Author name: Sergio Lázaro Martínez

This is Part II of a double feature discussing the current stage in research and development of the different classes of non-hallucinogenic psychedelics. In the previous installment, we explained the rationale and history behind this emergent field, as well as the different efforts underway. In this second part, we provide a critical view of the underlying techniques, alternative trans-species tests, medical models that can be exploited to implement these substances, clinical translations of the findings, and the outlook for the field.

a Dominant Readout under scrutiny

As we discussed in the first part of this series, the field of non-hallucinogenic psychedelic analogs has made great advancements since its conceptual inception circa 2018. In the last five years, this new “class of classes” of drugs has yielded a few potentially therapeutic serotonergic (LSD-like), opioidergic (ibogaine-like), and glutamatergic (ketamine-inspired) compounds labelled non-hallucinogenic on the basis of, almost exclusively, the absence of a head twitch response (HTR) when administered to rodents. However, across all these classes of putative non-hallucinogenic psychedelics, this field faces a central methodological challenge. The current tools for assessing hallucinogenic potential are insufficient, and in many cases conceptually misaligned with the target drug class.

​While most programs rely on receptor pharmacology, often simplified to 5-HT2A arrestin versus Gq bias, and the rodent HTR as primary indicators of hallucinogenic liability, both approaches carry assumptions that do not generalize across molecular scaffolds, mechanisms of action, or species. Given its widespread use and the weight of the claims derived from it, we will focus here on critically evaluating the validity of the HTR.

Head Twitch Response as a Proxy for Hallucinogenic Potential

The earliest report describing the induction of head-twitch behavior in mice by the psychedelic LSD dates back to the work of Keller and Umbreit in 1956. Several decades later, this behavior became widely adopted in molecular and pharmacological investigations of 5-HT2AR-dependent signaling. The head-twitch response is now commonly used as a proxy to assess the psychedelic potential of a 5-HT2AR-active compound, as the frequency of these side-to-side head movements in rodents has been shown to correlate in a dose-dependent manner with the intensity of hallucinogenic effects produced by classical psychedelics in humans. However, the leap from “reduced HTR” to “non-hallucinogenic in humans” is ambitious, to say the least.

The most rigorous definition for psychedelics is: compounds that bind to the serotonin 5-HT2AR and reliably produce profound alterations in perception, cognition, and self-experience. Accordingly, the HTR is a rodent-specific motor response triggered by cortical 5-HT2AR activation, which, just like psychedelic effects in humans, can be abolished by inhibition of 5-HT2AR’s activity, and has therefore historically been treated as a translational signature of 5-HT2AR-mediated hallucinations.

Polypharmacology and Cross-Class Limits of HTR Generalization

Many of you readers have likely already identified the core limitation of this assay for broadly assessing hallucinogenicity in this new non-hallucinogenic psychedelic class: How can a 5-HT2AR-specific behavior be used to study compounds that act through kappa opioid receptors, NMDA receptors, serotonin transporters, or that display polypharmacological profiles? The following table summarizes, to the best of our efforts, the available evidence relevant to this critical methodological concern.

