Scopolamine entersbreast milk bysecretion. 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.[28]
The pharmacological effects of scopolamine are mediated through the drug's competitiveantagonism of the peripheral and centralmuscarinic acetylcholine receptors. Scopolamine acts as a nonspecific muscarinic antagonist at all four (M1,M2,M3, andM4) receptor sites.[34][35]
In doses higher than intended for medicinal use, the hallucinogenicalteration of consciousness, as well as thedelirium in particular, are tied to the compound's activity at theM1 muscarinic receptor. M1 receptors are located primarily in thecentral nervous system and are involved in perception, attention, and cognitive functioning. Delirium is associated solely with the antagonism ofpostsynaptic M1 receptors; currently no other receptor subtypes have been implicated.[36]
Peripheral muscarinic receptors are part of theautonomic 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.[36] Due to the drug's inhibition of various signal transduction pathways, the decrease inacetylcholine 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.[37]
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 blocknicotinic receptors.[36]
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 theCYP3A4 enzyme, andgrapefruit juice decreases metabolism of scopolamine, consequently increasing plasma concentration.[8]
Aputrescine oxidase that specifically recognizes methylated putrescine catalyzes thedeamination 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 withacetoacetic acid yieldinghygrine. Noenzymatic activity could be demonstrated to catalyze this reaction. Hygrine further rearranges totropinone.[39]
Plants naturally containing scopolamine such asAtropa belladonna (deadly nightshade),Brugmansia (angels trumpet),Datura (Jimson weed),Hyoscyamus niger,Mandragora officinarum,Scopolia carniolica,Latua andDuboisia myoporoides have been known about and used for various purposes in both theNew andOld Worlds since ancient times.[41][42][43] 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 scientistAlbert Ladenburg in 1880,[44] and as various preparations from its plant-based form since antiquity and perhaps prehistoric times.
In 1899, Dr. Schneiderlin recommended the use of scopolamine andmorphine for surgical anaesthesia, and it started to be used sporadically for that purpose.[14][45] The use of this combination inobstetric anesthesiology (childbirth) was first proposed by Richard von Steinbuchel in 1902 and was picked up and further developed by Carl Gauss inFreiburg, Germany, starting in 1903.[46] The method, which was based on a drugsynergy between both scopolamine and morphine came to be known asDämmerschlaf ("twilight sleep") or the "Freiburg method".[45][46] It spread rather slowly, and different clinics experimented with different dosages and ingredients. In 1915, theCanadian Medical Association Journal reported, "the method [was] really still in a state of development".[45] It remained widely used in the US until the 1960s, when growingchemophobia and a desire for morenatural childbirth led to its abandonment.[47]
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 adeliriant drug, so repeated recreational use is rare.[50] In June 2008, more than 20 people were hospitalized withpsychosis in Norway after ingesting counterfeitrohypnol tablets containing scopolamine.[51] In January 2018, 9 individuals were hospitalized in Perth, Western Australia, after reportedly ingesting scopolamine.[52]
Historically, the various plants that produce scopolamine have been used psychoactively forspiritual andmagical purposes, particularly by witches in western culture andindigenous groups throughout theAmericas, such asNative American tribes like theChumash.[18][55][56][57] Whenentheogenic 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 notablyflying ointment.[58]
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 inEuropean witchcraft at least as far back as theearly 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.[58]
In theBible, there are multiple mentions ofMandrake, a psychoactive and hallucinogenic plant root that contains scopolamine. It was associated with fertility and (sexual) desire for which it was yearned byRachel, who was "barren" (infertile) but trying to conceive.[59][60]
The effects of scopolamine were studied for use as atruth serum in interrogations in the early 20th century,[61] but because of the side effects, investigations were dropped.[62] In 2009, theCzechoslovakstate security secret police were proven to have used scopolamine at least three times to obtain confessions from allegedantistatedissidents.[63]
Ingestion of scopolamine can render a victim unconscious for 24 hours or more. In large doses, it can cause respiratory failure and death. The highest prevalence of misuse seems to be recorded inColombia. Unofficial estimates there put the number of annual scopolamine incidents at approximately 50,000. A travel advisory published by theU.S. Overseas Security Advisory Council (OSAC) in 2012 stated:
One common and particularly dangerous method that criminals use 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 nightclubs 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.[64]
Between 1998 and 2004, 13% of emergency-room admissions for "poisoning with criminal intentions" in a clinic ofBogotá have been attributed to scopolamine, and 44% tobenzodiazepines.[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 inexpress kidnappings andsexual assault.[65] In 2008, the Hospital Clínic inBarcelona introduced aprotocol to help medical workers identify cases. In February 2015, Madrid hospitals adopted a similar working document.[65] Hospital Clínic has found little scientific evidence to support this use and relies on the victims' stories to reach any conclusion.[65]
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,[66][67][68] especially skin exposure, as the dose that can be absorbed by the skin is too low to have any effect.[65] Scopolamine transdermal patches must be used for hours to days.[33]
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 tobrainwash or control people into being defrauded by their attackers.[69] There is debate whether these claims are true.[70][71][72]
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.[73] Since then, scopolamine has become a standard drug for experimentally inducing cognitive defects in animals.[74][75] Results in primates suggest thatacetylcholine is involved in the encoding of new information into long-term memory.[76] Scopolamine has been shown to exert a greater impairment onepisodic memory,event-related potentials,memory retention andfree recall compared todiphenhydramine (an anticholinergic andantihistamine).[77]
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.[78][74][75] It does not seem to impair recognition and memory retrieval, though.[75] Acetylcholine projections in hippocampal neurons, which are vital in mediating long-term potentiation, are inhibited by scopolamine.[75][79] 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.[75] Scopolamine has been used to model the defects in cholinergic function for models ofAlzheimer's, dementia,fragile X syndrome, and Down syndrome.[75][80][81][82]
Scopolamine has been identified as apsychoplastogen, which refers to a compound capable of promoting rapid and sustainedneuroplasticity in a single dose.[83] It has been and continues to be investigated as a rapid-onsetantidepressant, with many small studies finding positive results, particularly in female subjects.[84][85][86][87]
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.[88]
Although a fair amount of research has been applied to scopolamine in the field of medicine, itshallucinogenic (psychoactive) effects as well as the psychoactive effects of other antimuscarinicdeliriants have not been extensively researched or as well understood compared to other types of hallucinogens such aspsychedelic anddissociative compounds, despite the alkaloid's long history of usage in mind-altering plant preparations.[89]
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