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Tabernanthalog

Tabernanthalog (TBG), also known by the developmental code name DLX-007 and developed by Delix Therapeutics, is a synthetic, water-soluble analog of the psychoactive alkaloid ibogaine, engineered as a non-hallucinogenic psychoplastogen to promote structural neural plasticity while avoiding the toxicity and hallucinogenic effects associated with ibogaine.^[1] Developed through function-oriented synthesis in a single-step process to isolate ibogaine's therapeutic pharmacophore, TBG acts as a non-selective serotonin receptor modulator, particularly via 5-HT2A receptors, alongside activation of TrkB, mTOR, and AMPA signaling pathways, to induce neuroplasticity without triggering immediate early gene expression or hallucinatory experiences.^[1]^[2] In preclinical studies, TBG has demonstrated robust antidepressant-like effects in rodent models of chronic stress, reversing behavioral deficits such as anxiety, cognitive inflexibility, and anhedonia with a single dose, while also promoting dendritic spine growth and synaptogenesis in cortical neurons.^[1]^[3] It effectively reduces motivation for substance use, including heroin and alcohol self-administration in progressive ratio tests, even in models of polydrug use where animals have prior histories of binge drinking and opioid intake, suggesting potential efficacy against addiction without altering general locomotor activity or causing toxicity.^[4] Additionally, TBG inhibits nicotinic acetylcholine receptors (α7 and α9α10 subtypes), which may contribute to its therapeutic profile in modulating reward and withdrawal pathways.^[5] As of 2025, ongoing research positions TBG as a promising candidate for treating mood disorders, substance use disorders, and stress-related conditions, with studies in rodents and pigs highlighting its scalability and safety as a non-psychedelic alternative to traditional hallucinogens.^[2]^[6]

Chemical properties

Molecular structure

Tabernanthalog (TBG) is a synthetic analog of the iboga alkaloid ibogaine, with the molecular formula C₁₄H₁₈N₂O and a molecular weight of 230.31 g/mol. Its core structure is a tryptamine alkaloid featuring an indole ring fused to a seven-membered tetrahydroazepine ring at the 4,5-b positions, forming a tricyclic system; the azepine ring includes a methyl group on the nitrogen at position 3, and a methoxy substituent is attached to the indole at position 8. This configuration can be represented by the IUPAC name 8-methoxy-3-methyl-2,4,5,6-tetrahydro-1H-azepino[4,5-b]indole.^[7]^[1] In comparison to ibogaine, which has a complex pentacyclic architecture incorporating an indole-tetrahydroazepine core along with a bicyclic isoquinuclidine moiety and a methoxycarbonyl group at position 18, tabernanthalog employs a simplified design by excising the isoquinuclidine and methoxycarbonyl elements. These alterations confer greater water solubility—achieving concentrations up to 40 mg/mL in saline—and diminish cardiotoxicity, with an IC₅₀ for hERG potassium channel inhibition approximately 10- to 100-fold higher than that of ibogaine (IC₅₀ ≈ 1 μM).^[1]^[8]