Pharmacological Class	Mechanisms	Drugs	HTR Elicited?	Notes
Classic psychedelics (tryptamines)	5-HT2A agonism	Psilocybin, DMT, 5-MeO-DMT	Yes	Strongly dose-dependent; blocked by 5-HT2A antagonists (e.g., ketanserin).
Classic psychedelics (ergolines)	5-HT2A agonism	LSD	Yes	LSD is among the most potent HTR inducers; long-term course.
Classic psychedelics (phenethylamines)	5-HT2A agonism	Mescaline, DOI, 2C-B	Yes	DOI is the canonical positive control for HTR assays.
Non-hallucinogenic 5-HT2A agonists	5-HT2A agonism	Lisuride, ergotamine	No / very weak	Critical exception: bind 5-HT2A but do not elicit HTR → shows efficacy/bias matters, not affinity alone.
Dissociative anesthetics	NMDA receptor blockade	Ketamine, PCP, dizocilpine	No/mixed	PCP does not produce HTR, ketamine only when held in tail suspension, or when rodents are pretreated with serotonin.
Dissociative psychedelics	Kappa-opioid receptor (KOR) agonism	Salvinorin A	No data	Salvinorin A causes overt sedative-like and locomotor-decreasing effects in rodents
Oneirogenic psychedelics	Polypharmacology (KOR + others)	Ibogaine, noribogaine	No	Despite significant subjective psychedelic effects, no effect on HTR
Deliriants	Muscarinic M1/M2 antagonist	Scopolamine, atropine	No	Delirium-producing hallucinogens are HTR-negative.
Entactogens/empathogens	5-HT release, weak 5-HT2AR agonism	MDMA, MDA	Variable	LSD is among the most potent HTR inducers; long-time course.
Non-5-HT2AR psychoactive drugs	Agonists at various receptors (CB1, GABA, etc.)	THC, muscimol	Reduce/mixed	TCH has been seen to reduce DOI-induced HTR. Muscimol has been found to increase and decrease 5-MeO-DMT-induced HTR.
Non-5-HT2AR psychostimulants	Dopamine reuptake inhibitors	Cocaine, amphetamine	No	MDA can induce modest HTR at high doses; racemic MDMA does not, while R(-)-MDMA does, reflecting indirect vs direct 5-HT2AR activation.

As expected, prior to examining the table, the head-twitch response represents a rodent-specific behavioral readout that is neither necessary nor sufficient to model human psychedelic phenomenology. Nevertheless, what becomes clear upon inspection of the literature is that classifying a compound as non-hallucinogenic on the basis of a negative HTR result is pharmacologically meaningful only for compounds whose primary mechanism of action engages the 5-HT2A receptor in a manner comparable to that of classical serotonergic psychedelics. For iboga alkaloids, kappa opioid receptor active analogs, and dissociative anesthetics or antidepressants, the absence of HTR provides little to no information about potential human subjective effects. Demonstrating a true dissociation between hallucinations and any one of these analogs will therefore require rigorous pharmacological characterization, blinded, controlled human studies, and validated translational biomarkers (some of which are described later in this text), rather than relying on a single behavioral assay such as the HTR.

Non-Hallucinogenic Labeling and Semantic Drifts

In parallel, the label “non-hallucinogenic agonist” has often been applied in an unnecessary and overly expansive manner. For example, DLX-2270 has been described as a “non-hallucinogenic neuroplastogen” despite functioning pharmacologically as a 5-HT2A receptor antagonist with concurrent 5-HT2C agonism. This mechanism is fundamentally distinct from that of a 5-HT2A agonist and illustrates the degree to which semantic drift and marketing pressures have shaped the space. Similarly, Tabernanthalog (or TBG) was grouped with non-hallucinogenic psychedelic analogs despite exhibiting substantially lower potency at the 5-HT2AR than serotonin itself. This raises questions about whether its primary therapeutic actions are instead mediated by kappa opioid receptors or by broader polypharmacological interactions. The original study did not report binding affinity or functional activity at the kappa opioid receptor, despite ibogaine and related scaffolds being well documented to interact with this receptor class, leaving mechanistic interpretation incomplete and rendering reliance on HTR even more useless.

​A similar limitation is evident in recent scaffold discovery efforts that explicitly optimize for the absence of the head twitch response. For example, a UC Davis-led study reported the identification of novel serotonin receptor-active compounds, described as “hallucination-free,” based primarily on their failure to induce HTR in rodents. While the chemical biology and photochemical strategy underlying this work are elegant, the interpretive leap from HTR negativity to hallucination-free status reflects the same conceptual overreach discussed above. In the absence of human data or perception-linked behavioral assays, the lack of a rodent motor reflex cannot establish the absence of altered states of consciousness, particularly when new scaffolds are designed to engage central neuromodulatory systems in noncanonical ways. This approach risks reifying the HTR not merely as a proxy, but as a defining criterion for hallucinogenicity, thereby embedding its limitations directly into early-stage drug discovery.

