blood–brain barrier, has been used as an antidote to treat the central nervous system depression symptoms of a scopolamine overdose.^[33] Other than this supportive treatment, gastric lavage and induced emesis (vomiting) are usually recommended as treatments for oral overdoses.^[32] The symptoms of overdose include:^[31][32]

• Tachycardia
• Arrhythmia
• Blurred vision
• Photophobia
• Urinary retention
• Drowsiness or paradoxical reaction, which can present with hallucinations
• Cheyne–Stokes respiration
• Dry mouth
• Skin reddening
• Inhibition of gastrointestinal motility

Scopolamine can be taken by mouth, subcutaneously, in the eye, and intravenously, as well as via a transdermal patch.^[34]

The pharmacological effects of scopolamine are mediated through the drug's competitive antagonism of the peripheral and central muscarinic acetylcholine receptors. Scopolamine acts as a nonspecific muscarinic antagonist at all four (M₁, M₂, M₃, and M₄) receptor sites.^[35][36]

In doses higher than intended for medicinal use; the hallucinogenic alteration of consciousness, as well as the deliriousness in particular are tied to the compound's activity at the M₁ muscarinic receptor. M₁ receptors are located primarily in the central nervous system and are involved in perception, attention and cognitive functioning. Delirium is only associated with the antagonism of postsynaptic M₁ receptors and currently other receptor subtypes have not been implicated.^[37]

Peripheral muscarinic receptors are part of the autonomic nervous system. M₂ receptors are located in the brain and heart, M₃ receptors are in salivary glands and M₄ receptors are in the brain and lungs.^[37] Due to the drug's inhibition of various signal transduction pathways, the decrease in acetylcholine signaling is what leads to many of the cognitive deficits, mental impairments and delirium associated with psychoactive doses. Medicinal effects appear to mostly be tied to activation of the peripheral receptors and only from marginal decreases in acetylcholine signaling.^[38]

Although often broadly referred to as simply being 'anticholinergic', antimuscarinic would be more specific and accurate terminology to use for scopolamine, as, for example, it is not known to block nicotinic receptors.^[37]

Scopolamine undergoes first-pass metabolism and about 2.6% is excreted unchanged in urine. It has a bioavailability of 20-40%, reaches peak plasma concentration in about 45 minutes, and in healthy subjects has an average half-life of 5 hours (observed range 2 - 10 hours).^[7] Scopolamine is primarily metabolized by the CYP3A4 enzyme, and Grapefruit juice decreases metabolism of scopolamine, consequently increasing plasma concentration.^[8]

Scopolamine is among the secondary metabolites of plants from Solanaceae (nightshade) family of plants, such as henbane (Hyoscyamus niger), jimson weed (Datura), angel's trumpet (Brugmansia), deadly nightshade (Belladonna), mandrake (Mandragora officinarum), and corkwood (Duboisia).^[39][19]

The biosynthesis of scopolamine begins with the decarboxylation of L-ornithine to putrescine by ornithine decarboxylase. Putrescine is methylated to N-methylputrescine by putrescine N-methyltransferase.^[40]

A putrescine oxidase that specifically recognizes methylated putrescine catalyzes the deamination of this compound to 4-methylaminobutanal, which then undergoes a spontaneous ring formation to N-methyl-pyrrolium cation. In the next step, the pyrrolium cation condenses with acetoacetic acid yielding hygrine. No enzymatic activity could be demonstrated to catalyze this reaction. Hygrine further rearranges to tropinone.^[40]

Subsequently, tropinone reductase I converts tropinone to tropine, which condenses with phenylalanine-derived phenyllactate to littorine. A cytochrome P450 classified as Cyp80F1^[41] oxidizes and rearranges littorine to hyoscyamine aldehyde. In the final step, hyoscyamine undergoes epoxidation catalyzed by 6beta-hydroxyhyoscyamine epoxidase yielding scopolamine.^[40]

Plants naturally containing scopolamine such as Atropa belladonna (deadly nightshade), Brugmansia (angels trumpet), Datura (Jimson weed), Hyoscyamus niger, Mandragora officinarum, Scopolia carniolica, Latua and Duboisia myoporoides have been known about and used for various purposes in both the New and Old Worlds since ancient times.^[42][43][44] Being one of the earlier alkaloids isolated from plant sources, scopolamine has been in use in its purified forms, such as various salts, including hydrochloride, hydrobromide, hydroiodide, and sulfate, since its official isolation by the German scientist Albert Ladenburg in 1880,^[45] and as various preparations from its plant-based form since antiquity and perhaps prehistoric times.