Synthesis and analogs

Tabernanthalog is synthesized via a concise, single-step Fischer indole cyclization, a function-oriented approach that simplifies the complex structures of natural iboga alkaloids. The reaction involves refluxing 3-methoxyphenylhydrazine hydrochloride (3.0 equivalents) and 1-methylazepan-4-one hydrochloride (1.0 equivalent) in ethanol (0.15 M) with concentrated hydrochloric acid (4.0 equivalents) for 12 hours, followed by basification with sodium hydroxide and extraction. The crude product is purified by column chromatography using dichloromethane:methanol (10:1) with 0.5% ammonium hydroxide, yielding the free base in 49%. The fumarate salt is then prepared by treating the free base with fumaric acid (0.8 equivalents) in acetone and cooling to -20°C, affording an additional 69% yield of the salt form.^[1] This method starts from commercially available phenylhydrazine and cyclic ketone precursors, enabling efficient production without the multi-step complexity of ibogaine synthesis. Key reagents in this process include the indole-forming 3-methoxyphenylhydrazine hydrochloride and the azepane ring precursor 1-methylazepan-4-one hydrochloride, with acid catalysis driving the cyclization under thermal conditions. Unlike traditional iboga alkaloid routes that employ Pictet-Spengler reactions for tetrahydro-β-carboline formation from tryptamine and aldehydes like formaldehyde, tabernanthalog's synthesis bypasses such steps, focusing instead on direct pharmacophore assembly. Reported yields for this route are around 50%, representing an improvement over early iboga-derived syntheses (20-30%), with further optimizations by Delix Therapeutics enhancing scalability for pharmaceutical manufacturing of tabernanthalog (developmental code DLX-007).^[9] Related analogs include ibogainalog, a non-hallucinogenic variant retaining a more ibogaine-like fused ring system but lacking the 18-methoxycarbonyl group. Ibogainalog is prepared in a multi-step sequence beginning with acylation of pyridine using Cbz-protected dihydropyridine, followed by a Diels-Alder cycloaddition with methyl vinyl ketone to form intermediates in 73% yield over three steps, and concluding with tosylhydrazide-mediated C-N bond formation (75% for hydrazone intermediates).^[1] This analog differs structurally from tabernanthalog by incorporating an additional fused cyclohexene ring, developed to probe structure-activity relationships for neuroplasticity without hallucinogenic liability. Another variant, 18-methoxycarbonyl-ibogainalog (related to 18-methoxycoronaridine), involves a nine-step process from the versatiline intermediate, featuring sodium borohydride reduction, hydrogenolysis, and acetal hydrolysis, achieving 35% overall yield; it was rationally designed to mimic ibogaine's anti-addictive effects while mitigating cardiotoxicity.^[10] These analogs were created to isolate therapeutic benefits like neural plasticity promotion from the iboga scaffold. The development of tabernanthalog and its analogs is protected under patents filed by Delix Therapeutics in 2020, covering DLX-007 for neuropsychiatric applications.^[11]

Pharmacology

Mechanism of action

Tabernanthalog acts as a non-selective serotonin receptor modulator, exhibiting partial agonism at the 5-HT_2A receptor and antagonism at the 5-HT_2B receptor, which contributes to its therapeutic profile while minimizing adverse effects associated with full agonism.^[1]^[2] This partial agonism at 5-HT_2A is sufficient to drive neuroplasticity without eliciting the full hallucinogenic response characteristic of classical psychedelics.^[1] Additionally, tabernanthalog modulates σ₁ receptors^[2] and inhibits nicotinic acetylcholine receptors, particularly the α₇ and α₉α₁₀ subtypes, with IC₅₀ values of approximately 10 μM for α₇ and 1-3 μM for α₉α₁₀, through non-competitive and competitive mechanisms, respectively.^[5] These interactions at nicotinic receptors may underlie its anti-addictive properties by attenuating reward-related signaling.^[5] The compound promotes neuroplasticity by enhancing dendrite spine growth and synaptogenesis in cortical neurons, independent of the hallucinogenic head-twitch response mediated by robust 5-HT_2A activation.^[1] This process involves activation of the BDNF/TrkB signaling pathway and mTOR, leading to sustained structural remodeling without requiring immediate early gene expression, as observed in classic psychedelics.^[2] Unlike traditional psychedelics, tabernanthalog's limited efficacy at 5-HT_2A avoids the behavioral disruptions tied to hallucinations, positioning it as a non-psychedelic psychoplastogen.^[1] Tabernanthalog demonstrates no significant blockade of hERG channels, reducing the risk of cardiotoxicity compared to ibogaine.^[1] In rodent models, it induces plasticity effects at doses of 10-20 mg/kg without causing behavioral disruption.^[2]

Pharmacokinetics

Tabernanthalog (TBG) has been administered primarily via intraperitoneal injection in preclinical rodent models, with doses ranging from 1 to 50 mg/kg, though its high water solubility as a fumarate salt (up to 40 mg/mL in 0.9% saline) supports potential for oral bioavailability not yet fully explored in vivo.^[8] Following intraperitoneal administration, TBG exhibits rapid absorption, achieving peak plasma concentrations within 15 minutes in rats. It exhibits rapid elimination, indicating a short duration that minimizes accumulation risk. TBG demonstrates efficient distribution across tissues, with high concentrations in the brain and liver shortly after dosing (e.g., detectable levels at 15 minutes post-50 mg/kg intraperitoneal injection in mice, though undetectable by 3 hours).^[8] This profile reflects its ability to cross the blood-brain barrier effectively, consistent with the lipophilicity of its iboga alkaloid scaffold despite enhanced aqueous solubility.^[8] Metabolism of TBG occurs primarily in the liver via cytochrome P450 enzymes.^[8] Excretion is predominantly renal.^[8] Pharmacokinetic parameters in rodents highlight species-specific differences that inform translational modeling.