Lisuride and TBG as Warnings Against Binary Classifications

The case of lisuride further illustrates the limitations of the HTR model’s binary classifications. Lisuride is a non-hallucinogenic and close structural analog of LSD that binds the 5-HT2A receptor yet fails to elicit robust HTR at therapeutic doses. At higher doses, however, lisuride has been reported to produce hallucinations in humans, highlighting that hallucinogenic potential exists on a continuum shaped by dose, receptor engagement, and signaling context. A similar principle applies to cocaine and amphetamine-induced hallucinations, which occur at high doses despite these compounds being classified as psychostimulants and remaining HTR negative.

​This is particularly relevant when considering that doses used in TBG studies were interpreted through an HTR framework without comparable attention to dose equivalency or cross-class pharmacology. Indeed, as discussed in Psychedelic Alpha’s 2023 report titled “Non Hallucinogenic Trip Reports Searching for the Tabernanthalog Tasters”, despite TBG being widely promoted as non-hallucinogenic based on an absent HTR signal, online communities were rapidly populated with self-reported experiences from individuals who had sourced or synthesized the compound. Since then, reports of doses ranging from 50 to 500 mg (!!) have described effects ranging from emotional intensification to visual distortions and dreamlike or oneirogenic mentation, effects consistent with expectations for iboga-derived scaffolds.

​While anecdotal, the convergence of these reports underscores the risk of equating a single rodent motor behavior with complex human subjective experience, particularly for compounds whose primary mechanisms lie outside canonical serotonergic psychedelic pathways.

Complementary behavioral and perceptual models Beyond HTR

Alternative tasks, such as drug discrimination paradigms, can assess whether animals perceive internal cues similar to known psychedelics, while prepulse inhibition and sensorimotor gating tasks capture cognitive and perceptual disruptions more closely aligned with human psychotomimetic effects, which could be used to study the hallucinogenic potential of drugs that aim to mimic the mechanism of ketamine and other dissociative anesthetics.

​Prepulse inhibition refers to the attenuation of the startle response when a startling stimulus is preceded by a weak non-startling cue and serves as an operational measure of sensorimotor gating and perceptual filtering. Disruption of PPI is a well-established effect of NMDA receptor antagonists such as PCP and ketamine and is thought to reflect a loss of subcortical filtering, leading to cortical sensory overload. Dissociative anesthetics reliably produce a behavioral profile in rodents that includes PPI disruption, a phenotype that parallels aspects of dissociative and hallucinogenic experiences in humans. Consistent with this interaction, NMDA receptor antagonists have also been shown to enhance head twitch responses in mice pretreated with serotonin, further underscoring the limits of interpreting HTR in isolation.

​More recently, the exciting work by Páleníček and colleagues in 2025 represented a conceptual advance by demonstrating that rodents and humans can be evaluated using homologous perceptual tasks. Using an apparent motion paradigm in which static stimuli are perceived as moving, the authors showed that psilocin induces parallel alterations in visual motion perception in humans and rodents. This study provided the first robust cross-species psychophysical evidence that rodents experience quantifiable analogues of human visual distortions, offering a direct bridge between a specific dimension of the psychedelic subjective experience and a measurable behavior that surpasses indirect proxies such as HTR or locomotor readouts, illustrating that hallucination-relevant endpoints could be operationalized behaviorally without reliance on narrow receptor-centric assumptions.

From animal models to clinical translation and therapeutic framing

These advances highlight a central need for the field to develop mechanistically agnostic, perception-linked, and behaviorally rich assays when evaluating the hallucinogenic liability of new psychedelic-adjacent compounds.

​At the same time, the preclinical findings discussed in the first part of this series face intrinsic limitations, since animal models cannot fully capture human phenomenology. Despite the rapid expansion of non-hallucinogenic analogs across serotonergic, kappa opioid, and ketamine-inspired scaffolds, it remains unknown whether these compounds can deliver durable therapeutic benefit in the absence of subjective experience. Until well-powered randomized trials report on efficacy, safety, and durability, claims of success remain provisional. This caution is supported by recent high-quality clinical data in related domains. For example, despite promising results of LSD-assisted psychotherapies for different mood disorders, the largest randomized trial of repeated subperceptual doses of LSD published in JAMA Psychiatry found no benefit over placebo for ADHD symptoms.

