Physostigmine (also known as eserine from éséré, the West African name for the Calabar bean) is a highly toxic parasympathomimetic alkaloid, specifically, a reversible cholinesterase inhibitor.

The positive medical applications of the drug were first suggested in the gold medal-winning final thesis of Thomas Richard Fraser at the University of Edinburgh in 1862.

[6] It has been shown to improve long-term memory,[7] and was once explored as a therapy for Alzheimer's disease, but in clinical trials it was not shown to confer convincing benefits, and it led to very common moderate to severe side-effects such as nausea, vomiting, diarrhea, loss of appetite, abdominal pain, and tremors, resulting in a high rate of withdrawal.

[8] Physostigmine's poor tolerability led to it being abandoned in favor of later acetylcholinesterase inhibitors, three of which are currently in use: donepezil, galantamine, and rivastigmine.

Physostigmine also has other proposed uses: it could reverse undesired side effects of benzodiazepines such as diazepam, alleviating anxiety and tension.

It is a reversible inhibitor of acetylcholinesterase, the enzyme responsible for the breakdown of acetylcholine in the synaptic cleft of the neuromuscular junction.

Other side effects may include nausea, vomiting, diarrhea, anorexia, dizziness, headache, stomach pain, sweating, dyspepsia, and seizures.

Physostigmine has two stereocenters—the two carbons where the five-membered rings join—so any attempt at the total synthesis must pay attention to obtaining the correct stereoisomer.

In one of his earlier works[19] Julian synthesized the ring of physostigmine from 1-methyl-3-formyl-oxindole as starting material, which was discovered by Paul Friedländer.

In his second work “Studies in the Indole Series III,” he had improved the yield of amine from nitrile significantly by using palladium and hydrogen.

In the years since this initial work, many other groups have used a variety of approaches to construct the ring system and showcase new synthetic methods.

Physostigmine biosynthesis is proposed from tryptamine methylation and post-heterocyclization catalyzed by an unknown enzyme:[20] The Efik people, living in Cross River State and the Ibibio people in Akwa Ibom State, in what is now the south-south of Nigeria, were the first to come in contact with physostigmine, the active ingredient in the Calabar bean.

These beans eventually made their way back to Scotland, the home of these particular missionaries, where in 1855 Robert Christison, a toxicologist, tested the toxicity of the poison on himself by eating one.

[22] In 1934, while working at St Alfege's Hospital in London, Dr Mary Walker discovered that a subcutaneous injection of physostigmine could temporarily reverse the muscle weakness found in patients with myasthenia gravis.

[24] Her article explaining the first case of myasthenia gravis being successfully treated with physostigmine was published in The Lancet in June 1934.