Non-Hallucinogenic Psychoplastogens: Neuroplasticity Without the Trip

Language: en

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Overview

What if you could get the brain-rewiring benefits of a psychedelic without the 6-8 hour journey into altered consciousness? What if the neuroplasticity — the new dendrites, new synapses, new connections that make psychedelics the most powerful brain restructuring tools ever discovered — could be separated from the hallucinations, ego dissolution, and emotional intensity that define the psychedelic experience?

David Olson’s laboratory at UC Davis has spent a decade pursuing this question, and the answer appears to be yes. Olson’s team has engineered a new class of compounds called non-hallucinogenic psychoplastogens — molecules that retain the neuroplasticity-promoting effects of psychedelics (dendritic growth, spinogenesis, synaptogenesis) while eliminating or dramatically reducing the subjective psychedelic experience. The flagship compound, tabernanthalog (TBG), is a synthetic analog of ibogaine that promotes cortical neuron growth without hallucination, cardiac toxicity, or the 24-36 hour duration that makes ibogaine clinically impractical.

If psychedelics are the complete renovation of a house — walls torn down, everything exposed, the whole structure rebuilt — psychoplastogens are the targeted renovation: new wiring, new plumbing, structural reinforcement, done while the occupants go about their daily lives. The question that will define this field is whether the targeted renovation is enough, or whether the complete exposure is what makes the renovation transformative.

The Science of Psychoplastogens

Defining the Term

David Olson introduced the term “psychoplastogen” in 2018 to describe any compound that rapidly promotes structural and functional neural plasticity. The term encompasses both hallucinogenic psychedelics (psilocybin, LSD, DMT) and non-hallucinogenic compounds that produce similar structural effects through related molecular pathways. The key insight: psychoplastogenesis (promoting neural plasticity) and psychedelic experience (altered consciousness) are pharmacologically separable — they involve overlapping but distinct signaling pathways downstream of the same receptor.

The Molecular Dissection

Both the plasticity-promoting and hallucinogenic effects of classical psychedelics begin with agonism at the serotonin 5-HT2A receptor. But 5-HT2A activation triggers multiple intracellular signaling cascades, and these cascades can be differentially engaged by different agonists — a phenomenon called biased agonism.

The plasticity pathway: 5-HT2A → Gq protein → phospholipase C → IP3/DAG → intracellular calcium → CaMKII → TrkB transactivation → BDNF signaling → mTOR → protein synthesis → dendritic growth and synaptogenesis.

The hallucinogenic pathway: 5-HT2A → beta-arrestin 2 recruitment → receptor internalization → altered thalamocortical signaling → cortical excitation-inhibition imbalance → perceptual distortion and hallucination.

The key finding from Olson’s and others’ laboratories: the plasticity pathway and the hallucinogenic pathway can be dissociated through biased agonism. A compound that strongly activates the Gq/TrkB/mTOR pathway while weakly activating the beta-arrestin pathway will promote neuroplasticity without producing hallucinations.

This dissociation was demonstrated directly by Hesselgrave et al. (2021) at Yale, who showed that psilocybin’s antidepressant-like behavioral effects and synaptic plasticity effects in mice were preserved even in beta-arrestin 2 knockout mice — proving that the plasticity mechanism does not require the beta-arrestin signaling that contributes to hallucinogenic effects.

TrkB as the Convergence Point

A critical insight from multiple laboratories is that the neuroplasticity effects of psychedelics converge on TrkB (tropomyosin receptor kinase B) — the receptor for BDNF (brain-derived neurotrophic factor). TrkB is the master switch for structural neural plasticity: when activated, it triggers the signaling cascades (mTOR, MAPK/ERK, PI3K/Akt) that drive dendritic growth, spine formation, and synaptogenesis.

Psychedelics activate TrkB through transactivation — the 5-HT2A intracellular cascade triggers TrkB without BDNF being present. This is why psychedelics are such potent plasticity promoters: they bypass the normal requirement for BDNF release and directly activate the downstream plasticity machinery.