​Clinical practice has already begun to converge on models that prioritize pharmacological delivery over subjective experience. In the case of rapid-acting antidepressants, treatments could quickly follow the Spravato-based framework, in which esketamine is administered intranasally without structured psychotherapy under a restricted safety program. This pharmacology-first and integration-light approach may be particularly attractive to developers of non-hallucinogenic analogs. If these compounds enter clinical testing, will they follow the same “pill in, pill out” model? Although Delix Therapeutics previously indicated plans to advance tabernanthalog-derived compounds into first-in-human studies in 2023, the Phase I trial ultimately conducted evaluated zalsupindole, with full results reported in December 2024. As of January 2026, no clinical trial, press release, or public registry entry indicates that TBG has entered human testing, adding to the continued uncertainty around its translational trajectory.

​Promise, Uncertainty, and Responsibility in Clinical contexts

A central question regarding this new class of compounds is what patients will ultimately value most. For some, rapid symptom relief may be sufficient, while for others, meaning-making, insight, and existential transformation, often associated with phenomenological intensity, may contribute to long-term benefit.

Treating these compounds solely as pharmacotherapies risks reducing them to another class of fast-acting antidepressants, potentially overlooking therapeutic processes that many proponents consider central to psychedelic efficacy. Accordingly, informed consent should address not only dosing and safety, but also the expected nature of subjective experience or its absence, and whether the therapeutic goal is to preserve, minimize, or decouple phenomenology from mechanism. Respecting patient autonomy requires individuals to choose whether their treatment prioritizes rapid, integration-free symptom relief or creates space for psychological integration, meaning, and possible subjective transformation.

In conclusion, the promise of “non-hallucinogenic psychedelics” is real, but still largely speculative. Until clinical trials are completed and real-world data emerge, we must resist hype, embrace methodological rigor, and preserve ethical clarity about what “psychedelic-inspired therapy and therapeutics” should really mean.

