Scopolamine

Scopolamine

Systematic (IUPAC) name
(–)-(S)-3-hydroxy-2-phenylpropionic acid(1R,2R,4S,7S,9S)-9-methyl-3-oxa-9-azatricyclo[3.3.1.02,4]non-7-yl ester
Clinical data
Trade names	Transdermscop
AHFS/Drugs.com	monograph
Pregnancy cat.	C(US)
Legal status	℞-only (US)
Routes	transdermal, ocular, oral, subcutaneous, intravenous, sublingual, rectal, buccal transmucousal, intramuscular
Pharmacokinetic data
Bioavailability	10 - 50% [1]
Half-life	4.5 hours[1]
Identifiers
CAS number	51-34-3 Y
ATC code	A04AD01 N05CM05, S01FA02
PubChem	CID 5184
DrugBank	DB00747
ChemSpider	10194106 Y
UNII	DL48G20X8X Y
KEGG	D00138 Y
ChEBI	CHEBI:16794 Y
ChEMBL	CHEMBL1201069 N
Chemical data
Formula	C17H21NO4
Mol. mass	303.353 g/mol
SMILES	eMolecules & PubChem
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
N(what is this?)  (verify)

Scopolamine, also known as levo-duboisine, and hyoscine, is a tropane alkaloid drug with muscarinic antagonist effects. It is among the secondary metabolites of plants from Solanaceae (nightshade) family of plants, such as henbane, jimson weed and Angel's Trumpets (Datura resp. Brugmansia spec.), and corkwood (Duboisia species ^[2]). Scopolamine exerts its effects by acting as a competitive antagonist at muscarinic acetylcholine receptors, specifically M1 receptors; it is thus classified as an anticholinergic, anti-muscarinic drug. (See the article on the parasympathetic nervous system for details of this physiology.)

Although scopolamine is often portrayed in the media as a dangerous drug, its anticholinergic properties give it some legitimate medical applications in very minute doses. As an example, in the treatment of motion sickness, the dose, gradually released from a transdermal patch, is only 330 micrograms (µg) per day. In rare cases, unusual reactions to ordinary doses of scopolamine have occurred including confusion, agitation, rambling speech, hallucinations, paranoid behaviors, and delusions.

Etymology

Scopolamine is named after the plant genus Scopolia. The name "hyoscine" is from the scientific name for henbane, Hyoscyamus niger.

Biosynthesis in plants

The biosynthesis of scopolamine begins with the decarboxylation of L-ornithine to putrescine by ornithine decarboxylase (EC 4.1.1.17). Putrescine is methylated to N-methylputrescine by putrescine N-methyltransferase (EC 2.1.1.53).^[3]

A putrescine oxidase (EC 1.4.3.10) that specifically recognizes methylated purtrescine catalizes the deamination of this compound to 4-methylaminobutanal which then undergoes a spontanous ring formation to N-Methyl-pyrrolium cation. In the next step, the pyrrolium cation condenses with acetoacetic acid yielding hygrine. No enzmyatic activity could be demonstrated that catalyzes this reaction. Hygrine further rearranges to tropinone.^[3]

Subsequently, Tropinone reductase I (EC 1.1.1.206) converts tropinone to tropine which condenses with phenylalanine-derived phenyllactate to littorine. A cytochrome P450 classified as Cyp80F1^[4] oxidizes and rearranges littorine to hyoscyamine aldehyde. In the final step, hyoscyamine undergoes epoxidation which is catalyzed by 6beta-hydroxyhyoscyamine epoxidase (EC 1.14.11.14) yielding scopolamine.^[3]

Biosynthesis of scopolamine in plants.