History and development

Discovery

Tabernanthalog was discovered in 2020 by a team of researchers led by David E. Olson at the University of California, Davis (UC Davis), in collaboration with scientists from UC Santa Cruz, UC San Francisco, the Medical College of Wisconsin, and the University of Colorado Denver.^[12]^[1] This work emerged from Olson's psychoplastogen program, which aims to develop synthetic compounds that promote neural plasticity without the psychoactive effects of traditional psychedelics.^[12] The compound, a semi-synthetic analog of the alkaloid ibogaine derived from the Tabernanthe iboga plant, was designed through function-oriented synthesis to retain ibogaine's therapeutic benefits while eliminating its drawbacks.^[1] The primary rationale for developing tabernanthalog stemmed from ibogaine's well-documented limitations, including its potent hallucinogenic effects, cardiotoxicity via hERG potassium channel blockade, and challenges in scalable production due to its natural sourcing.^[1]^[13] These issues have hindered ibogaine's clinical advancement for treating substance use disorders and depression, despite its historical use in addiction therapy.^[12] By modifying ibogaine's structure, the researchers created a water-soluble, non-hallucinogenic version that avoids these risks, with tabernanthalog exhibiting only one-hundredth the potency of ibogaine in hERG blockade.^[1]^[13] The discovery was first detailed in a seminal paper published in Nature on December 9, 2020, where tabernanthalog was described as a non-hallucinogenic analog capable of promoting dendritogenesis and spinogenesis in neurons, thereby supporting its potential to induce neural plasticity for neuropsychiatric applications.^[1] Designated as DLX-007 in development, the compound has been patented by Delix Therapeutics—a biotechnology company co-founded by Olson—for therapeutic use in treating brain disorders.^[12]^[14] In 2023, Delix Therapeutics received a $320,000 NIH grant to further research DLX-007 for substance use disorders, completing IND-enabling studies with Phase 1 trials planned for 2024; as of 2025, development remains preclinical.^[14] This research was supported by grants from the National Institutes of Health (NIH), including funding for projects exploring safer ibogaine analogs, as well as private investments in Delix Therapeutics, which raised $70 million in Series A financing in 2021 to advance psychoplastogen development.^[15]^[14]^[16] The licensing of tabernanthalog-related technology from UC Davis to Delix has facilitated its progression toward clinical evaluation.^[12]

Preclinical research

Preclinical research on tabernanthalog (TBG), a non-hallucinogenic analog of ibogaine, has primarily utilized rodent models to evaluate its potential therapeutic effects through induction of neuroplasticity and modulation of stress- and addiction-related behaviors. In a seminal study, a single intraperitoneal dose of 10 mg/kg TBG administered to mice following chronic unpredictable mild stress promoted rapid regrowth of dendritic spines on layer V pyramidal neurons in the medial prefrontal cortex, with effects observable within 24 hours and persisting for at least 12 days.^[17] This neuroplasticity was evidenced by a doubling of spine formation rates compared to controls, with a significant proportion of new spines (32%) emerging near sites of stress-induced spine loss, highlighting TBG's capacity to restore structural integrity in key neural circuits disrupted by chronic stress.^[17] Behavioral studies in rodents have demonstrated TBG's efficacy in reversing stress-induced deficits. In mice subjected to chronic stress, TBG (10 mg/kg) alleviated anxiety-like behaviors in the elevated plus maze and restored cognitive flexibility in an attentional set-shifting task, effects that correlated with enhanced synaptic plasticity in the prefrontal cortex.^[17] In addiction models, TBG reduced self-administration of alcohol and heroin in Wistar rats under a progressive ratio schedule, with a 30 mg/kg dose significantly lowering breakpoints indicative of diminished motivation for these substances, even in animals with a history of polydrug use.^[4] Safety profiling in preclinical models indicates a favorable profile for TBG. Unlike classic psychedelics, TBG elicited no head-twitch response in mice at doses up to 100 mg/kg, a behavioral proxy for hallucinogenic effects. Cardiovascular assessments revealed minimal inhibition of hERG potassium channels (IC50 ≈ 100 μM), approximately 100-fold less potent than ibogaine (IC50 ~1 μM), with no observed bradycardia or arrhythmias in zebrafish larvae at therapeutic concentrations. Toxicity studies in rodents supported low acute risk, with no adverse effects reported at doses exceeding 500 mg/kg, consistent with an LD50 >500 mg/kg. Recent investigations have elucidated TBG's neuroplasticity mechanisms, showing induction of cortical spinogenesis via pathways independent of 5-HT2A receptor activation and without reliance on immediate early gene expression or glutamate bursts. In rodents, TBG (10-30 mg/kg) increased dendritic spine density in the prefrontal cortex through TrkB/mTOR signaling, distinct from hallucinogenic psychedelics, with effects persisting up to 12 days in stress models.^[2] These findings underscore TBG's potential as a psychoplastogen for neuropsychiatric conditions, with neuroplastic changes linked to behavioral improvements in anxiety and addiction paradigms.^[2]