References

1. The Promise of Non-Hallucinogenic Psychedelics: A Field Coming into Focus. OPEN Foundation blog, Sergio Lázaro Martínez, 2025
2. Wallach, J., Cao, A.B., Calkins, M.M. et al. Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential. Nat Commun 14, 8221 (2023). https://doi.org/10.1038/s41467-023-44016-1
3. KELLER DL, UMBREIT WW. Permanent alteration of behavior in mice by chemical and psychological means. Science. 1956 Oct 19;124(3225):723-4. doi: 10.1126/science.124.3225.723. PMID: 13371313.
4. de la Fuente Revenga M, Shin JM, Vohra HZ, Hideshima KS, Schneck M, Poklis JL, González-Maeso J. Fully automated head-twitch detection system for the study of 5-HT2A receptor pharmacology in vivo. Sci Rep. 2019 Oct 3;9(1):14247. doi: 10.1038/s41598-019-49913-4. PMID: 31582824; PMCID: PMC6776537.
5. Nichols DE. Psychedelics. Pharmacol Rev. 2016 Apr;68(2):264-355. doi: 10.1124/pr.115.011478.
6. González-Maeso J, Weisstaub NV, Zhou M, Chan P, Ivic L, Ang R, Lira A, Bradley-Moore M, Ge Y, Zhou Q, Sealfon SC, Gingrich JA. Hallucinogens recruit specific cortical 5-HT(2A) receptor-mediated signaling pathways to affect behavior. Neuron. 2007 Feb 1;53(3):439-52. doi: 10.1016/j.neuron.2007.01.008. PMID: 17270739.
7. Silverstein BH, Kolbman N, Nelson A, Liu T, Guzzo P, Gilligan J, Lee U, Mashour GA, Vanini G, Pal D. Intravenous psilocybin induces dose-dependent changes in functional network organization in rat cortex. Transl Psychiatry. 2025 Mar 25;15(1):93. doi: 10.1038/s41398-025-03308-4. PMID: 40128190; PMCID: PMC11933319.
8. Halberstadt AL, Chatha M, Klein AK, Wallach J, Brandt SD. Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species. Neuropharmacology. 2020 May 1;167:107933. doi: 10.1016/j.neuropharm.2019.107933. Epub 2020 Jan 7. PMID: 31917152; PMCID: PMC9191653.
9. Jefferson SJ, Gregg I, Dibbs M, Liao C, Wu H, Davoudian PA, Woodburn SC, Wehrle PH, Sprouse JS, Sherwood AM, Kaye AP, Pittenger C, Kwan AC. 5-MeO-DMT modifies innate behaviors and promotes structural neural plasticity in mice. Neuropsychopharmacology. 2023 Aug;48(9):1257-1266. doi: 10.1038/s41386-023-01572-w. Epub 2023 Apr 4. PMID: 37015972; PMCID: PMC10354037.
10. Halberstadt AL, Geyer MA. Characterization of the head-twitch response induced by hallucinogens in mice: detection of the behavior based on the dynamics of head movement. Psychopharmacology (Berl). 2013 Jun;227(4):727-39. doi: 10.1007/s00213-013-3006-z. Epub 2013 Feb 14. PMID: 23407781; PMCID: PMC3866102.
11. Halberstadt AL, Chatha M, Chapman SJ, Brandt SD. Comparison of the behavioral effects of mescaline analogs using the head twitch response in mice. J Psychopharmacol. 2019 Mar;33(3):406-414. doi: 10.1177/0269881119826610. Epub 2019 Feb 21. PMID: 30789291; PMCID: PMC6848748.
12. Halberstadt AL, Chatha M, Stratford A, Grill M, Brandt SD. Comparison of the behavioral responses induced by phenylalkylamine hallucinogens and their tetrahydrobenzodifuran (“FLY”) and benzodifuran (“DragonFLY”) analogs. Neuropharmacology. 2019 Jan;144:368-376. doi: 10.1016/j.neuropharm.2018.10.037. Epub 2018 Oct 29. PMID: 30385253; PMCID: PMC6863604.
13. Cichon J, Wasilczuk AZ, Looger LL, Contreras D, Kelz MB, Proekt A. Ketamine triggers a switch in excitatory neuronal activity across neocortex. Nat Neurosci. 2023 Jan;26(1):39-52. doi: 10.1038/s41593-022-01203-5. Epub 2022 Nov 24. PMID: 36424433; PMCID: PMC10823523.
14. Kim HS, Park IS, Lim HK, Choi HS. NMDA receptor antagonists enhance 5-HT2 receptor-mediated behavior, head-twitch response, in PCPA-treated mice. Arch Pharm Res. 1999 Apr;22(2):113-8. doi: 10.1007/BF02976533. PMID: 10230499.
15. Butelman ER, Kreek MJ. Salvinorin A, a kappa-opioid receptor agonist hallucinogen: pharmacology and potential template for novel pharmacotherapeutic agents in neuropsychiatric disorders. Front Pharmacol. 2015 Sep 8;6:190. doi: 10.3389/fphar.2015.00190. Erratum in: Front Pharmacol. 2015 Nov 30;6:285. doi: 10.3389/fphar.2015.00285. PMID: 26441647; PMCID: PMC4561799.
