|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|
|Pregnancy cat.||B2 (AU) C (US)|
|Legal status||Prescription Only (S4) (AU) ℞-only (CA) POM (UK) ℞-only (US)|
|Routes||transdermal, ocular, oral, subcutaneous, intravenous, sublingual, rectal, buccal transmucousal, intramuscular|
|Bioavailability||0.13-8% (Oral), 3% (Rectal)|
|ATC code||A04 N05, S01|
|Mol. mass||303.353 g/mol|
|(what is this?)|
Scopolamine (USAN), hyoscine (BAN) also known as levo-duboisine or burundanga, sold as Scopoderm, 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 (Datura), angel's trumpets (Brugmansia), and corkwood (Duboisia). Scopolamine exerts its effects by acting as a competitive antagonist at muscarinic acetylcholine receptors, specifically M1 receptors; it is thus classified as an anticholinergic, antimuscarinic drug. (See the article on the parasympathetic nervous system for details of this physiology.)
- 1 Medical use
- 2 Adverse effects
- 3 Biosynthesis in plants
- 4 History
- 5 Methods of administration
- 6 Recreational use
- 7 Scopolamine related hospitalizations
- 8 Use in interrogation
- 9 Criminal use
- 10 Research as treatment for depression and anxiety
- 11 References
- Postoperative nausea and vomiting and sea sickness, leading to its use by scuba divers.
- Motion sickness (where it is often applied as a transdermal patch behind the ear)
- Gastrointestinal spasms
- Renal or biliary spasms
- Aid in GI radiology and endoscopy
- Irritable bowel syndrome (IBS)
- Clozapine-induced hypersalivation (drooling)
- Bowel colic
- Uncommon (0.1%-1% incidence) adverse effects include
- Dry mouth
- Dyshidrosis (reduced ability to sweat to cool off)
- Tachycardia (usually occurs at higher doses and is succeeded by bradycardia)
- Rare (<0.1% incidence) adverse effects include
- Urinary retention (being unable to urinate)
- Unknown frequency adverse effects include
- Anaphylactic shock
- Anaphylactic reactions
- Dyspnea (shortness of breath)
- Other hypersensitivity reactions
- Blurred vision
Physostigmine is an acetylcholinesterase inhibitor that readily crosses the blood-brain barrier, and has been used to treat the CNS depression symptoms of scopolamine overdose. Other than this supportive treatment, gastric lavage and induced emesis (vomiting) are usually recommended as treatments for overdoses. The symptoms of overdose include:
- Blurred vision
- Urinary retention
- Drowsiness or paradoxical excitement which can present with hallucinations
- Cheyne-Stokes respiration
- Dry mouth
- Skin reddening
- Inhibition of gastrointestinal motility
Biosynthesis in plants
The steps of the biosynthesis of scopolamine are:
- Ornithine decarboxylase (EC 126.96.36.199) decarboxylates L-ornithine to putrescine.
- Putrescine N-methyltransferase (EC 188.8.131.52) methylates putrescine to N-methylputrescine.
- Putrescine oxidase (EC 184.108.40.206) deaminates N-methylputrescine to 4-methylaminobutanal.
- 4-methylaminobutanal spontaneously ring-closes to N-methyl-pyrrolium cation.
- Something (no enzyme has been found) condenses pyrrolium cation with acetoacetic acid yielding hygrine.
- Hygrine rearranges to tropinone.
- Tropinone reductase I (EC 220.127.116.11) converts tropinone to tropine.
- Tropine condenses with phenyllactate (made from phenylalanine) to form littorine.
- A cytochrome P450 classified as Cyp80F1 oxidizes and rearranges littorine to hyoscyamine aldehyde.
- 6beta-hydroxyhyoscyamine epoxidase (EC 18.104.22.168) epoxidizes hyoscyamine to scopolamine.
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 prehistoric 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 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 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 (OTC) smoking preparation marketed in the 1950s and '60s claiming to combat asthma and bronchitis. In November 1990, the US Food and Drug Administration forced OTC products with scopolamine and several hundred other ingredients that had allegedly not been proved 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 such as Sominex, Tylenol PM, NyQuil, etc.
