A non-hallucinogenic psychedelic analogue with therapeutic potential

Cameron and colleagues situate their work in the context of ibogaine, a psychedelic alkaloid with reported anti-addictive properties across multiple substances but with serious safety drawbacks including cardiotoxicity, long-lasting hallucinations and limited synthetic accessibility. Previous studies have implicated neurotrophic signalling and structural neural plasticity—for example, increases in GDNF and effects on BDNF signalling—as potential mechanisms that could explain ibogaine's enduring behavioural effects after single administrations. However, clinical development has been impeded by ibogaine's high lipophilicity, hERG channel inhibition, long and low-yield syntheses, and hallucinogenic profile. To address these problems the researchers applied function-oriented synthesis to identify the minimal psychoplastogenic pharmacophore of ibogaine and to design simplified analogues that retain therapeutic effects while reducing toxicity and hallucinogenic potential. Their primary aim was to produce water-soluble, non-hallucinogenic, synthetically tractable analogues, prioritising compounds that promote structural neural plasticity and that reduce drug-seeking and depressive-like behaviours in rodent models. The study therefore combines chemical design, in vitro and in vivo neuroplasticity assays, receptor profiling, safety pharmacology and behavioural models of addiction and depression to evaluate candidate analogues, notably IBG and tabernanthalog (TBG).

The study used a function-oriented synthetic approach to create simplified iboga alkaloid analogues (ibogalogs). Chemical work produced series of compounds lacking selected ibogaine structural elements; notably IBG (ibogainalog) and TBG (tabernanthalog) each are accessible in a single synthetic step and were converted to fumarate salts for in vivo use to improve solubility. Receptor and safety pharmacology included functional assays across the serotonin (5-HT) and opioid receptor families using high-throughput platforms (calcium flux, cAMP GloSensor, β-arrestin Tango) for human and some mouse isoforms; a wider 81-target safety panel was used for selectivity profiling. hERG inhibition was assessed by manual whole-cell patch clamp in HEK293 cells stably expressing hKv11.1 (hERG) to estimate cardiotoxic potential. Conditioned place preference (CPP) and other reward-related assays were performed in mice. Zebrafish assays tested acute cardiac and developmental toxicity and behavioural profiles. Larval zebrafish heart rate and arrhythmia (atrial/ventricular bpm ratio) were recorded after drug exposure; behavioural responses to light and acoustic stimuli were analysed with classifiers; seizure potential was assessed in GCaMP5-expressing larvae; developmental toxicity (mortality and malformations) was assessed from 6 hours post-fertilisation through 5 days post-fertilisation. Neuroplasticity was evaluated in vitro using rat embryonic cortical cultures: dendritic complexity was measured by Sholl analysis and spine density was quantified after 24 h treatments. Ketanserin (a 5-HT2A antagonist) was used to probe receptor dependence. In vivo spinogenesis was measured by transcranial two-photon imaging of Thy1-GFP-M mice, quantifying spine formation and elimination 24 h after a single systemic dose. Pharmacokinetic sampling (brain and liver) used targeted LC–MS/MS to measure tissue concentrations after intraperitoneal dosing. Behavioural paradigms included: forced swim test (FST) after 7 days of unpredictable mild stress (UMS) and in drug-naive mice, with drug or antagonist administration timed to assess effects at 24 h and 7 days; intermittent-access two-bottle choice (20% ethanol versus water) in mice over 7 weeks to model binge drinking, with TBG given 3 h before drinking sessions; sucrose preference and two-bottle sucrose tests to probe specificity; and heroin self-administration in rats with schedules progressing from FR1 to VR15, followed by extinction and cued reinstatement. In heroin (and parallel sucrose) studies, TBG (40 mg kg-1 in rats) or vehicle was administered at three distinct time points (during self-administration, before first extinction, and immediately before cued reinstatement) to probe both acute and long-lasting effects. Treatments were randomized and experimenters were blinded; power analyses were used to estimate animal numbers for in vivo experiments. Statistical analyses employed t-tests, one-way or two-way ANOVAs with appropriate post hoc tests, Fisher's exact tests, and repeated-measures ANOVAs as applicable; data are presented as mean ± s.e.m.