16. González J, Prieto JP, Rodríguez P, Cavelli M, Benedetto L, Mondino A, Pazos M, Seoane G, Carrera I, Scorza C, Torterolo P. Ibogaine Acute Administration in Rats Promotes Wakefulness, Long-Lasting REM Sleep Suppression, and a Distinctive Motor Profile. Front Pharmacol. 2018 Apr 27;9:374. doi: 10.3389/fphar.2018.00374. PMID: 29755349; PMCID: PMC5934978.
17. de la Fuente Revenga M, Shin JM, Vohra HZ, Hideshima KS, Schneck M, Poklis JL, González-Maeso J. Fully automated head-twitch detection system for the study of 5-HT2A receptor pharmacology in vivo. Sci Rep. 2019 Oct 3;9(1):14247. doi: 10.1038/s41598-019-49913-4. PMID: 31582824; PMCID: PMC6776537.
18. Fantegrossi WE, Kiessel CL, De la Garza R 2nd, Woods JH. Serotonin synthesis inhibition reveals distinct mechanisms of action for MDMA and its enantiomers in the mouse. Psychopharmacology (Berl). 2005 Sep;181(3):529-36. doi: 10.1007/s00213-005-0005-8. Epub 2005 Oct 12. PMID: 15983787.
19. Ceci C, Proietti Onori M, Macrì S, Laviola G. Interaction between the endocannabinoid and serotonergic system in the exhibition of head twitch response in four mouse strains. Neurotox Res. 2015 Apr;27(3):275-83. doi: 10.1007/s12640-014-9510-z. Epub 2014 Dec 17. PMID: 25516122.
20. Singh L, Heaton JC, Rea PJ, Handley SL. Involvement of noradrenaline in potentiation of the head-twitch response by GABA-related drugs. Psychopharmacology (Berl). 1986;88(3):315-9. doi: 10.1007/BF00180831. PMID: 2870531.
21. Moser PC, Redfern PH. The effect of benzodiazepines on the 5-HT agonist-induced head-twitch response in mice. Eur J Pharmacol. 1988 Jul 7;151(2):223-31. doi: 10.1016/0014-2999(88)90802-3. PMID: 2844552.
22. Vallersnes OM, Dines AM, Wood DM, Yates C, Heyerdahl F, Hovda KE, Giraudon I; Euro-DEN Research Group; Dargan PI. Psychosis associated with acute recreational drug toxicity: a European case series. BMC Psychiatry. 2016 Aug 18;16:293. doi: 10.1186/s12888-016-1002-7. 
23. Leach P, Prince R, Agrawal R, Gillie D, Mungenast A, McTighe S, et al. (2025). “569. Preclinical Pharmacology of DLX-2270: A Novel, Next Generation, Non-Hallucinogenic Neuroplastogen With the Potential for Treating Schizophrenia“. Biological Psychiatry. 97 (9): S333. doi:10.1016/j.biopsych.2025.02.808. 
24. Tombari RJ, Lu J, Pell AJ, Hurley ZQ, Ehinger Y, Vargas MV, McCarroll MN, Taylor JC, Myers-Turnbull D, Liu T, Yaghoobi B, Laskowski LJ, Anderson EI, Zhang G, Viswanathan J, Brown BM, Tjia M, Dunlap LE, Rabow ZT, Fiehn O, Wulff H, McCorvy JD, Lein PJ, Kokel D, Ron D, Peters J, Zuo Y, Olson DE. A non-hallucinogenic psychedelic analogue with therapeutic potential. Nature. 2021 Jan;589(7842):474-479. doi: 10.1038/s41586-020-3008-z. Epub 2020 Dec 9. PMID: 33299186; PMCID: PMC7874389.
25. Kehler J, Lindskov MS (May 2025). “Are the LSD-analogs lisuride and ergotamine examples of non-hallucinogenic serotonin 5-HT2A receptor agonists?” Journal of Psychopharmacology. 39 (9): 889–895. doi:10.1177/02698811251330741. PMID 40322975.
26. Joseph O. S. Beckett, Ryan Buzdygon, Steven Nguyen, Allison A. Clark, Serena S. Schalk, Lena E. H. Svanholm, Trey J. Brasher, Marc Bazin, Bruna Cuccurazzu, Adam L. Halberstadt, John D. McCorvy, and Mark Mascal. Transforming Amino Acids into Serotonin 5-HT2A Receptor Ligands Using Photochemistry. Journal of the American Chemical Society 2025 147 (52), 48400-48415. DOI: 10.1021/jacs.5c19817
27. Non Hallucinogenic Trip Reports Searching for the Tabernanthalog Tasters. Psychedelic Alpha, 2023.
28. Halberstadt AL, Slepak N, Hyun J, Buell MR, Powell SB. The novel ketamine analog methoxetamine produces dissociative-like behavioral effects in rodents. Psychopharmacology (Berl). 2016 Apr;233(7):1215-25. doi: 10.1007/s00213-016-4203-3. Epub 2016 Jan 13. PMID: 26758284; PMCID: PMC5403250.
29. Vejmola Č, Šíchová K, Syrová K, Janečková L, Koudelka V, Tesař M, Nikolič M, Viktorinová M, Tylš F, Korčák J, Viktorin V, Kelemen E, Nekovářová T, Brunovský M, Horáček J, Kuchař M, Páleníček T. Cross-Species Evidence for Psilocin-Induced Visual Distortions: Apparent Motion Is Perceived by Both Humans and Rats. Biol Psychiatry Glob Open Sci. 2025 May 2;5(5):100524. doi: 10.1016/j.bpsgos.2025.100524. PMID: 40599633; PMCID: PMC12209919.