Methods of administration
Scopolamine can be administered orally, subcutaneously, ophthalmically and intravenously, as well as via a transdermal patch. The transdermal patch (e.g., Transderm Scōp) for prevention of nausea and motion sickness employs scopolamine base, and is effective for up to three days. 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).
While it is occasionally used recreationally for its hallucinogenic properties, the experiences are often mentally and physically extremely unpleasant, and frequently physically dangerous, so repeated use is rare.
About one in five emergency room admissions for poisoning in Bogotá, Colombia, have been attributed to scopolamine. In June 2008, more than 20 people were hospitalized with psychosis in Norway after ingesting counterfeit Rohypnol tablets containing scopolamine.
Use in interrogation
The effects of scopolamine were studied by criminologists in the early 20th century. In 2009, it was proved that Czechoslovak communist State Security secret police used scopolamine at least three times to obtain confessions from alleged anti-state conspirators. Because of a number of undesirable side effects, scopolamine was shortly disqualified as a truth serum.
In 1910, scopolamine 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.
Per the United States State Department (March 4, 2012): "One common and particularly dangerous method that criminals use in order to rob a victim is through the use of drugs. The most common has been scopolamine. Unofficial estimates put the number of annual scopolamine incidents in Colombia at approximately 50,000. Scopolamine can render a victim unconscious for 24 hours or more. In large doses, it can cause respiratory failure and death. It 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. To avoid becoming a victim of scopolamine, one should never accept food or beverages offered by strangers or new acquaintances or leave food or beverages unattended. Victims of scopolamine or other drugs should seek immediate medical attention."
Research as treatment for depression and anxiety
Scopolamine has been shown in multiple studies to be a potent antidepressant and anxiolytic medication. Two methods of administration have been studied. The first is in-patient sessions where the patients receive an intravenous infusion of a relatively large quantity of scopolamine during a session that lasts 1–2 hours. The patients are monitored during the infusion and released soon after as the effects wear-off quickly. The second route of administration is oral scopolamine in a pill.
In another, randomized, double-blind, placebo-controlled study of intravenously infused scopolamine for patients with bipolar depression, it again showed rapid and robust antidepressant effects, as well as strong anti-anxiety effects.
In November 2010, results of another experiment about the impacts of scopolamine infusions were reported, this time assessing the reductions in depression and anxiety for the two sexes and for unipolar vs. bipolar depression with and without co-morbid anxiety. The experiment followed a block design where all patients first received a placebo infusion and then were assessed as base-line (in order to capture some of the placebo effect in the base-line). They then received either three placebo infusions or three scopolamine infusions (block one) followed by the opposite treatment - three scopolamine infusions or three placebo infusions, respectively (block two). They were assessed after each infusion, and statistical inference was performed using the results at the end of each block. The infusions were very effective in reducing both anxiety (as measured by HAM-A) and depression (as measured by MADRS) for all groups - men, women, unipolar depressives, patients with biploar disorder, patients with and without co-morbid anxiety.
For depression, the infusion treatment was especially effective for the women. Their results achieved statistical significance on each block even analyzed separately. For example, of the 16 women treated with scopolamine in block one, seven had a MADRS decrease of over 50% and six of them had complete remission, defined as a MADRS of less than 10. In contrast, of the 15 women receiving placebo infusions in block one, none of them achieved the 50% decrease or remission. The female group had a larger sample and a larger treatment effect than the male group - hence the statistical significance in each block separately. For men, 14 out of 21 patients had a decrease in MADRS of more than 25% during the study, and 9 had a decrease of over 50%. Six out of 21 had complete remission (although one of those six remissions occurred entirely during a placebo block). For men, both blocks needed to be analyzed in tandem in some way for statistical significance, but if so, the study-end treatment effect was statistically significant and very large (an average MADRS reduction of 14.0 with an average starting MADRS of 31.5). Over 40% of the men reduced MADRS by more than 50%, and 28% had full remission. The positive effects for the women were even larger. For example, over 70% of the women had a MADRS decrease of more than 50%, and well over half (58%) had total remission of their major depressive disorder.