In 1899, a Dr. Schneiderlin recommended the use of scopolamine and morphine for surgical anaesthesia, and it started to be used sporadically for that purpose.^[14][46] The use of this combination in obstetric anesthesiology (childbirth) was first proposed by Richard von Steinbuchel in 1902 and was picked up and further developed by Carl Gauss in Freiburg, Germany, starting in 1903.^[47] The method, which was based on a drug synergy between both scopolamine and morphine came to be known as Dämmerschlaf ("twilight sleep") or the "Freiburg method".^[46][47] It spread rather slowly, and different clinics experimented with different dosages and ingredients. In 1915, the Canadian Medical Association Journal reported, "the method [was] really still in a state of development".^[46] It remained widely used in the US until the 1960s, when growing chemophobia and a desire for more natural childbirth led to its abandonment.^[48]

Hyoscine hydrobromide is the international nonproprietary name, and scopolamine hydrobromide is the United States Adopted Name. Other names include levo-duboisine, devil's breath, and burundanga.^[17][49]

A bush medicine developed by Aboriginal peoples of the eastern states of Australia from the soft corkwood tree (Duboisia myoporoides) was used by the Allies in World War II to stop soldiers from getting seasick when they sailed across the English Channel on their way to France during the Invasion of Normandy. Later, the same substance was found to be usable in the production of scopolamine and hyoscyamine, which are used in eye surgery, and a multimillion-dollar industry was built in Queensland based on this substance.^[50]

While it has been occasionally used recreationally for its hallucinogenic properties, the experiences are often unpleasant, mentally and physically. It is also physically dangerous and officially classified as a deliriant drug, so repeated recreational use is rare.^[51] In June 2008, more than 20 people were hospitalized with psychosis in Norway after ingesting counterfeit rohypnol tablets containing scopolamine.^[52] In January 2018, 9 individuals were hospitalized in Perth, Western Australia, after reportedly ingesting scopolamine.^[53]

The alkaloid scopolamine, when taken recreationally for its psychoactive effect is usually taken in the form of preparations from plants of the genera Datura or Brugmansia, often by adolescents or young adults in order to achieve hallucinations and an altered state of consciousness induced by muscarinic antagonism.^[54][55] In circumstances such as these, the intoxication is usually built on a synergistic, but even more toxic mixture of the additional alkaloids in the plants which includes atropine and hyoscyamine.

Historically, the various plants that produce scopolamine have been used psychoactively for spiritual and magical purposes, particularly by witches in western culture and indigenous groups throughout the Americas such as Native American tribes like the Chumash.^{[18][56][57][58]} When entheogenic preparations of these plants were used, scopolamine was considered to be the main psychoactive compound and was largely responsible for the hallucinogenic effects, particularly when the preparation was made into a topical ointment, most notably flying ointment.^[59]

Scopolamine is reported to be the only active alkaloid within these plants that can effectively be absorbed through the skin to cause effects.^[13] Different recipes for these ointments were explored in European witchcraft at least as far back as the Early Modern period and included multiple ingredients to help with the transdermal absorption of scopolamine, such as animal fat, as well as other possible ingredients to counteract its noxious and dysphoric effects.^[59]

In the Bible, there are multiple mentions of Mandrake, a psychoactive and hallucinogenic plant root that contains scopolamine. It was associated with fertility and (sexual) desire where it was yearned for by Rachel, who apparently was "barren" (infertile) but trying to conceive.^[60][61]

The effects of scopolamine were studied for use as a truth serum in interrogations in the early 20th century,^[62] but because of the side effects, investigations were dropped.^[63] In 2009, the Czechoslovak state security secret police were proven to have used scopolamine at least three times to obtain confessions from alleged antistate dissidents.^[64]

Ingestion of scopolamine can render a victim unconscious for 24 hours or more. In large doses, it can cause respiratory failure and death. The most common seems to be recorded in Colombia, where unofficial estimates put the number of annual scopolamine incidents at approximately 50,000. A travel advisory published by the U.S. Overseas Security Advisory Council (OSAC) in 2012 stated:

One common and particularly dangerous method that criminals use in order to rob a victim is through the use of drugs. Scopolamine is most often administered in liquid or powder form in foods and beverages. The majority of these incidents occur in night clubs and bars, and usually men, perceived to be wealthy, are targeted by young, attractive women. It is recommended that, to avoid becoming a victim of scopolamine, a person should never accept food or beverages offered by strangers or new acquaintances, nor leave food or beverages unattended in their presence. Victims of scopolamine or other drugs should seek immediate medical attention.^[65]

Between 1998 and 2004, 13% of emergency-room admissions for "poisoning with criminal intentions" in a clinic of Bogotá have been attributed to scopolamine, and 44% to benzodiazepines.^[17] Most commonly, the person has been poisoned by a robber who gave the victim a scopolamine-laced beverage, in the hope that the victim would become unconscious or unable to effectively resist the robbery.^[17]

Beside robberies, it is also allegedly involved in express kidnappings and sexual assault.^[66] In 2008, the Hospital Clínic in Barcelona introduced a protocol to help medical workers identify cases. In February 2015, Madrid hospitals adopted a similar working document.^[66] Hospital Clínic has found little scientific evidence to support this use and relies on the victims' stories to reach any conclusion.^[66]

Although poisoning by scopolamine appears quite often in the media as an aid for raping, kidnapping, killing, or robbery, the effects of this drug and the way it is applied by criminals (transdermal injection, on playing cards and papers, etc.) are often exaggerated,^[67][68][69] especially skin exposure, as the dose that can be absorbed by the skin is too low to have any effect.^[66] Scopolamine transdermal patches must be used for hours to days.^[34]

There are certain other aspects of the usage of scopolamine in crimes. Powdered scopolamine is referred to as "devil's breath". In popular media and television, it is portrayed as a method to brainwash or control people into being defrauded by their attackers.^[70] There is debate whether these claims are true.^[71][72][73]

Scopolamine is used as a research tool to study memory encoding. Initially, in human trials, relatively low doses of the muscarinic receptor antagonist scopolamine were found to induce temporary cognitive defects.^[74] Since then, scopolamine has become a standard drug for experimentally inducing cognitive defects in animals.^[75][76] Results in primates suggest that acetylcholine is involved in the encoding of new information into long-term memory.^[77] Scopolamine has been shown to exert a greater impairment on episodic memory, event-related potentials, memory retention and free recall compared to diphenhydramine (an anticholinergic and antihistamine).^[78]

Scopolamine produces detrimental effects on short-term memory, memory acquisition, learning, visual recognition memory, visuospatial praxis, visuospatial memory, visuoperceptual function, verbal recall, and psychomotor speed.^[79][75][76] It does not seem to impair recognition and memory retrieval, though.^[76] Acetylcholine projections in hippocampal neurons, which are vital in mediating long-term potentiation, are inhibited by scopolamine.^[76][80] Scopolamine inhibits cholinergic-mediated glutamate release in hippocampal neurons, which assist in depolarization, potentiation of action potential, and synaptic suppression. Scopolamine's effects on acetylcholine and glutamate release in the hippocampus favor retrieval-dominant cognitive functioning.^[76] Scopolamine has been used to model the defects in cholinergic function for models of Alzheimer's, dementia, fragile X syndrome, and Down syndrome.^{[76][81][82][83]}

Scopolamine has been identified as a psychoplastogen, which refers to a compound capable of promoting rapid and sustained neuroplasticity in a single dose.^[84] It has been, and continues to be investigated as a rapid-onset antidepressant, with a number of small studies finding positive results, particularly in female subjects.^{[85][86][87][88]}

NASA agreed to develop a nasal administration method. With a precise dosage, the NASA spray formulation has been shown to work faster and more reliably than the oral form to treat motion sickness.^[89]

Although a fair amount of research has been applied to scopolamine in the field of medicine, its hallucinogenic (psychoactive) effects as well as the psychoactive effects of other antimuscarinic deliriants haven't been extensively researched or as well understood compared to other types of hallucinogens such as psychedelic and dissociative compounds, despite the alkaloid's long history of usage in mind-altering plant preparations.^[90]

• Media related to Scopolamine at Wikimedia Commons