History

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 isolation by the German scientist Albert Ladenburg in 1880, and as various preparations from its plant-based form since antiquity and perhaps pre-historic times. Following the description of the structure and activity of scopolamine by Ladenburg, the search for synthetic analogues of and methods for total synthesis of scopolamine and/or atropine in the 1930s and 1940s resulted in the discovery of diphenhydramine, an early antihistamine and the prototype of its chemical subclass of these drugs, and pethidine, the first fully synthetic opioid analgesic, known as Dolatin and Demerol amongst many other trade names.

Scopolamine was used in conjunction with morphine, oxycodone, or other opioids from before 1900 up into the 1960s to put mothers in labor into a kind of "twilight sleep". The analgesia from scopolamine plus a strong opioid is deep enough to allow higher doses to be used as a form of anaesthesia.

Scopolamine mixed with oxycodone (Eukodal), and ephedrine was marketed by Merck as SEE (from the German initials of the ingredients) and Scophedal starting in 1928, and the mixture is sometimes mixed up on site on rare occasions in the area of its greatest historical usage, namely Germany and Central Europe.

Scopolamine was also one of the active ingredients in Asthmador, an over-the-counter smoking preparation marketed in the 1950s and '60s claiming to combat asthma and bronchitis. In November 1990 the U.S. Food and Drug Administration forced OTC products with scopolamine and several hundred other ingredients that had allegedly not been proven effective off the market. Scopolamine shared a small segment of the OTC sleeping pill market with diphenhydramine, phenyltoloxamine, pyrilamine, doxylamine and other first generation antihistamines, many of which are still used for this purpose in drugs like Sominex, Tylenol PM, NyQuil, etc.

Methods of administration

Scopolamine can be administered orally, subcutaneously, opthalmically and intravenously, as well as via a transdermal patch.^[5] The transdermal patch (e.g. Transderm Scōp) for prevention of nausea and motion sickness employs scopolamine base, and is effective for up to 3 days.^[6] The oral, ophthalmic and intravenous forms have shorter half-lives and are usually found in the form scopolamine hydrobromide (for example in Scopace, soluble 0.4 mg tablets or Donnatal).

Medical use

Scopolamine has a number of uses in medicine:

• Primary Uses:
  • Treatment of nausea and motion sickness.
  • Treatment of intestinal cramping.
  • For ophthalmic purposes.
  • As a general depressant and adjunct to narcotic painkillers.

• Secondary Uses:
  • As a preanesthetic agent.
  • As a drying agent for sinuses, lungs, and related areas.
  • To reduce motility and secretions in the GI tract—most frequently in tinctures or other belladonna or stramonium preparations, often used in conjunction with other drugs as in Donnagel original forumulation, Donnagel-PG (with paregoric), Donnabarb/Barbadonna/Donnatal (with phenobarbital), and a number of others.
  • Uncommonly, for some forms of Parkinsonism.
  • As an adjunct to opioid analgesia, such as the product Twilight Sleep which contained morphine and scopolamine, some of the original formulations of Percodan and some European brands of methadone injection.^{[citation needed]}.
  • As an over-the-counter sedative, (Up until November 1990 scopolamine in minute doses could be purchased OTC legally in the United States).

Nausea

Its use as an antiemetic in the form of a transdermal patch (applied behind the external ear).

Ophthalmic

The drug is used in eye drops to induce mydriasis (pupillary dilation) and cycloplegia (paralysis of the eye focusing muscle), primarily in the treatment of eye disorders that benefit from its prolonged effect, e.g. uveitis, iritis, iridocyclitis, etc.

Memory research

Because of its anticholinergic effects, scopolamine has been shown to prevent the activation of medial temporal lobe structures for novel stimuli during spatial memory tasks. It has also been shown to impair memory in humans to mimic the cognitive deficits found in Alzheimer's Dementia.