AUTHOR

This is Part I of a dual feature on the current state of research and development of non-hallucinogenic psychedelics. In this installment, we introduce the rationale and history behind this emerging field and highlight the major efforts underway across different pharmacological classes. Part II examines the limitations of the techniques, the challenges of psychedelic translatability, and the medical and clinical models these compounds might follow.

You can read Part II of the series here.

A Field Split on the Role of Subjective Experience

As of 2025, our field is still debating whether the profound subjective experiences triggered by psychedelics are required for their therapeutic benefit. A memorable moment in this discussion came in 2020, when Yaden & Griffiths (2020) and David Olson (2020) published back-to-back papers, each championing one side of the dilemma. 

Focusing on clinical trials and correlational analyses showing that higher ratings of mystical experience predict greater symptom reduction, Yaden & Griffiths contended that the subjective effects are necessary for the enduring benefits of psychedelic-assisted psychotherapies, arguing that cathartic states, mystical-type experiences, and other types of altered states of consciousness are key mediators of the emotional breakthroughs that foster long-term improvements of psychedelic-assisted therapies. On the other side, discussing preclinical and early clinical data, Olson countered that, upon binding to different brain receptors, psychedelics trigger a series of molecular, neuronal, and brain network-level events that, independently of an acute conscious experience, produce those persistent cognitive and behavioral changes, suggesting a possible dissociation of subjective phenomenology from therapeutic mechanisms, and therefore the plausibility of “non-hallucinogenic psychedelics”. 

What counts as a (non-)hallucinogenic psychedelic

The term psychedelic drug remains contested across pharmacology, neuroscience, and clinical and recreational practices. Nichols’ 2016 Pharmacological Reviews article describes that, in the late 1960s, these molecules were all lumped together in a class known first as psychotomimetics (suggesting that they foster psychosis) and then hallucinogens (again somewhat discrediting the class and suggesting that they principally produce hallucinations). According to Nichols, the most rigorous, useful, and widely adopted definition for psychedelics is “compounds that act as full or partial agonists at the serotonin 2A receptor (meaning they bind to the 5-HT2AR on the neuron and trigger a full or partial signaling cascade) and reliably produce profound alterations in perception, cognition, and self-experience”. 

This 5-HT2AR-centric view anchors the “classic psychedelics” or tryptamines (DMT, Psilocybin), phenethylamines (mescaline), and lysergamides (LSD) under a coherent pharmacological umbrella: shared mechanism and outcome despite diverse chemical scaffolds. Within this framework, the notion of a non-hallucinogenic psychedelic emerges from work seeking to decouple 5-HT2AR–mediated therapeutic potential from its associated “trippy” subjective experience. 

From Psychedelics to Psychoplastogens

Olson and colleagues (2018) proposed the term “psychoplastogen” to describe small molecules capable of promoting structural and functional neuroplasticity, independent of subjective phenomenology. This (if I may say, somewhat redundant) category includes all endogenous neurotransmitters, neuromodulators, and hormones, and classic/atypical psychedelics and newly engineered small molecules for their brain plasticity effects. Hence, in this framework, a non-hallucinogenic psychedelic is best understood as a molecule that binds to the 5-HT2AR and triggers the therapeutically beneficial neurobiological changes without inducing the characteristic subjective effects. Importantly, these drug-development programs operate under the assumption that this conceptual backbone will yield safer, more scalable, and accessible interventions, given an understanding that places hallucinations as undesirable side effects of both classic and atypical psychedelic drugs.