Casarotto et al. (2021, Cell) from Eero Castren’s laboratory in Finland made a further discovery: psychedelics (and antidepressants generally) bind directly to TrkB in addition to their primary receptor targets. This direct TrkB binding may contribute to the plasticity effects and provides another molecular target for designing non-hallucinogenic psychoplastogens.

Tabernanthalog (TBG): The Flagship Compound

Design and Synthesis

Tabernanthalog is a synthetic analog of ibogaine — the psychoactive alkaloid from the African shrub Tabernanthe iboga used in Bwiti ceremonies and studied for addiction interruption. Ibogaine is one of the most pharmacologically interesting psychedelics: it produces profound anti-addictive effects (interrupting opioid, cocaine, and alcohol dependence) through a mechanism that involves critical period reopening and massive neuroplasticity. But ibogaine has two critical liabilities: it causes potentially fatal cardiac arrhythmias (by blocking hERG potassium channels), and its psychoactive effects last 24-36 hours — making it both medically dangerous and clinically impractical.

Olson’s group systematically modified ibogaine’s chemical structure to eliminate these liabilities while preserving the neuroplasticity effects. The key modifications: replacing the indole ring system with a benzofuran core (removing hERG channel blockade) and optimizing the stereochemistry for selective Gq-biased 5-HT2A agonism (reducing hallucinogenic potential while preserving plasticity signaling).

The result — tabernanthalog — was published in Nature in 2021 (Cameron et al.). TBG promotes cortical neuron growth with potency comparable to ibogaine but without cardiac toxicity or hallucinogenic effects.

Preclinical Evidence

TBG has shown robust effects in multiple preclinical models:

Structural plasticity: TBG increases dendritic arbor complexity (approximately 35% increase), dendritic spine density (approximately 40% increase), and functional synapse number (approximately 25% increase) in cortical neurons in vitro, comparable to the effects of DMT and psilocybin.

Antidepressant effects: In the forced swim test and sucrose preference test (rodent behavioral models relevant to depression), TBG produces rapid antidepressant-like effects after a single dose, lasting at least 7 days.

Anti-addictive effects: TBG reduces alcohol self-administration and heroin-seeking behavior in rodent models, reproducing ibogaine’s anti-addictive profile without its toxicity.

Anxiolytic effects: TBG reduces anxiety-like behavior in the elevated plus maze and open field test, consistent with neuroplasticity-mediated anxiolysis.

No hallucinogenic effects: TBG does not produce the head-twitch response in mice (the standard behavioral proxy for hallucinogenic effects in rodents), confirming the dissociation of plasticity from hallucination.

No cardiac toxicity: TBG does not block hERG potassium channels at pharmacologically relevant concentrations, eliminating the arrhythmia risk of ibogaine.

Clinical Development

As of 2025, TBG and related non-hallucinogenic psychoplastogens are in early clinical development:

Delix Therapeutics: Founded by Olson, Delix is developing TBG analogs (designated DLX-001 and successors) for clinical trials. Phase 1 safety and tolerability studies began enrollment in 2024-2025.

Other companies: Multiple pharmaceutical companies (Gilgamesh Pharmaceuticals, Neumora Therapeutics, Bright Minds Biosciences) are developing their own non-hallucinogenic psychoplastogens based on different chemical scaffolds but similar biased agonism strategies.

Other Non-Hallucinogenic Psychoplastogens

AAZ-A-154 and Related Compounds

Researchers at the University of North Carolina (Bryan Roth’s laboratory) have developed 5-HT2A agonists with extreme bias toward Gq signaling over beta-arrestin recruitment. AAZ-A-154 promotes cortical plasticity markers in mice without producing head-twitch responses, demonstrating that the biased agonism strategy can be applied to compounds beyond the ibogaine scaffold.

