The unbearable lightness of flying

Flying has always fascinated mankind, so much that it has inspired the invention of several devices and machines. Now, however, we are going to talk about a special kind of flight related to witchcraft. While legends about witches are numerous and diversified, being strongly influenced by local traditions, maybe one common trait is that they were believed to meet to celebrate Witches’ Sabbath and to fly to the meeting location. According to these legends, they would use an unguent to anoint parts of their bodies and some objects (perhaps a broom is the most popular one) and thanks to this magic ointment they were able to fly…or at least their imagination suggested them so. Of course, the flight was only happening in their mind.
Leaving aside the underlying misogyny of stories about witches, a few ointments inducing flight hallucinations have been documented. These contained among their ingredients several nightshades, including deadly nightshade (Atropa belladonna), jimsonweed (Datura stramonium), henbane (Hyoscyamus niger), mandrake (Mandragora officinarum). Therefore, it is likely that the responsible for the flight hallucination are some tropane alkaloids produced by these plants, in particular hyoscyamine and scopolamine.^a Absorbed through the skin, they indeed induce hallucinations, sensation of lightness and sensation of flying.
Structurally, tropane alkaloids are characterized by a specific nitrogenous bicyclic moiety.^b Alkaloids, in general, are particular basic nitrogen containing compounds, in which the nitrogen is typically part of a cyclic structure (although there are a few exceptions to this definition) [1].

Effects and uses of hyoscyamine and scopolamine

Hyoscyamine and scopolamine have anticholinergic effects [2], which means that they block the action of a neurotransmitter called acetylcholine. There are two classes of receptors that respond to acetylcholine (i.e., nicotinic and muscarinic) and the ones affected by tropane alkaloids are the muscarinic receptors. Hyoscyamine and scopolamine competitively antagonise these receptors, which means that they bind to the receptor, preventing binding of the physiological neurotransmitter and stopping it from producing a response [3]. As a result, they induce several therapeutic and adverse effects.
When reading about these effects, remember that, like for any other drug, the dose makes the poison. Also, please be aware that drug regulations may vary in different countries.

Hyoscyamine induces increase in heart rate and bronchodilation, while it reduces peristalsis, bladder contraction, sweating, salivary, gastric, and bronchial secretions [2]. It also causes dilation of the pupil and paralysis of the ciliary muscle of the eye [4]. Antagonism of muscarinic receptors in the central nervous system leads to cognitive impairment [5]. Further side effects include, but are not limited to confusion, hallucinations, disorientation, depersonalization, memory impairment, auditory changes, ataxia, muscular incoordination, blurred vision, hyperthermia, reduced salivation [6].
A racemic mixture^c of the two enantiomeric^c forms of hyoscyamine, atropine, finds clinical applications: it is used to treat organophosphate poisoning, to treat acute cases of bradyarrhythmia, to decrease saliva production during surgery [7]. Furthermore, it is used in ophthalmology to induce pupil dilation for specific eye exams and to treat a few medical conditions [7].
Scopolamine can be used for the prevention of nausea and vomiting associated with motion sickness and surgical procedures [2]. It is also sometimes used in palliative care [8]. Finally, its use in reducing depressive symptoms and as an antianxiety drug in patients with clinical depression and bipolar disorder is under investigation [9]. However, scopolamine can induce several side effects: exacerbated psychosis, hallucinations, euphoria, restlessness, disorientation, delirium, dizziness, light-headedness, blurred vision, dilation of pupils, muscle weakness, shortness of breath, slow or irregular heartbeat, etc. [6]. Due to its effects on cognitive function and the ability to cause amnesia, scopolamine has also an infamous record of criminal use to facilitate robberies and is listed among the “date-rape drugs” [10]. In the past it has been used, together with morphine and chloroform, to induce the controversial twilight sleep during childbirth [9]. This sleep was characterized by a state of anaesthesia, but also by complete amnesia. It was observed that women in twilight sleep became talkative and accurately answered questions, without remembering it later. This observation led to another scientifically, ethically and legally controversial application of scopolamine, as the “truth serum”, during interrogations of suspected criminals [11].

Role of hyoscyamine and scopolamine in planta

Why do plants produce these specific tropane alkaloids? Of course, they have a function in the producing organism. It has been suggested that they could be involved in the protection from herbivore insects [12, 13, 14]. The negative effects on insects have been linked to the fact that hyoscyamine and scopolamine affect the activity of the neurotransmitter acetylcholine [12].^d Nevertheless, the ecological role of hyoscyamine and scopolamine still needs to be explored since conflicting evidence is present in the literature. For example, in a study where scopolamine was tested on a specialist adapted to Solanaceae plants (Manduca sexta) and a generalist herbivore caterpillar (Galleria mellonella), it was shown that neither of them was significantly affected by the compound [15]. In another study on the desert locust, Schistocerca gregaria, no physiological cost associated with consuming hyoscyamine was observed, although it was shown that hyoscyamine deterred feeding in solitary locusts (but not in locusts in the gregarious phase) [16]. It must be said that these studies did not explore the possibility of synergistic effects by other compounds present in the plants.
Furthermore, the interaction plant/insect is often quite complex. Some insects that commonly feed on tropane alkaloids producing plants evolved adaptation mechanisms like sequestration and detoxification [14,17]. This means that they can either store the compounds in parts of their body far away from the receptors (and often use them to their own advantage) and/or to chemically modify them into non-toxic (or less toxic) compounds.
It is also possible that, while we do observe effects on some insects, scopolamine actually evolved in response to herbivory by mammals [15]. 

---

Hyoscyamine and scopolamine are an example of natural products which probably evolved as chemical defence in the producing plants and ended up being used for different purposes by mankind. Their use goes far back in time than here described and to discuss this we should (and will) delve into the fascinating traditional uses of the toxic nightshades that produce them.

Notes
a. hyoscyamine = (-)-hyoscyamine; scopolamine = (-)-hyoscine
b. N-Methyl-8-azabicyclo[3.2.1]octane
c. For the readers not familiar with organic chemistry: some objects are chiral. A chiral object is not superimposable to its mirror image. Example: your hands. Go in front of a mirror and look at the image of your right hand reflected by the mirror: it is your left hand. Now try to superimpose the right and left hands (i.e., put the palm of one on the back of the other). They are not superimposable. Some molecules are also chiral, because of specific structural features. In case of the tropane alkaloids in object, it is because one of the carbon atoms binds 4 different substituents. In this case, there exist two different molecules with the same atom connection which are the respective non-superimposable mirror images. These two molecules are called enantiomers. A racemic mixture is a mixture of the two enantiomers in a 1:1 ratio.
d. Therefore, we observe a different mechanism compared to caffeine