Chemical synthesis and structure–activity mapping identified the indole-fused tetrahydroazepine as the key psychoplastogenic pharmacophore of ibogaine. Ibogalogs lacking the isoquinuclidine but retaining the tetrahydroazepine were generally efficacious in promoting neuronal growth, whereas many compounds containing the isoquinuclidine but lacking the tetrahydroazepine were weak or inactive. IBG (ibogainalog) displayed psychoplastogenic activity comparable to ibogaine and improved physicochemical properties (lower clogP and higher CNS MPO score). TBG, a 6-methoxy indole-fused tetrahydroazepine, was synthesised as a conformationally restricted analogue and prioritised for further study due to its one-step synthesis and solubility as a fumarate salt. Safety and receptor profiling: in the head-twitch response (rodent proxy for 5-HT2A-mediated hallucinations), 5-MeO-DMT produced a robust response while IBG showed significantly reduced head-twitch potential and TBG was devoid of head-twitch responses at tested doses. Patch-clamp assays showed ibogaine inhibits hERG channels with an IC50 of ≈1 μM; IBG and TBG were approximately 10- and 100-fold less potent inhibitors, respectively, indicating lower cardiotoxic risk. In larval zebrafish, ibogaine decreased heart rate and increased atrial-to-ventricular beat ratio and produced behavioural and developmental toxicity at 100 μM (increased malformations and mortality, P < 0.0001 versus vehicle). By contrast, IBG and TBG did not induce bradycardia or arrhythmias, produced behavioural profiles closer to vehicle, and yielded significantly fewer non-viable fish than ibogaine; reducing TBG concentration from 100 to 66 μM produced viability indistinguishable from vehicle after 5 dpf (P = 0.3864). Functional receptor assays found that IBG and TBG are potent agonists at human and mouse 5-HT2A receptors but act as antagonists at 5-HT2B receptors. Both compounds showed weak or no opioid agonist activity. Broad profiling indicated increased selectivity for 5-HT2 receptors compared with less conformationally restricted hallucinogens, and a safety panel confirmed high selectivity of TBG for 5-HT2 targets. Reward and abuse liability: conditioned place preference in mice showed no effect at a low dose of TBG (1 mg kg-1, P = 0.8972), whereas higher doses produced modest conditioned place aversion (P = 0.0199 for 10 mg kg-1; P = 0.0489 for 50 mg kg-1), suggesting low abuse potential. Neuroplasticity and spinogenesis: in cultured rat cortical neurons, TBG increased dendritic arbor complexity (Sholl analysis) and raised dendritic spine density in mature cultures (DIV20) to an extent comparable to ibogaine; these dendritogenic effects were blocked by the 5-HT2A antagonist ketanserin. In vivo two-photon imaging in mouse sensory cortex revealed increased spine formation, with no change in elimination, 24 h after a single systemic dose of TBG; this effect paralleled that of the hallucinogenic 5-HT2A agonist DOI and resembled previously reported ketamine effects. Antidepressant-like effects: in mice subjected to 7 days of unpredictable mild stress, TBG at 50 mg kg-1 (but not 10 mg kg-1) rescued stress-induced increases in immobility in the forced swim test. In drug-naive mice, both ketamine and TBG reduced immobility 24 h after administration, though ketamine's effect appeared more durable at later time points. Ketanserin pre-treatment blocked TBG's antidepressant-like effect. TBG did not alter locomotion 24 h after administration. Effects on alcohol and heroin seeking: in a 7-week intermittent-access two-bottle alcohol paradigm, systemic TBG given 3 h before a session reduced binge-like ethanol intake during the initial 4 h and maintained lower alcohol consumption for at least 2 days; water intake and sucrose preference were unaffected, indicating selective reduction of alcohol consumption. In a rat heroin self-administration model, acute TBG administration (40 mg kg-1) at three different stages (during self-administration, before first extinction, immediately before cued reinstatement) acutely reduced heroin-seeking and intake. Acute TBG also reduced sucrose self-administration, suggesting some non-selective disruption of operant responding when given acutely. Crucially, a single earlier administration of TBG (given during self-administration or before the first extinction session, 12–14 days prior) reduced cue-induced reinstatement of heroin seeking, indicating a long-lasting protection against relapse after a single treatment.

The investigators interpret their findings to show that function-oriented synthesis can identify a simplified psychoplastogenic pharmacophore—specifically the indole-fused tetrahydroazepine—that preserves ibogaine-like neural plasticity while enabling substantial improvements in safety, solubility and synthetic tractability. Simplifying ibogaine to produce TBG yielded a compound that is water-soluble, non-hallucinogenic in rodent head-twitch assays, less likely to inhibit hERG channels, and less toxic in zebrafish developmental assays. The authors highlight that TBG promotes dendritic growth and spinogenesis in vitro and in vivo, produces antidepressant-like behavioural responses, and reduces alcohol consumption and cue-induced relapse to heroin in rodents. They position these results relative to earlier work by noting parallels between psychoplastogens and ketamine—both classes promote cortical neuronal growth and can yield sustained behavioural effects after single doses—but they emphasise that a causal link between psychedelic-induced neuronal growth and behavioural outcomes remains to be definitively established. The authors contrast TBG with other ibogaine derivatives such as 18‑MC, noting differences in mechanism, reported biomarkers (for example GDNF induction), safety profiles and synthetic complexity; TBG's one-step synthesis and psychoplastogenic profile distinguish it from many prior analogues. Key limitations acknowledged include the absence of direct causal proof that structural plasticity mediates the behavioural effects, uncertainty about optimal dosing regimens and time courses for durable behavioural benefits, and the need for further characterisation of acute non-selective effects on operant responding. The authors also imply translational uncertainty: these are preclinical data and human efficacy and safety remain untested. Future research directions they note include mechanistic studies to probe causality between spinogenesis and behaviour, optimisation of dosing schedules, and broader behavioural investigations (for example, measures of anhedonia) to fully characterise antidepressant-like efficacy.