Gaddum and LSD: the birth and growth of experimental and clinical neuropharmacology research on 5-HT in the UK

Green frames the review as a historical account of early UK work on 5-hydroxytryptamine (5-HT, serotonin), emphasising two complementary ways of reconstructing recent science: tracing the published literature and drawing on personal recollection or conversations with the scientists involved. He notes strengths and pitfalls of each approach, arguing that a literature-only history can be sterile while memories can be biased, and therefore blends both sources to give a narrative that highlights people as well as findings. The paper concentrates on the period 1950–1970 and aims to document how a relatively small group of UK investigators established much of the early experimental and clinical neuropharmacology of 5-HT. Specifically, Green intends to review how UK scientists developed assays for 5-HT in the CNS, characterised enzymes of synthesis and metabolism, investigated drug effects on brain 5-HT, studied LSD’s interaction with 5-HT, and explored links between 5-HT and affective disorders. The review is presented as both a record of discovery and an argument that these early UK contributions laid foundations for later ideas about mood regulation and antidepressant action.

This paper is a narrative historical review rather than a systematic review or primary experimental study. Green draws primarily on the published literature from 1950–1970 and supplements that record with personal recollections, conversations with key figures (including Maurice Rapport), and the author’s own involvement in the field. The review selectively highlights UK-based studies while occasionally referencing important non-UK work for context. The author does not report a formal search strategy, inclusion/exclusion criteria, or structured quality appraisal; instead the approach is thematic and chronological, organised around major topics (identification and assay of 5-HT, synthesis and metabolism, receptors, pharmacology including LSD, and the emerging clinical literature). Where useful, Green integrates methodological details from original studies (for example bioassay preparations and emerging fluorometric assays) to explain how findings were obtained. He also acknowledges limitations of personal recollection and the potential for selection bias in choosing which studies and people to emphasise.

Characterisation and early identification: The review recounts how the vasoconstrictive substance known as serotonin was chemically identified as 5-HT in 1949 (Maurice Rapport et al.) and how independent lines of work (Page’s group in the USA and Erspamer in Italy) converged on the same indoleamine. Naming conventions (serotonin, enteramine, 5-hydroxytryptamine) and the early synthesis and distribution of the pure compound are described; notably Rapport supplied small samples to UK investigators, including John Gaddum (0.65 mg initially and 25 mg in 1951), which enabled rapid UK experimental work. Measurement of 5-HT in tissues: Green details how early UK research relied heavily on bioassays (rat oestrus uterus, guinea-pig ileum, rabbit ear, and mollusc heart preparations) to detect and quantify 5-HT in tissues, and credits John Gaddum for expertise in bioassay methods. He then describes methodological advances: the Aminco-Bowman fluorescence spectrophotometer (mid-1950s) and chemical derivatisation approaches (ninhydrin and later o-phthaldialdehyde with cysteine) increased sensitivity and throughput, enabling measurements of 5-HT and its metabolite 5-HIAA in brain regions until HPLC replaced these techniques in the late 1970s. Synthesis and metabolic pathways: The review traces elucidation of the biosynthetic and degradative enzymes. Work showed tryptophan is the precursor and that tryptophan hydroxylase and aromatic L-amino-acid decarboxylase are present in brain (Grahame-Smith’s group established brain tryptophan hydroxylase and its presence in synaptosomes). Monoamine oxidase (MAO) had been characterised earlier, and UK groups (notably Merton Sandler’s laboratory) contributed to recognising multiple MAO forms, later classified functionally as MAO A and MAO B. The synthesis of selective MAO A inhibitors (for example clorgyline) assisted functional studies. Aldehyde-metabolising enzymes (aldehyde dehydrogenase/reductase) and pathways producing 5-HIAA or 5-HTOH are also covered. Tryptophan availability and transport: Green summarises work showing tryptophan hydroxylase is rate-limiting and unsaturated with substrate, so changes in free plasma tryptophan alter brain 5-HT synthesis. He notes UK contributions (Curzon, Grahame-Smith, Parfitt) to understanding synaptosomal uptake and competition between large neutral amino acids, although much of the detailed mechanistic work on diet–insulin effects was published later in the early 1970s. Control of synthesis and turnover: The review recounts development of the turnover concept (largely from US groups) and experiments showing that raising precursor plus inhibiting MAO produced characteristic behavioural syndromes (the so-called serotonin syndrome). Parke Davis work establishing the 5-HTP-induced head-twitch model is noted, including its pharmacological blockade by LSD and other 5-HT antagonists, foreshadowing receptor-specific interpretations made later. Platelets, uptake and relevance to brain: Platelet studies are reviewed as an accessible model of uptake and storage: early UK and international work showed platelets concentrate 5-HT via an active high-affinity uptake mechanism, that reserpine depletes platelet 5-HT, and that platelet assays were used to study drug effects (e.g. tricyclics inhibiting uptake). These platelet findings preceded and paralleled recognition of a brain high-affinity uptake system. Receptor heterogeneity and LSD pharmacology: Gaddum’s early bioassay studies proposed multiple receptor types (initially labelled D and M), a prescient proposal later mapped onto central subtypes (D ≈ 5-HT2, M ≈ 5-HT3). Crucially, Gaddum and colleagues showed LSD antagonised 5-HT responses in peripheral bioassays and suggested this might underlie LSD’s psychoactive effects. The review recounts extensive early human experimentation with LSD in volunteers and patients: Gaddum’s own self-administration experiments are described (he took 30 mg, then 40 mg, later 85–86 mg on occasions), and multiple UK groups studied EEG changes, behavioural effects and adverse responses, including severe adverse events in some patients and volunteers. Thermoregulation and other physiological roles: Feldberg and collaborators showed intraventricular 5-HT altered body temperature (species-dependent effects), implicating hypothalamic sites; subsequent UK and industry studies reported both hyperthermic and hypothermic responses in different species. 5-HT, antidepressants and psychiatric disorder: Green reviews how clinical observations with reserpine (depleting stored amines) and iproniazid (an MAO inhibitor) stimulated hypotheses linking monoamines to mood. Preclinical and clinical studies of tricyclic antidepressants and MAO inhibitors showed effects on monoamine concentrations, uptake and MAO activity. Coppen’s clinical work (tranylcypromine with tryptophan augmentation, and tryptophan alone) provided early human data suggesting enhancement of 5-HT could have antidepressant effects. Post-mortem and CSF studies are reviewed: early reports of decreased 5-HT or 5-HIAA in suicides or CSF of depressed patients were inconsistent; Edinburgh groups measured CSF 5-HIAA and performed ventricular–lumbar comparisons but later concerns emerged about lumbar CSF origin and confounding by activity level. The monoamine hypothesis and UK contribution: The cumulative UK and international data of the 1950s–1960s coalesced into the monoamine hypothesis of affective disorder — the idea that reduced monoamine concentration or function contributes to depression and that antidepressants act via monoaminergic mechanisms. Green stresses the heuristic value of this hypothesis while acknowledging that the evidence did not yield a single encompassing etiological theory and that further receptor and systems-level work was needed.