For anxiety, the treatment effect (as measured by HAM-A) for the men was again positive (beneficial) and relatively large for each block, but was again too small to reach statistical significance with a sample of 21 if the blocks were considered as two separate experiments. As in the case of depression, combining the men's blocks yielded a treatment effect that was again statistically significant, but not as large as the men's depression treatment effect. The anxiety treatment effect had a greater difference between the men and women than the depression treatment effect had, with both effects being larger for the women. For example, for anxiety, the study-end results for men were a HAMS-A decrease from 17.7 to 11.7, and for the women, the average change was an impressive drop from 20.3 to 7.9.
In a forty-patient, randomized, double-blind, placebo-controlled study of oral scopolamine as an augmentation to citalopram, adding oral scopolamine more than tripled the number of patients who achieved remission in 6 weeks (13 out of 20 vs. 4 out of 20; treatment group = citalopram and scopolamine, control group = citalopram and placebo; remission = HDRS score below 7). The experiment was performed in 2010. Study participants were diagnosed with major depressive disorder and had a minimum HDRS of 22.
Based on the results, the researchers concluded that oral scopolamine-hydrobromide augmentation of 1 mg/day was a safe and effective adjunct for patients with moderate to severe major depressive disorder. A 2013 expert review of the same study was published in the journal "Expert Review of Neurotherapeutics". The reviewers agreed with the conclusion.
- "Buscopan Tablets - Summary of Product Characteristics (SPC)". electronic Medicines Compendium. Boehringer Ingelheim Limited. 11 September 2013. Retrieved 22 October 2013.
- "BUSCOPAN Tablets and Ampoules BUSCOPAN FORTE Tablets". TGA eBusiness Services (BOEHRINGER INGELHEIM PTY LIMITED). 8 November 2010. Retrieved 22 October 2013.
- Putcha, L.; Cintrón, N. M.; Tsui, J.; Vanderploeg, J. M.; Kramer, W. G. (1989). "Pharmacokinetics and Oral Bioavailability of Scopolamine in Normal Subjects". Pharmacology Research 6 (6): 481–485. doi:10.1023/A:1015916423156. PMID 2762223.
- Uribe-Granja, Manuel; Moreno-López, Claudia L.; Zamora S., Adriana; Acosta, Pilar J. (September 2005). "Perfil epidemiológico de la intoxicación con burundanga en la clínica Uribe Cualla S. A. de Bogotá, D. C" (pdf). Acta Neurológica Colombiana (in Spanish) 21 (3): 197–201.
- Muranaka, T.; Ohkawa, H.; Yamada, Y. (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.
- The Chambers Dictionary. Allied Publishers. 1998. pp. 788, 1480. ISBN 978-81-86062-25-8.
- "TRANSDERM SCOP (scopalamine) patch, extended release [Baxter Healthcare Corporation]". DailyMed. Baxter Healthcare Corporation. April 2013. Retrieved 22 October 2013.
- "DBL™ HYOSCINE INJECTION BP". TGA eBusiness Services. Hospira Australia Pty Ltd. 30 January 2012. Retrieved 22 October 2013.
- Cattell, Henry Ware (1910). Lippincott's new medical dictionary: a vocabulary of the terms used in medicine, and the allied sciences, with their pronunciation, etymology, and signification, including much collateral information of a descriptive and encyclopedic character. Lippincott. p. 435. Retrieved 25 February 2012.
- Joint Formulary Committee (2013). British National Formulary (BNF) (65 ed.). London, UK: Pharmaceutical Press. pp. 49, 266, 822, 823. ISBN 978-0-85711-084-8.
- Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.
- Bitterman, N.; Eilender, E.; Melamed, Y. (1991). "Hyperbaric Oxygen and Scopolamine". Undersea Biomedical Research 18 (3): 167–174. PMID 1853467. Retrieved 2008-08-13.
- Williams, T. H.; Wilkinson, A. R.; Davis, F. M.; Frampton, C. M. (1988). "Effects of Transcutaneous Scopolamine and Depth on Diver Performance". Undersea Biomedical Research 15 (2): 89–98. PMID 3363755.