Ketamine Analogs

Ketamine itself occupies an interesting middle ground — it produces dissociative effects at clinical doses but has well-documented neuroplasticity effects through BDNF/TrkB/mTOR signaling (triggered by NMDA receptor blockade and subsequent glutamate surge). Several groups are developing ketamine analogs that preserve the plasticity effects while reducing or eliminating dissociation. Hydroxynorketamine (HNK), a metabolite of ketamine, has been shown to produce antidepressant-like effects in rodents without dissociative properties, though human data are limited.

IsoDMT and DMT Analogs

Structural analogs of DMT (N,N-dimethyltryptamine) that have reduced 5-HT2A efficacy while maintaining TrkB engagement are under development at multiple institutions. These compounds aim to preserve DMT’s rapid neuroplasticity induction while eliminating the profound perceptual effects of the parent compound.

The Great Debate: Trip vs. No Trip

The Case for Separating Plasticity from Experience

Scalability: Psychedelic-assisted therapy currently requires 6-8 hour supervised sessions with trained therapists in controlled clinical settings. This is expensive ($5,000-15,000 per treatment episode), labor-intensive, and inherently limited in throughput. Non-hallucinogenic psychoplastogens could be prescribed like conventional medications — daily or weekly dosing, no specialized clinical setting, no prolonged supervision.

Safety: Challenging psychedelic experiences (bad trips, psychiatric emergencies, retraumatization) are rare but real risks of hallucinogenic psychedelic therapy. Eliminating the subjective experience eliminates these risks.

Accessibility: The specialized therapeutic training, clinical infrastructure, and time commitment required for psychedelic-assisted therapy create barriers that disproportionately exclude low-income, rural, and marginalized populations. Non-hallucinogenic psychoplastogens could be distributed through existing healthcare infrastructure.

Regulatory: The FDA approval pathway for a conventional oral medication (daily pill, standard clinical trial design) is well-established. The pathway for a drug that requires 8-hour supervised sessions, cannot be placebo-controlled, and produces profound altered states is unprecedented and uncertain.

The Case for the Trip

The mystical experience predicts outcome: In every published psilocybin clinical trial, the intensity of the mystical experience during the session (rated on the Mystical Experience Questionnaire) is the strongest predictor of therapeutic outcome. If you remove the mystical experience, you may remove the mechanism of action.

The REBUS model: Carhart-Harris’s REBUS model proposes that the therapeutic mechanism of psychedelics involves the conscious processing of emotional material during the state of relaxed beliefs. The psychological work — confronting suppressed emotions, revising rigid beliefs, experiencing unity and meaning — IS the therapy. The neuroplasticity provides the biological substrate for consolidating the insights, but the insights are generated by the subjective experience.

Critical period reopening + input: Dolen’s critical period mechanism suggests that psychedelics create a window of enhanced plasticity that must be filled with appropriate input to produce lasting change. In psychedelic-assisted therapy, the “input” is the therapeutic relationship and the processing of the psychedelic experience itself. Without the experience, what fills the plasticity window?

Antidepressants already promote neuroplasticity: SSRIs, the most widely prescribed antidepressants, promote neuroplasticity through BDNF/TrkB signaling — the same pathway activated by psychoplastogens, though more slowly. If neuroplasticity alone were sufficient for treating depression, SSRIs would be more effective than they are. The fact that SSRIs work modestly while psychedelic therapy works dramatically suggests that something beyond neuroplasticity — perhaps the experience itself — is doing critical therapeutic work.

The Middle Path

The most likely resolution is that both approaches have value for different clinical scenarios:

Non-hallucinogenic psychoplastogens may be most appropriate for: maintenance therapy (sustaining the gains of an initial psychedelic session through ongoing neuroplasticity support), conditions where neuroplasticity deficit is the primary pathology (neurodegenerative disease, TBI recovery, stroke rehabilitation), patients who cannot tolerate psychedelic experiences (severe psychosis, cardiac conditions, extreme anxiety), and population-level intervention (where individual psychedelic therapy is impractical).

Full psychedelic-assisted therapy may be most appropriate for: conditions involving entrenched psychological patterns (PTSD, addiction, treatment-resistant depression), patients who need the experiential insight and emotional processing that the psychedelic state enables, spiritual and existential concerns (end-of-life distress, meaning-making), and initial treatment episodes (with psychoplastogens used for maintenance).

