Beyond the 5-HT2A Receptor: Classic and Nonclassic Targets in Psychedelic Drug Action

Cameron and colleagues frame serotonergic psychedelics (for example LSD, psilocybin/psilocin, DMT, and certain phenethylamines) as rapidly acting agents with therapeutic promise across a range of neuropsychiatric conditions, including depression, anxiety, PTSD, substance use disorders (SUDs), anorexia, and chronic pain. Although these compounds are conventionally defined by agonism at the serotonin 5-HT2A receptor—the receptor most consistently linked to the subjective, hallucinogenic effects—the authors argue that 5-HT2A activation alone is unlikely to explain the full spectrum of therapeutic actions. They note that classic psychedelics show broad polypharmacology, binding multiple 5-HT subtypes and other targets (for example TrkB and several dopamine and adrenergic receptors), and that some downstream effects (notably induction of neuroplasticity) may depend on non-5-HT2A mechanisms. The review therefore sets out to summarise recent findings that extend beyond 5-HT2A signalling, to highlight alternative or complementary molecular targets (including 5-HT1A, 5-HT2C, TrkB and potential covalent protein modifications via transglutaminase 2), and to introduce the concept of nonhallucinogenic or ‘‘second-generation’’ psychedelic analogues that might retain therapeutic plasticity while minimising perceptual effects. The authors also emphasise gaps in mechanistic understanding, translational challenges (including safety, cost and regulatory barriers), and the need to disentangle hallucinogenic from therapeutic pathways.

The extracted text does not present a formal Methods section. The paper is a narrative mini-review and a summary of a 2023 Society for Neuroscience Mini‑Symposium rather than a systematic review or original experimental study. As such, the authors synthesise recent preclinical and clinical findings across molecular, cellular, behavioural and early clinical literature, integrating mechanistic studies (for example receptor pharmacology, knockout and antagonist experiments, binding assays and molecular dynamics), animal behavioural models relevant to antidepressant and addiction domains, and emerging human data when available. Because no explicit search strategy, inclusion criteria, databases, or formal risk-of-bias assessment are reported in the extracted text, details regarding literature selection and potential publication bias are not available from the extraction. The conclusions therefore reflect the authors' interpretive synthesis of contemporary studies rather than a meta-analytic or reproducible systematic search.

