BJPsych Advances (2019), vol. 25, 265–268 doi: 10.1192/bja.2019.21 CLINICAL Histamine in psychiatry: REFLECTION promethazine as a sedative anticholinergic John Cookson (strongly influenced by the ideas of Claude Bernard John Cookson, FRCPsych, FRCP, is SUMMARY and Louis Pasteur). There he met Filomena Nitti, a consultant in general adult psych- iatry for the Royal London Hospital The author reflects on discoveries over the course daughter of a former prime minister of Italy. They of a century concerning histamine as a potent and East London NHS Foundation married in 1938 and she became her husband’slife- chemical signal and neurotransmitter, the develop- Trust. He trained in physiology and long co-worker. They moved in 1947 to the pharmacology at the University of ment of antihistamines, including promethazine, Institute of Health in Rome. In 1957 he was Oxford and he has a career-long and chlorpromazine from a common precursor, interest in psychopharmacology. His and the recognition of a major brain pathway awarded a Nobel Prize for his work in developing duties have included work in psychi- involving histamine. Although chlorpromazine has drugs ‘blocking the effects of certain substances atric intensive care units since 1988. been succeeded by numerous other antipsycho- occurring in the body, especially in its blood vessels He has co-authored two editions of tics, promethazine remains the antihistamine and skeletal muscles’ (Oliverio 1994). He and his Use of Drugs in Psychiatry, published recommended for sedation in acutely disturbed by Gaskell. research student Marianne Staub introduced the Correspondence: Dr John Cookson, patients, largely because it is potently anticholiner- first antihistamine in 1937, developed by altering Tower Hamlets Centre for Mental gic at atropinic muscarinic receptors and therefore the structures of drugs found to block known trans- Health, Mile End Hospital, Bancroft anti-Parkinsonian: this means it is also useful in mitters – acetylcholine and adrenaline – such as atro- Road, London E1 4DG, UK. Email: combination with older antipsychotics such as [email protected] pine. Their compound, called 929F, counteracted the haloperidol. actions of histamine on smooth muscle and reduced First received 12 Mar 2019 DECLARATION OF INTEREST anaphylactic shock; however, it was too toxic for clin- Accepted 25 Mar 2019 ical use. None. Copyright and usage © The Royal College of Psychiatrists KEYWORDS 2019. Histamine; antihistamines; tranquillisation; anti- The synthesis of promethazine psychotics; history. The synthesis of promethazine (Box 1) was first reported in 1944 by Dr Henry Gilman and David Stanley, chemists at Iowa State College, working Histamine is a small positively charged molecule on phenothiazines in a search for antimalarials. derived from the amino acid histidine, originating The antihistamine properties of promethazine from ergot, the fungal putrefaction of protein in rye (phenergan) were discovered in France in 1946 by (Fig. 1). It was identified as biologically active by Halpern, who was at the French National Centre one of the founding fathers of British pharmacology, for Scientific Research in Paris. This was the most Henry Dale: working with Patrick Laidlaw in the potent of a series of antihistamines that were deriva- laboratories of Sir Henry Wellcome in London, tives of phenothiazine. In the 1940s academic they described all its main actions – except that of laboratories and the pharmaceutical industry stimulating gastric acid secretion (Dale 1910). strove to discover new and safer antihistamines, They very presciently compared its effect in lowering with such success that more than 50 were synthe- blood pressure to that of anaphylactic ‘shock’. sised by 1965 (Dripps 1965). Histamine was suspected to be released in allergic The sedative properties of promethazine were conditions: urticaria, hay fever, bronchospasm and studied by the French-Vietnamese surgeon-anaes- anaphylaxis. And drugs that would antagonise his- thetist and pioneer-explorer Henri Laborit. tamine had obvious therapeutic potential. Between 1948 and 1952 he developed what he called his ‘lytic cocktail’, intended to reduce the need for inhaled anaesthetic agents and to combat The first antihistamines surgical ‘shock’ and post-operative vomiting. It con- Daniel Bovet (1907–1992) led in the search for anti- tained initially barbiturates, promethazine and histaminics, working first in the therapeutic chemis- opioids such as pethidine. ‘Lytic’ implied loosening try laboratory at the Pasteur Institute in Paris or relaxing (Valenstein 2002). 