- "Kwells 300 microgram tablets - Summary of Product Characteristics". electronic Medicines Compendium. Bayer plc. 7 January 2008. Retrieved 22 October 2013.
- Clinical anesthesia (6th ed. ed.). Philadelphia: Wolters Kluwer/Lippincott Williams & Wilkins. 2009. p. 346. ISBN 978-0-7817-8763-5.
- Ziegler, J.; Facchini, P. J. (2008). "Alkaloid Biosynthesis: Metabolism and Trafficking". Annual Review of Plant Biology 59 (1): 735–769. doi:10.1146/annurev.arplant.59.032607.092730. PMID 18251710.
- Li, R.; Reed, D. W.; Liu, E.; Nowak, J.; Pelcher, L. E.; Page, J. E.; Covello, P. S. (2006). "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. PMID 16720272.
- White, P. F.; Tang, J.; Song, D. et al. (2007). "Transdermal Scopolamine: An Alternative to Ondansetron and Droperidol for the Prevention of Postoperative and Postdischarge Emetic Symptoms". Anesthesia and Analgesia 104 (1): 92–96. doi:10.1213/01.ane.0000250364.91567.72. PMID 17179250.
- "Transderm Scop patch prescribing information".
- "NASA Signs Agreement to Develop Nasal Spray for Motion Sickness".
- Freye, E. (2010). "Toxicity of Datura Stramonium". Pharmacology and Abuse of Cocaine, Amphetamines, Ecstasy and Related Designer Drugs. Netherlands: Springer. pp. 217–218. doi:10.1007/978-90-481-2448-0_34. ISBN 978-90-481-2447-3.
- "Bilsykemedisin i falske rohypnol-tabletter". Aftenposten.no.
- House, R. E. (September 1922). "The Use of Scopolamine in Criminology". Texas State Journal of Medicine 18: 256–263.
reprinted House, R. E. (1931). "The Use of Scopolamine in Criminology". American Journal of Police Science (Northwestern University) 2 (4): 328–336. doi:10.2307/1147361. JSTOR 1147361.
- Gazdík, J.; Navara, L. (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. Retrieved 2009-08-10.
- ""Truth" Drugs in Interrogation". Central Intelligence Agency. Retrieved 14 June 2012.
- "The Trial of H.H. Crippen" ed. by Filson Young (Notable British Trials series, Hodge, 1920), p. xxvii; see also evidence, pp. 68-77.
- https://www.osac.gov/Pages/ContentReportDetails.aspx?cid=12118 Colombia 2012 Crime and Safety Report: Cartagena
- Frankel, E; Drevets, W; Luckenbaugh, D; Speer, A; Nugent, A; Zarate, C; Furey, M (June 2011). "Scopolamine as a fast-acting antidepressant agent in bipolar depression: A randomized placebo-controlled clinical trial". Bipolar disorders (Wiley-Blackwell) 13 (s1): 45. ISSN 1398-5647.
- Martinowich, K; Jimenez, DV; Zarate, CA; Jr, Manji, HK (August 2013). "Rapid antidepressant effects: moving right along". Molecular Psychiatry 18 (8): 856–863. doi:10.1038/mp.2013.55. PMID 23689537.
- Furey, ML; Khanna, A; Hoffman, EM; Drevets, WC (November 2010). "Scopolamine produces larger antidepressant and anti-anxiety effects in women than in men". Neuropsychopharmacology 35 (12): 2479–2488. doi:10.1038/npp.2010.131. PMID 20736989.
- Khajavi, Danial, et al. (2012). "Oral scopolamine augmentation in moderate to severe major depressive disorder: a randomized, double-blind, placebo-controlled study". Journal of Clinical Psychiatry 73 (12): 1428–1433. doi:10.4088/JCP.12m07706.
- Han, C; Pae, CU (January 2013). "Oral scopolamine augmentation for major depression". Expert Review of Neurotherapeutics 13 (1): 19–21. doi:10.1586/ern.12.150. PMID 23253388.