The review organises current evidence around several major themes: the centrality but insufficiency of 5-HT2A for therapeutic effects; roles for other serotonin receptors (notably 5-HT1A and 5-HT2C); direct engagement of TrkB (the BDNF receptor); and non-receptor mechanisms such as TGM2-mediated monoaminylation of proteins and histones. 5-HT2A receptor: The authors reiterate that 5-HT2A activation underpins the hallucinogenic experience—human perceptual effects are blocked by the antagonist ketanserin and the head-twitch response in rodents (abolished in 5-HT2A knockout animals) predicts hallucinogenic potency. Psychedelics increase structural and functional plasticity in cortical pyramidal neurons, and many behavioural antidepressant-like effects in rodents are prevented by 5-HT2A antagonists or absent in 5-HT2A-KO mice. However, findings are not uniform: some endpoints (for example spine size, or certain behavioural assays) are variably affected by 5-HT2A blockade, and experimental confounds (ketanserin off-target effects, constitutive knockout phenotypes) complicate interpretation. The authors note hypotheses to reconcile divergent data, including functional selectivity (biased signalling), receptor dimerisation (for example 5-HT2A–mGluR2 complexes), and targeting of intracellular 5-HT2A pools by lipophilic psychedelics such as DMT and psilocin. Serotonergic psychedelics and substance use disorders: The review summarises rodent and emerging human data suggesting psychedelics can reduce alcohol and nicotine use and may be associated with lower odds of opioid use disorder in population data (psilocybin linked to a 30% decrease in odds of developing OUD in a cited survey). Mechanistically, 5-HT2A-expressing cortical pyramidal neurons projecting to nucleus accumbens (NAc) are proposed to modulate dopamine tone and goal-directed behaviour implicated in addiction. Preclinical results are mixed: some psychedelics’ effects on intracranial self-stimulation were attenuated by a selective 5-HT2A antagonist (volinanserin) for some compounds but not others, suggesting non-5-HT2A mechanisms contribute depending on structure. Single-dose LSD and psilocybin produced sex-dependent or dose-dependent reductions in ethanol consumption in mice in limited studies. The authors discuss feedback inhibition via 5-HT1A and potential crosstalk between serotonin and opioid signalling (MOR co-localisation with 5-HT2A), and outline ongoing circuit-level approaches (for example FLP/Cre-mediated expression) to identify critical cell populations. Nonhallucinogenic analogues and 2‑Br‑LSD: A range of nonhallucinogenic derivatives (lisuride, tabernanthalog, AAZ analogues, 2‑Br‑LSD) are described. 2‑Br‑LSD is highlighted as a partial 5-HT2A agonist that promotes PFC neuroplasticity and reverses stress-related behaviours in mice without producing hallucinogenic effects; it lacks 5-HT2B agonism (reducing cardiac valvulopathy risk) and shows greater selectivity than LSD, including D2/D4 dopamine receptor agonism. 2‑Br‑LSD's antidepressant- and plasticity-like effects are 5-HT2A activity-dependent in preclinical assays and are not associated with tolerance, possibly because of weak β-arrestin2 recruitment. The authors stress that human efficacy of nonhallucinogenic analogues remains to be demonstrated in trials. 5-HT2C receptor: 5-HT2C is reviewed as a candidate target for impulse-related disorders and SUDs. The receptor couples canonically to Gq/11 but also promiscuously to Gi/o and G12/13, complicating pathway attribution. Preclinical work shows selective 5-HT2C agonists can reduce self-administration of alcohol, cocaine and nicotine and modulate satiety (5-HT2C KO mice are hyperphagic). The withdrawn weight-loss drug lorcaserin (a 5-HT2C agonist) reduced alcohol drinking in rodents but was removed from the market due to cancer signal in trials, illustrating safety trade-offs. The authors argue that ligand bias and pathway-selective 5-HT2C agonists may yield therapeutic benefit with fewer side effects. BDNF and TrkB: A notable finding summarised is that LSD and psilocin bind to the transmembrane domain of TrkB with much higher affinity than conventional antidepressants (reported as ~1000-fold higher), acting as positive allosteric modulators that promote activity-dependent BDNF signalling, TrkB dimerisation, spinogenesis and dendritogenesis. Psychedelics are not direct TrkB agonists—extracellular BDNF is required—and a transmembrane point mutation that disrupts psychedelic binding prevents neuroplastic and antidepressant-like effects without affecting 5-HT2A-linked head-twitch responses. Volinanserin (a 5-HT2A antagonist) does not block TrkB dimerisation or plasticity induced by psychedelics in the cited studies, supporting the possibility that TrkB-mediated plasticity may be separable from hallucinogenic actions. Protein monoaminylation and TGM2: The authors review evidence that psychedelics, because of structural resemblance to endogenous monoamines and increased lipophilicity, may act as substrates for transglutaminase 2 (TGM2), catalysing covalent monoaminylation (for example serotonylation or dopaminylation) of proteins including Rac1 and histone H3. DOI-induced spinogenesis required TGM2 and involved serotonylation of Rac1; histone H3 serotonylation (H3Q5ser) has been linked to permissive gene expression and decreased in stressed animals and some patients with major depressive disorder. The review suggests that psychedelic-induced changes in monoaminylation of histones and other proteins could contribute to lasting transcriptional and structural plasticity relevant to mood and addiction phenotypes, although mechanistic and in vivo human data remain limited.

The authors interpret the assembled evidence as supporting a model in which classical psychedelics act via complex polypharmacology rather than solely through 5-HT2A-mediated hallucinogenic signalling. They highlight TrkB, 5-HT2C and 5-HT1A as especially promising nonclassic targets that may mediate plasticity and therapeutic effects independently of perceptual alterations, and they note that psychedelic compounds likely engage multiple mechanisms concurrently. Cameron and colleagues position these insights as opening avenues for developing ‘‘second-generation’’ psychedelic analogues that preserve beneficial neuroplastic and behavioural effects while reducing hallucinogenic liability and other safety risks. They also stress the need to delineate downstream signalling pathways (including biased agonism and receptor dimerisation), to clarify the role of intracellular receptor pools, and to probe circuit-level mechanisms that translate molecular actions into changes in behaviour. Key uncertainties the authors acknowledge include inconsistent antagonist and knockout results (complicated by off-target effects and constitutive KO phenotypes), incomplete mapping of TrkB versus serotonin receptor contributions across brain regions, and limited human data for nonhallucinogenic analogues. Finally, the review calls for further mechanistic, translational and clinical work—including clinical trials of nonhallucinogenic candidates and studies of histone and protein monoaminylation—to determine which molecular and circuit-level pathways are essential for therapeutic efficacy and to guide safer, more accessible therapeutic development.