Therapeutic applications

Neuropsychiatric disorders

Tabernanthalog (TBG), a non-hallucinogenic ibogaine analog classified as a psychoplastogen, has demonstrated preclinical efficacy in rodent models of depression by rapidly alleviating behavioral deficits associated with chronic stress. In mice subjected to seven days of unpredictable stress, a single dose of TBG (10 mg/kg, intraperitoneal) reduced immobility time in the forced swim test, indicating antidepressant-like effects comparable to those observed with established agents but with faster onset.^[1] These effects emerged within hours to one day post-administration and persisted for up to at least seven days, highlighting TBG's potential for sustained symptom relief without requiring chronic dosing.^[17]^[2] In anxiety models, TBG corrected stress-induced cognitive inflexibility, a core feature of anxiety disorders. Stressed mice treated with TBG showed normalized performance in probabilistic reversal learning tasks, requiring fewer trials to adapt to reward contingencies (p < 0.01), which reflects improved behavioral adaptability disrupted by chronic stress.^[18] This restoration targeted prefrontal-amygdala circuits, where TBG promoted dendritic spine regrowth in cortical pyramidal neurons (approximately 20% recovery of stress-induced spine loss, p < 0.01), thereby enhancing synaptic connectivity impaired in conditions like generalized anxiety disorder.^[18] Unlike selective serotonin reuptake inhibitors (SSRIs), which typically require weeks of daily administration to achieve efficacy, TBG's single-dose action offers a more rapid intervention, positioning it as a candidate for treatment-resistant depression where traditional therapies fail.^[18] The therapeutic rationale for TBG in neuropsychiatric disorders stems from its ability to induce neuroplasticity, remodeling maladaptive neural circuits underlying major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). By activating 5-HT_2A receptors without hallucinogenic effects or immediate early gene activation, TBG fosters structural changes in brain regions affected by trauma and chronic stress, such as increased spine density in the medial prefrontal cortex persisting beyond seven days, which could address the circuit dysfunctions central to PTSD's persistent fear responses and anxiety disorders.^[18]^[19]^[2] Preclinical stress models further support this, showing TBG's reversal of fear-related behaviors relevant to PTSD symptomatology.^[18]