Addiction

Scopolamine has been used in the past to treat addiction to drugs such as heroin and cocaine. The patient was given frequent doses of scopolamine until they were delirious. This treatment was maintained for 2 to 3 days after which they were treated with pilocarpine. After recovering from this they were said to have lost the acute craving to the drug to which they were addicted.^[7]

Currently, scopolamine is being investigated for its possible usefulness alone or in conjunction with other drugs in treating nicotine addiction.^{[citation needed]} The mechanism by which it mitigates withdrawal symptoms is different from that of clonidine meaning that the two drugs can be used together without duplicating or canceling out the effects of each other.^{[citation needed]}

Other medical uses

• It can be used as a depressant of the central nervous system, and was formerly used as a bedtime sedative.
• Anesthetic; Its use in general anesthesia is favored by some^{[citation needed]} due to its amnesic effect. Scopolamine causes memory impairments to a similar degree as diazepam.^[8]
• In otolaryngology it is used to dry the upper airway (anti-sialogogue action) prior to instrumentation of the airway.
• In October 2006 researchers at the US National Institute of Mental Health found that scopolamine reduced symptoms of depression within a few days, and the improvement lasted for at least a week after switching to a placebo.^[9]
• Intravenously administered scopolamine has been found to be effective ^[10] against major depressive disorder. A phase II clinical trial ^[11] of its efficacy against both major depressive disorder and depression due to bipolar disorder when administered via transdermal patches is scheduled to finish in September 2011.
• Due to its effectiveness against sea-sickness it has become commonly used by scuba divers.^[12][13]
• In Colombia a plant admixture containing scopolamine called Burundanga has been used shamanically for decades.^{[citation needed]}
• Scopolamine has been tested as a topical treatment for Aquagenic pruritus and was shown in several cases to be effective.^[14]

Adverse effects

The common side effects are related to the anticholinergic effect on parasympathetic postsynaptic receptors: dry mouth, throat and nasal passages in overdose cases progressing to impaired speech, thirst, blurred vision and sensitivity to light, constipation, difficulty urinating and tachycardia. Other effects of overdose include flushing and fever, as well as excitement, restlessness, hallucinations, or delirium. These side effects are commonly observed with oral or parenteral uses of the drug and generally not with topical ophthalmic use.

Use in scuba diving to prevent sea sickness has led to the discovery of another side effect. In deep water, below 50–60 feet, some divers have reported pain in the eyes that subsides quickly if the diver ascends to a depth of 40 feet or less. Mydriatics can precipitate an attack of glaucoma in susceptible patients, so the medication should be used with extra caution among divers who intend to go below 50 feet.

Drug interactions

When combined with morphine, scopolamine is useful for pre-medication for surgery or diagnostic procedures and was widely used in obstetrics in the past; the mixture also produces amnesia and a tranquillised state known as Twilight Sleep, also the name of a proprietary drug available in the past in ampoules of injectable fluid containing morphine sulfate and scopolamine hydrobromide (and in some cases the phenothiazine anti-nauseants prochlorperazine or promethazine as a third ingredient). Although originally used in obstetrics, it is now considered dangerous for that purpose for both mother and baby.^{[citation needed]}

Recreational use

The use of medical scopolamine/opioid combination preparations for euphoria is uncommon but does exist and can be seen in conjunction with opioid use. Doses of scopolamine by itself near the therapeutic range create euphoria and anxiolysis of anticholinergic origin, similar to that of some first-generation antihistamines and similar drugs.

Another separate group of users prefer dangerously high doses, especially in the form of datura preparations, for the deliriant and hallucinogenic effects. The hallucinations produced by scopolamine, in common with other potent anticholinergics, are especially real-seeming, with many users reporting hallucinations such as spiders crawling on walls and ceilings, especially in the dark. While some users find this pleasant, often the experience is not one that the user would want to repeat. An overdose of scopolamine is also exceedingly unpleasant physically, and can be fatal, unlike the effect of other more commonly used hallucinogens. For these reasons, naturally occurring anticholinergics are rarely used for recreational purposes.

