Thursday, 29 April 2010

Putting a spring in your step with strychnine

Everyone should be familiar with this favourite of crime fiction. Strychnine is not the most poisonous substance known to man (you need at least 50 mg to kill someone), but a you'd have to go a long way to find something that provokes a more violent death. So why the hell would you try to use it as a medicine?

Strychnine has two notable actions. Firstly, its taste is intensely bitter, and can be detected in quite dilute solutions. Secondly, it blocks receptors for the neurotransmitter glycine, which is present in the spinal cord, brain and retina. Glycine is an inhibitory neurotransmitter, meaning that when it is released and binds to receptors on other neurons, its effect is to reduce neuronal activity. It is important in the spinal cord, most notably because inhibitory neurons are required in the quite precise way the nervous system controls our muscles. When one muscle contracts, the neuronal circuitry in the spinal cord simultaneously ensures that any apposing muscles do not, using inhibitory neurotransmission to the neurons that control them. If you block glycine receptors, the delicate control system is lost and the result is violent, uncontrollable convulsions all over the body. Eventually, control of respiration ceases and death follows. Because glycine is also an inhibitory neurotransmitter in the eye, victims often notice visual disturbances as well.

Strychnine is isolated from nux vomica, the seeds of Strychnos nux-vomica. Nux vomica may ring a few bells, because it is a favourite of homeopaths. Of course, homeopaths dilute strychnine down until no active ingredient can possibly be left, and like all their potions, nux vomica is nothing but water. Conventional medicine, it turns out, has treated strychnine in a ironically similar way. It is the bitter taste of strychnine that is the key to this interesting story.

Strychnine was promoted as a "tonic" (a dangerously vague term) well into the twentieth century, having first appeared in routine medical use in the 18 century. It properties as a tonic were thought to be two-fold: stimulation of appetite and digestion and an increase in the excitability of muscle. You can taste the bitterness of strychnine at quite dilute, and harmless, concentrations. Bitterness was long held to stimulate the stomach, and indeed there is something to this theory. Reflex (Pavlovian, if you like) stimulation of gastric secretion by a bitter taste in the mouth probably does occur. Most 'digestive' drinks in many cultures have a bitter taste. But remember, this is all about bitterness, and not any effect on the central nervous system. The supposed effect on the excitability of muscles was presumed, based on the observations of the effects of poisoning; it was thought that at lower doses a useful, milder version of events would unfold. Although it sounds reasonable, the doses of strychnine that were taken for the 'tonic' effect would have no effect on the nervous system at all. To quote my battered copy of Goodman and Gilman's The pharmacological basis of therapeutics (1975):

"To the drug have been ascribed properties that it does not possess, or that is exhibits only when administered in toxic doses"
People took this bitter placebo for a couple of hundred years, all the same.

Cocaine for asthma

Cocaine has two effects on the body, mediated in different ways. This isn't an uncommon thing for a drug to do - most drugs have side effects. The first thing that cocaine does is induce local anaesthesia when it is injected into tissues (or dropped into the eye). It was a very handy drug around the turn of the 19th century for this effect as it allowed minor surgery without pain. The second thing that cocaine does is interfere with neurotransmission - the way that neurons talk to other neurons (or other cells, like muscles).

Nerve terminals release neurotransmitters to communicate with other cells. These generally small chemicals diffuse across to the target cell and bind to receptors to elicit a response. The fate of released neurotransmitters is either degradation by enzymes in the vicinity or re-uptake by the nerve terminal. Re-uptake requires a transporter in the nerve terminal, and it is some of these transporters that cocaine blocks.

Now, in the brain cocaine blocks dopamine and noradrenaline re-uptake, leaving more of these neurotransmitters free to bind with receptors, causing the euphoric effects that cocaine is rather famous for. The story in the rest of the body is rather simpler, and this is where the connection to asthma comes in.

There are nerves that release noradrenaline all over your body, and they affect various processes without you having to think about it (in fact, you have no direct control over these nerves at all). These nerves constitute the sympathetic nervous system, and two of the things that they cause when stimulated are vasoconstriction (decreased diameter of blood vessels) and increased activity by the heart. Users of cocaine will be familiar with the increase in heart rate (and force of contraction) and physicians regularly warn against the increase in blood pressure that cocaine produces via its twin effects on the heart and the blood vessels. But how would these effects be of any clinical use in the treatment of asthma?

The answer is a historically interesting one. Around the mid 1870's early attempts at bronchoscopy (looking inside the airways) revealed that during an asthma attack the lining of the airways (the mucosa) becomes red and swollen. It was (quite correctly) surmised that during an attack, blood flow to the mucosa increases, causing swelling that reduces the diameter of the airways and hence limits airflow. It didn't take to long for someone to reason that if you inhaled cocaine, it would constrict the blood vessels in the mucosa and reduce the swelling. It would have worked (but not as well as current treatments), and it had a brief life as an asthma treatment from about 1885 to 1900. Suffers would have found the relief produced by cocaine better than the mixed bag of very strange advice given by physicians at the time.

We don't use any drugs for asthma that work in a similar way today. We tend to use drugs that cause relaxation of the muscles around the airways, rather than constriction of the muscles surrounding the blood vessels in the mucosa. We do have cocaine-like drugs in modern use though, and they have their uses. But that's another post.

Thursday, 15 April 2010


This is not technically a poison, but it's a good example of something we'd consider barmy today. (And I had to start somewhere). It's also entertaining because the practitioners of quack medicine are mad keen cuppers. One of the most startlingly obvious features of quack medical practices is that - irrespective of the modality - they are very often something that has been discarded by medicine during its evolution. Only the really whacky ones aren't.

Cupping is an ancient approach, that much is true. Egyptians were cupping around 1000 BC and the practice may be older still (and have evolved more than once, in different places). The Hippocratic and Galenic traditions that physicians still adhered to at the turn of the 19th century encouraged cupping for a variety of ailments, and the practice only died out over the following hundred years.

There were two forms of cupping, which were often mixed together. The basic process was common to both: heated cups were placed over the skin, and as the air cooled inside them (and the pressure dropped) they sucked the skin outwards. That much is dry cupping. Wet cupping involves scarifying the skin before applying the cup, and was a form of bloodletting. The two forms were often mixed, dry cupping being applied first to form a blister, which was subsequently lanced and re-cupped to be bled.

How did it work? It almost certainly didn't do any therapeutic good whatsoever. The idea of bloodletting came from the ancients and was thought to restore the balance of humors in the body (they being blood, phlegm and yellow and black bile). Bloodletting in specific locations on a small scale was thought to draw inflammation away from nearby tissues. On a larger scale, patients would be bled from a large vein until they fainted. Since all conditions were thought to be due to an imbalance of the humors, this practice was quite widespread until the revolutions that occurred in medical practice during the 19th century. Untold unnecessary deaths resulted. On the other hand, more benign dry cupping probably arose from the notion of counter-irritants - the idea that a disease-induced irritation could be resolved by a deliberate one elsewhere.

Modern quacks promote dry cupping as an ancient and traditional Chinese healing system, similar to acupuncture. Western medicine employed it for thousands of years, and only discarded it (with a lot of other practices) when people started to pay careful attention to whether treatments actually worked or not.