Substance use disorders

Tabernanthalog (TBG), a synthetic non-hallucinogenic analog of the psychedelic alkaloid ibogaine, has shown promise in preclinical models for treating substance use disorders (SUDs), particularly those involving opioids and alcohol. Unlike ibogaine, which exhibits anti-addictive properties but is limited by hallucinogenic effects and cardiotoxicity, TBG promotes neural plasticity without inducing altered states of consciousness or significant safety concerns.^[1] In rodent models of opioid use disorder, a single administration of TBG (40 mg/kg or cumulative 42.5 mg/kg) inhibits heroin self-administration and cue-induced seeking behaviors, with therapeutic effects persisting for at least two weeks. This reduction is selective, as TBG diminishes motivation for heroin in progressive ratio schedules without affecting responding for natural rewards like food, suggesting a targeted impact on drug reinforcement pathways. In a polydrug self-administration paradigm using Wistar rats with prior alcohol exposure, TBG (30 mg/kg, intraperitoneal) significantly lowered break points for intravenous heroin (p = 0.040) and oral alcohol (p = 0.001) compared to vehicle controls, indicating efficacy in comorbid opioid-alcohol use scenarios.^[20] TBG's effects on alcohol use disorder are similarly evidenced by reduced alcohol-seeking behaviors in rats following administration, aligning with its broader capacity to modulate corticolimbic circuits disrupted in addiction. Mechanistically, TBG induces structural neuroplasticity in the prefrontal cortex via activation of neurotrophic factors such as BDNF and GDNF, enhancing top-down inhibitory control over compulsive drug-seeking. These findings position TBG as a potential psychoplastogen for SUDs, though human clinical trials remain pending to validate efficacy and safety as of 2025.^[1]^[21]

References

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A non-hallucinogenic psychedelic analogue with therapeutic potential
Dec 9, 2020 · In rodents, tabernanthalog was found to promote structural neural plasticity, reduce alcohol- and heroin-seeking behaviour, and produce ...<|control11|><|separator|>
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The psychoplastogen tabernanthalog induces neuroplasticity ...
Aug 4, 2025 · Nonhallucinogenic psychoplastogens, such as tabernanthalog (TBG), are being developed as potentially safer, more scalable alternatives to ...
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Non-hallucinogenic psychedelic analog reverses effects of stress in ...
May 25, 2021 · Researchers found that a single dose of tabernanthalog (TBG) can correct stress-induced behavioral deficits, including anxiety and cognitive inflexibility.
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Tabernanthalog Reduces Motivation for Heroin and Alcohol in a ...
Jun 14, 2023 · TBG effectively reduced motivation for heroin and alcohol in this test, indicating its efficacy is preserved in animals with a history of heroin and alcohol ...
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Tabernanthalog and ibogainalog inhibit the α7 and α9α10 nicotinic ...
In this study, we have investigated the pharmacological activity and structural interaction of two novel psychoplastogens, tabernanthalog (TBG) and ...
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Tabernanthalog, a Non-Hallucinogenic Psychedelic, Alleviates ...
Tabernanthalog (TBG), a water-soluble, non-hallucinogenic, and non-toxic analog of ibogaine, has been observed to elicit antidepressant-like effects via the ...
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Tabernanthalog | 2483829-58-7 | BT182116 - Biosynth
Chemical Formula. C14H18N2O. Molecular Weight. 230.31 g/mol. Smiles. CN1CCC2=C(CC1)NC3=C2C=CC(=C3)OC. Long Term Storage. store at 2°C - 8°C. Storage. store at 2 ...
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Jun 9, 2021 · The hallmarks of ibogaine's structure include an indole, a 7-membered tetrahydroazepine, and a bicyclic isoquinuclidine (Fig. 1). We ...
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Disrupting Substance Use Disorder: The Chemistry of Iboga Alkaloids
Jul 7, 2024 · Ibogaine's key structural features incorporate nitrogen heterocycles: an indole, which is merged with a seven-membered tetrahydroazepine and a ...<|control11|><|separator|>
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Tabernanthalog and ibogainalog inhibit the α7 and α9α10 nicotinic acetylcholine receptors via different mechanisms and with higher potency than the GABAA ...Missing: 007 | Show results with:007
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... DLX-007. DLX-007 is a novel, first-in-class, neuroplastogen being evaluated in a range of substance use disorders (SUDs), including opioid and stimulant use.Missing: Tabernanthalog | Show results with:Tabernanthalog
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Total project funding amount for 2 projects is $5,439,548*. * Only NIH, CDC and FDA funding data. Export. Project Number, Sub, Principal Investigator(s)/ ...
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May 25, 2021 · Recently, tabernanthalog (TBG), an analog of the psychedelic 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), was synthesized and found not to ...
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Jun 14, 2023 · Coupled with observations from this study, this suggests that TBG selectively reduces motivation for drug but not food reward. We are only ...<|separator|>