Scopolamine in transdermal, oral, sublingual, and injectable formulations can produce a cholinergic rebound effect when high doses are stopped. This is the opposite of scopolamine's therapeutic effects: sweating, runny nose, abdominal cramps, nausea, vomiting, vertigo, dizziness, irritability, and diarrhea. Psychological dependence is also possible when the drug is taken for its tranquilizing effects.

Use in interrogation

The effects of scopolamine were studied by criminologists in the early 20th century.^[15] However, scopolamine as a truth drug was not seriously tested for this purpose until the 1950s when it was experimented on by various intelligence agencies, including the CIA as part of Project MKULTRA. In 2009, it was proven that Czechoslovak communist secret police used scopolamine at least three times to obtain confessions from alleged anti-state conspirators.^[16]

Criminal use and urban legends

In 1910 it was detected in the remains believed to be those of Cora Crippen, wife of Dr. Hawley Harvey Crippen, and was accepted at the time as the cause of her death since her husband was known to have bought some at the start of the year.^[17] Scopolamine poisoning is sometimes reported by the media as method by which people are raped, killed, or robbed, although largely exaggerated in many unfounded rumors.

For example, there have been a number of unfounded circulating rumors that Colombian robbers were using a transcutaneous delivery mechanism involving business cards, pamphlets or flyers laced with the drug. However, in actual fact, the quantity of toxin diffusing through the skin barrier after one short contact of the fingers with an object is much too small to be readily absorbed in the body and to have any significant effect. The use of burundanga (aka scopolamine) impregnated visit cards to attack and to rob isolated people is often propagated by chain emails and is presently reported as hoax or urban legend by many specialized web sites.^[18][19][20]

Nevertheless, approximately one in five emergency room admissions for poisoning in Bogotá have been attributed to scopolamine.^[21] In June 2008, more than 20 people were hospitalized with psychosis in Norway after ingesting counterfeit Rohypnol tablets containing scopolamine.^[22]

There have also been reports of tourists being robbed after having scopolamine slipped into their food or drink. Recently, these incidents have been reported in Thailand.^[23]

Witchcraft and sorcery

Scopolamine was one of the active principles in many of the "flying ointments" used by witches, sorcerers and fellow travellers of many countries and cultures from millennia ago ostensibly down to the late 19th century or even to the present day. Scopolamine and related tropanes contributed both to the flying sensations and hallucinations sought by users of these compounds. Potions, solids of various types, and other forms were also used in some cases.

These ointments could contain any number of ingredients with belladonna, henbane, and other plants of the belladonna and datura families being present almost invariably; they were applied to large areas of the skin with the objective being to see the Gods or spirits, and/or be transported to the Sabbat.

The hallucinations, sensation of flying, often a rapid increase in libido, and other characteristic effects of this practice are largely attributable to the CNS and peripheral effects of scopolamine and other active drugs present in the ointments such as atropine, hyoscyamine, mandragorine, scopoline, solanine, optical isomers of scopolamine and other tropane alkaloids.

The inclusion of belladonna/datura type plants amongst the dozens of ingredients in the Haitian zombie drug is thought by some authorities to be at least somewhat likely, although scopolamine-bearing plant matter is almost certainly not the main active ingredient, which has been theorised to possibly be Tetrodotoxin or a related substance.