265 Downloaded from https://www.cambridge.org/core. 26 Sep 2021 at 18:38:56, subject to the Cambridge Core terms of use. Cookson Histidine Histamine O CO 2 N N OH N NH N NH 2 2 H H Promethazine Chlorpromazine S S Cl N N CH 3 CH N 3 N H C CH CH 3 3 3 FIG 1 The structure of histidine, histamine, promethazine and chlorpromazine, and conversion of histidine to histamine (imidazolyl ethylamine) by histidine decarboxylase. to explore the drug. The introduction of chlorpro- BOX 1 Pharmacokinetics of promethazine mazine by psychiatrists Delay and Deniker in 1952 represented something ‘very different’ and Oral promethazine is almost completely absorbed from the the drug was also associated with Parkinsonian gut and metabolised by hydroxylation (involving the hepatic side-effects, giving rise later to the name ‘neurolep- enzyme CYP 2D6) and sulphoxidation in the liver, leading to ’– – a bioavailability of 25% and a peak concentration at 2–4h. tic literally meaning seizing the neuron by The peak is at 2 h after intramuscular (IM) administration. Delay in 1955. The elimination half-life is 12–15 h. However, Henri Laborit’s suggestion for using chlorpromazine in premedication for anaesthesia was by 1965 outdated. It did not counteract surgi- Atropinic plants and drugs (hyoscine (scopolam- cal shock but produced arterial hypotension and its ine) and atropine from henbane and nightshades) sedative and anti-emetic properties could be had long been used for their calming effects in psy- achieved with other agents if necessary (Dripps chiatric settings but were associated with toxicity 1965). (Shorter 1997). Psychiatrists began to investigate antihistamines from 1943, and promethazine was used in sleep therapy for agitation (Guiraud 1950; Histamine and antihistamines Healy 2002). Histamine is stored predominantly in mast cell granules (Riley 1953) and in basophils. After their discovery of immunoglobin E (IgE) in 1966, Neuroleptanalgesia Kimishige Ishizaka in Denver found IgE binding Further phenothiazines were synthesised by Paul sites on basophils and mast cells and that their Charpentier of Rhône-Poulenc (now Aventis) in aggregation by anti‐IgE on basophils caused them Paris cooperating with academic laboratories to release histamine and a slow-reacting substance (Halpern 1948). In 1950 Charpentier synthesised of anaphylaxis (SRS-A), later called leukotriene chlorpromazine as a variant of promethazine, and (Tomioka 1971), during allergic reactions. his associated pharmacologist Simone Courvoisier Antihistamines were confirmed to be useful in con- recognised its more diverse range of actions in the trolling these. laboratory. Laborit described the novel effect of It became known that certain drugs lower blood adding chlorpromazine to his cocktail as ‘calm pressure by releasing histamine (Schachter 1952); without sleep’. The combination was later called these include morphine, pethidine, atropine, certain ‘neuroleptanalgesia’. He encouraged psychiatrists muscle relaxants, antibiotics and quinine. 266 BJPsych Advances (2019), vol. 25, 265–268 doi: 10.1192/bja.2019.21 Downloaded from https://www.cambridge.org/core. 26 Sep 2021 at 18:38:56, subject to the Cambridge Core terms of use. Histamine in psychiatry The tuberomammillary nucleus (TMN) The pharmacological activity of The sedative effect of antihistamines indicated that promethazine histamine must have a role in the brain, and in Perhaps reflecting its origin from compounds block- 1957 histamine was identified within the brain. ing the actions of other biogenic amines, prometha- But it was not until much later, in 1984, that zine has broad pharmacological activity. As well as the main pathway was demonstrated, originating being a antihistamine, it has significant atropinic from approximately 64 000 histamine-producing effects (Halpern 1948). neurons in the tuberomammillary nucleus (TMN) Other actions include local anaesthetic effects near the mammillary bodies behind the hypothal- stronger than procaine (blocking sodium channels), amus (Box 2) (see Haas 2008). The TMN projects ictogenic effects (lowering the seizure threshold), to diffuse areas of the forebrain, including the prin- antiemetic effects and blocking the HERG-encoded cipal cells in the cerebral cortex, and is part of the IKr potassium channel in heart muscle fibres, thus reticular activating system. It is activated by the prolonging the QT interval – although there is neighbouring orexin-containing neurons of the little evidence for it causing ventricular dysrhyth- lateral hypothalamus during wakefulness and not mia. In higher doses it causes delirium. This was during sleep. The TMN neurons express orexin-2 found in 31% of people reported to be taking 250 receptors. Furthermore, the histamine neurons mg daily, and in a greater proportion of those on project to other areas involved in wakefulness, higher doses. (Page 2009). Perhaps being regarded such as the noradrenergic nucleus locus coeruleus,