Four Directions Integration

• Serpent (Physical/Body): Non-hallucinogenic psychoplastogens are the purest embodiment of the serpent’s healing — physical restructuring of neural tissue without the higher-level experiential transformation. New dendrites grow. New spines form. New synapses connect. The body’s neural architecture is rebuilt from the molecular level up. This is the most tangible, measurable, materialist form of healing psychedelics offer, stripped of everything that cannot be photographed under an electron microscope.

• Jaguar (Emotional/Heart): The great concern with non-hallucinogenic psychoplastogens is that they may bypass the emotional work that gives psychedelic therapy its power. Growing new synapses without processing the emotional content that the new synapses should encode is like building new roads without knowing where they should go. The jaguar’s fire demands that healing include the felt dimension — the tears, the rage, the grief, the love — not just the structural change.

• Hummingbird (Soul/Mind): The philosophical question raised by psychoplastogens is profound: what is the relationship between brain structure and mind? If changing brain structure (adding synapses) produces lasting psychological change without any corresponding psychological experience, this supports a materialist view — the mind is what the brain does, and changing the brain changes the mind regardless of experience. If, however, the psychological experience is necessary for lasting change, this supports a more integrated view — mind and brain are coupled, and changing one without the other is incomplete.

• Eagle (Spirit): The eagle sees the deepest tension: psychedelic therapy at its best is a spiritual practice — an encounter with the sacred, with death and rebirth, with the dissolution of the ego and the discovery of something greater. Non-hallucinogenic psychoplastogens offer the physical benefit without the spiritual encounter. This is the ancient tension between medicine and ceremony, between the pill and the practice, between fixing the body and transforming the soul. The eagle’s vision encompasses both: the body needs healing AND the soul needs awakening, and the wisest path uses both tools where each is appropriate.

Key Takeaways

• Non-hallucinogenic psychoplastogens are compounds that promote the neuroplasticity effects of psychedelics (dendritic growth, synaptogenesis) without producing hallucinations, through biased agonism at the 5-HT2A receptor.
• David Olson’s tabernanthalog (TBG), a non-hallucinogenic ibogaine analog, produces antidepressant and anti-addictive effects in preclinical models without cardiac toxicity or hallucinogenic effects.
• The molecular dissection: plasticity operates through the Gq/TrkB/mTOR pathway; hallucination involves additional beta-arrestin signaling and thalamocortical disruption. These can be separated by biased agonists.
• The key question remains: is the subjective psychedelic experience necessary for therapeutic benefit, or is neuroplasticity alone sufficient? Evidence from the mystical experience correlation and the REBUS model suggests the experience matters.
• Non-hallucinogenic psychoplastogens and full psychedelic therapy are likely complementary, not competing — each suited to different clinical scenarios.
• Multiple compounds from multiple companies are entering clinical trials (2024-2025), potentially enabling pharmaceutical-scale deployment of psychedelic neuroplasticity.

References and Further Reading

• Olson, D. E. (2018). Psychoplastogens: A promising class of plasticity-promoting neurotherapeutics. Journal of Experimental Neuroscience, 12, 1179069518800508.
• Cameron, L. P., et al. (2021). A non-hallucinogenic psychedelic analogue with therapeutic potential. Nature, 589, 474-479.
• Ly, C., et al. (2018). Psychedelics promote structural and functional neural plasticity. Cell Reports, 23(11), 3170-3182.
• Hesselgrave, N., et al. (2021). Psilocybin antidepressant-like and synaptic actions are independent of 5-HT2R/beta-arrestin2 signaling. PNAS, 118(17).
• Casarotto, P. C., et al. (2021). Antidepressant drugs act by directly binding to TRKB neurotrophin receptors. Cell, 184(5), 1299-1313.
• Roth, B. L. (2023). Molecular pharmacology of biased agonism at 5-HT2A receptors. Trends in Pharmacological Sciences.