In popular culture

• The fictional use of scopolamine as a truth serum is featured in a number of works including The House on 92nd Street, Farewell, My Lovely, Where Eagles Dare and The Guns of Navarone.
• In 1957, scopolamine achieved a moderate level of notoriety via its mention in the film I Was a Teenage Werewolf, where Dr. Alfred Brandon uses it as part of his endeavor to regress the titular character to his "primitive roots." According to Dr. Liz Kingsley's film review site "And You Call Yourself a Scientist", Brandon's line "Prepare the scopolamine!" is "the only scientifically accurate line in the whole film."
• In Fear and Loathing In Las Vegas by Hunter S. Thompson, Dr. Gonzo mentions an incident in which he was given an entire datura root as a gift, ate the entire thing at once, and subsequently went blind, had to be taken back to his house in a wheelbarrow, and started making noises like a raccoon.
• In Carlos Castaneda's series of books The Teachings of Don Juan: A Yaqui Way of Knowledge, the datura plant is the least favored shamanic, revelatory drug of the titular character, however Castaneda shows an affinity for it. The book explores, in depth, Castaneda's alleged experiences under the influence of the drug, as well as the alleged rites surrounding its use and preparation.
• Scopolamine and "Twilight Sleep" were integral to the plot of The X-Files season four episode Unruhe. The drug was used as an interrogation tool during Episode 9 of NBC's Kidnapped. It was also featured in "Smut", a December 2008 episode of Law & Order: Special Victims Unit's tenth season, in which a rapist used scopolamine to prevent the women he raped from resisting him and from forming memories.
• According to Janet Flanner (Genêt), in her 1972 book Paris was Yesterday (1925–1939), a collection of her New Yorker pieces, Prince Yussupoff was accused of poisoning with scopolamine the family of Princess Demidoff at regular tea parties, producing,

  on her noble family, and all their tea-drinking friends – a state of complete stupidity which none of these aristocrats found strange. Memory vanished, general conversation lagged, the two children dropped behind in their studies and became unable to add two and two without exciting comment from their proud parents. Casual guests popping in for a le five-o'clock were led back to their limousines in a state of complete imbecility; and an aunt, the Duchesse de Luynes, fell flat on her face after having sipped a cup of weak Orange Pekoe ('which was abnormal for Her Grace').^[24]