Green interprets the reviewed material as showing that a relatively small, closely interacting group of UK scientists, centred in Edinburgh and London, made disproportionately large contributions to the formative neuropharmacology of 5-HT during 1950–1970. He attributes rapid progress to early access to chemically synthesised 5-HT, technical advances in assay methods, inventive use of bioassays, and the close translation between animal studies and clinical investigation. The author emphasises John Gaddum’s central role in detecting cerebral 5-HT and in recognising LSD’s antagonism of 5-HT actions, which stimulated hypotheses about 5-HT and mood. The paper places UK work in its international context, acknowledging major contemporaneous contributions from groups in the USA (NIH/NHI) and Sweden (Karolinska/Gothenburg) and noting that some mechanistic advances (for example turnover measurements and dietary regulation of tryptophan transport) had important non-UK origins. Green also flags methodological and interpretative limitations of the early literature: many clinical studies lacked randomisation or blinding, early human experiments sometimes exposed volunteers and patients to substantial risk, post-mortem and CSF findings were inconsistent and subject to confounds (age, sampling/post-mortem delay, anatomical origin of lumbar CSF), and reliance on personal recollection can introduce bias in historical synthesis. In terms of implications, the author argues that these early discoveries provided the empirical basis for later receptor-subtype work and for the development of antidepressant pharmacotherapy. He stresses the heuristic value of the monoamine hypothesis while conceding that it does not fully explain affective disorders. Finally, Green calls for awareness of the historical trajectory of the field—both to avoid redundant rediscovery and to appreciate how method and serendipity combined under systematic enquiry to produce progress — echoing Gaddum’s view that many “accidental” discoveries arose only because investigators were pursuing a systematic research programme.

Green concludes that UK investigators, particularly a core group in Edinburgh supplemented by collaborators in London, drove many of the early advances in 5-HT neuropharmacology between 1950 and 1970. He argues that their methodological innovations, rapid translation between animal and human work, and conceptual leaps (for example linking LSD’s pharmacology to 5-HT and proposing receptor heterogeneity) established much of the foundation for subsequent research and for antidepressant therapy. While acknowledging the role of serendipity, he emphasises that such discoveries depended on systematic experimental work and available techniques. The review closes by underscoring the importance of remembering this history and credits the early researchers for paving the way to later receptor and clinical developments.