References

Notes

1. ^ ^{a b} Putcha L, Cintrón NM, Tsui J, Vanderploeg JM, Kramer WG (June 1989). "Pharmacokinetics and oral bioavailability of scopolamine in normal subjects". Pharm. Res. 6 (6): 481–5. doi:10.1023/A:1015916423156. PMID 2762223. 
2. ^ Muranaka T, Ohkawa H, Yamada Y (November 1993). "Continuous production of scopolamine by a culture of Duboisia leichhardtii hairy root clone in a bioreactor system". Applied Microbiology and Biotechnology 40 (2-3): 219–223. doi:10.1007/BF00170370. http://www.springerlink.com/content/g7x30m6495332j8j/. 
3. ^ ^{a b c} Ziegler, Jörg; Facchini, Peter J. (1 June 2008). "Alkaloid Biosynthesis: Metabolism and Trafficking". Annual Review of Plant Biology 59 (1): 735–769. doi:10.1146/annurev.arplant.59.032607.092730. 
4. ^ Li, Rong; Reed, Darwin W., Liu, Enwu, Nowak, Jacek, Pelcher, Lawrence E., Page, Jonathan E., Covello, Patrick S. (NaN undefined NaN). "Functional Genomic Analysis of Alkaloid Biosynthesis in Hyoscyamus niger Reveals a Cytochrome P450 Involved in Littorine Rearrangement". Chemistry & Biology 13 (5): 513–520. doi:10.1016/j.chembiol.2006.03.005. 
5. ^ White PF, Tang J, Song D, et al. (2007). "Transdermal scopolamine: an alternative to ondansetron and droperidol for the prevention of postoperative and postdischarge emetic symptoms". Anesth. Analg. 104 (1): 92–6. doi:10.1213/01.ane.0000250364.91567.72. PMID 17179250. http://www.anesthesia-analgesia.org/cgi/pmidlookup?view=long&pmid=17179250. 
6. ^ Transderm Scop patch prescribing information
7. ^ Evelyn Clare Pearce (1941). Pearce's Medical and Nursing Dictionary and Encyclopaedia. Faber & Faber. 
8. ^ Jones DM; Jones ME, Lewis MJ, Spriggs TL. (May 1979). "Drugs and human memory: effects of low doses of nitrazepam and hyoscine on retention.". Br J Clin Pharmacol. 7 (5): 479–83. PMC 1429587. PMID 475944. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1429587. 
9. ^ Furey, ML; Drevets, WC (October 2006). "Antidepressant efficacy of the antimuscarinic drug scopolamine: a randomized, placebo-controlled clinical trial". Archives of General Psychiatry, vol 63, p 1121 63 (10): 1121. doi:10.1001/archpsyc.63.10.1121. PMID 17015814. 
10. ^ Drevets WC, Furey ML (March 2010). "Replication of scopolamine's antidepressant efficacy in major depressive disorder: a randomized, placebo-controlled clinical trial". Biol. Psychiatry 67 (5): 432–8. doi:10.1016/j.biopsych.2009.11.021. PMID 20074703. http://linkinghub.elsevier.com/retrieve/pii/S0006-3223(09)01414-0. 
11. ^ ClinicalTrials.gov NCT00369915 The Antidepressant Efficacy of the Anticholinergic Scopolamine
12. ^ Bitterman N, Eilender E, Melamed Y (May 1991). "Hyperbaric oxygen and scopolamine". Undersea Biomed Res 18 (3): 167–74. PMID 1853467. http://archive.rubicon-foundation.org/2573. Retrieved 2008-08-13. 
13. ^ Williams TH, Wilkinson AR, Davis FM, Frampton CM (March 1988). "Effects of transcutaneous scopolamine and depth on diver performance". Undersea Biomed Res 15 (2): 89–98. PMID 3363755. http://archive.rubicon-foundation.org/2495. Retrieved 2008-08-13. 
14. ^ M W Greaves, A K Black, R A Eady, and A Coutts. [1], "BMJ" (Clin Res Ed). 1981 June 20; 282(6281): 2008–2010
15. ^ House, Robert E. (September 1922). "The Use of Scopolamine in Criminology". Texas State Journal of Medicine 18: 256–263. 
    reprinted House, Robert E. (1931). "The Use of Scopolamine in Criminology". American Journal of Police Science (Northwestern University) 2 (4): 328–336. doi:10.2307/1147361. http://www.jstor.org/pss/1147361. ^{[citation needed]}
16. ^ Gazdík, Jan; Navara, Luděk (2009-08-08). "Svědek: Grebeníček vězně nejen mlátil, ale dával jim i drogy [A witness: Grebeníček not only beat prisoners, he also administered drugs to them]" (in Czech). iDnes. http://zpravy.idnes.cz/svedek-grebenicek-vezne-nejen-mlatil-ale-daval-jim-i-drogy-pmd-/domaci.asp?c=A090807_205833_domaci_vel. Retrieved 2009-08-10. 
17. ^ "The Trial of H.H. Crippen" ed. by Filson Young (Notable British Trials series, Hodge, 1920), p. xxvii; see also evidence, pp. 68-77.
18. ^ Hoax: Burundanga Business Card Drug Warning
19. ^ Urband legend: Burundanga Drug Warning
20. ^ Snopes.com: Burundanga Business Card
21. ^ Manuel Uribe G., Claudia L. Moreno L, Adriana Zamora S., Pilar J. Acosta (2005). "Perfil epidemiológico de la intoxicación con burundanga en la clínica Uribe Cualla S. A. de Bogotá, D. C." (PDF). Acta Neurol Colomb 21: 197–201. http://publicaciones.acnweb.org/acta/2005_21_3_197.pdf. 
22. ^ "Bilsykemedisin i falske rohypnol-tabletter — Nyheter — Innenriks — Aftenposten.no". http://www.aftenposten.no/nyheter/iriks/article2507100.ece. 
23. ^ http://travel.state.gov/travel/cis_pa_tw/cis/cis_1040.html
24. ^ from page 51 of the Penguin edition.

External links

• The Erowid Scopolamine Vault
• U.S. National Library of Medicine: Drug Information Portal - Scopolamine