Atypical Psychedelics and Blurred Boundaries

It is important to mention that contemporary research routinely blurs these receptor-centric boundaries. Molecules such as ketamine, MDMA, or ibogaine are sometimes referred to as atypical psychedelics, a class of drugs that bind to different receptors and elicit overlapping subjective states and therapeutic outcomes, but produce distinct neurobiological signaling cascades and generally lack the canonical hallucinogenic signature characteristic of the classic psychedelics.

Nevertheless, these molecules are crucial to examine because (1) they broaden the discussion about which mechanisms are necessary or sufficient both for classic hallucinations and clinical efficacy, (2) because they have also undergone the probing of “molecular de-hallucination” and (3), because despite Nichol’s definition, researchers and users alike are still considering MDMA a psychedelic substance anyway.

The Current state of R&D on canonical non-hallucinogenic psychedelics

In the last five years, non-hallucinogenic psychedelic analog programs have progressed from proof-of-concept chemistry to several lead molecules now in advanced preclinical and early clinical pipelines, as candidates with therapeutic promise for mood disorders without hallucinogenic liability.

To begin with a more familiar example, the LSD analog 2-Bromo-LSD shows partial agonism at multiple receptors (including the 5-HT2AR), reverses stress-induced behavioral deficits, and promotes cortical neuroplasticity, all while failing to elicit the rodent head-twitch response (HTR).

This concept will be examined in more detail in our Part II. For now, it is essential to note that the HTR serves as a common proxy for evaluating a drug’s potential to induce 5-HT2AR-mediated psychedelic effects. Research has shown that the number of side-to-side head movements in rodents correlates in a dose-dependent manner with the intensity of hallucinogenic effects experienced by humans when using classic psychedelics.

At the forefront of the non-hallucinogenic psychedelics’ development efforts are:

• Delix Therapeutics, an American biotech company developing neuroplasticity-promoting therapeutics for central nervous system diseases
• The Olson Lab at UC Davis, whose studies exemplify how precision medicinal chemistry, combined with multimodal functional assays, could decouple 5-HT2AR-mediated molecular plasticity from the associated subjective effects. 

One of their candidates is IBG, a conformationally restricted 5-MeO-DMT analog designed to retain therapeutic activity while lacking hallucinogenic signatures.

Structure–activity receptor pharmacology work showed that IBG has reduced potency at the 5-HT2AR and a markedly diminished HTR in mice as evidence of a non-hallucinogenic profile.

Zalsupindole, also produced and advanced by Delix using multiple behavioral paradigms such as social defeat and chronic stress to build a translational case, is an isotryptamine chemically optimized to enhance brain penetrance, dendritic spine density, and antidepressant-like effects comparable to ketamine and classic psychedelics while eliminating dissociative or hallucinogenic behaviors in rodents (meaning, no HTR).

Even more recently, Delix has produced isoindole-LSD derivatives (such as JRT) through purposely transposing atoms in the LSD scaffold, creating molecules that retain neuroplasticity while lowering hallucinogenic potential. Their strategies combine rational design, total synthesis, in vitro receptor-binding/functional synaptogenesis assays, and in vivo behavioral testing (HTR, depression-relevant tasks) to demonstrate therapeutic effects without causing hallucinations. 

The efforts of this lab and company have produced DLX-159, a “next-generation psychoplastogen” that is already entering human trials, having shown robust 5-HT2AR-mediated rapid, enduring antidepressant-like effects and, of course, no HTR side effects. 

Non-hallucinogenic oneirogens enter the pipeline

Sometimes labelled “dissociative psychedelics”, studying kappa-opioid receptor (KOR) agonists represents a parallel strategy to engineer another class of non-hallucinogenic atypical psychedelics, particularly from the iboga alkaloid family.

Ibogaine and its active metabolite, noribogaine, display complex, polypharmacological profiles that involve KOR activity but also include modulation of the N-methyl-D-aspartate receptor (NMDAR), serotonin reuptake inhibition, and sigma-1 receptor interactions. Despite promising clinical and observational data regarding their therapeutic potential for the treatment of diverse mood and substance use disorders, their research has long been tempered by cardiotoxicity and intense oneirogenic or dissociatively-hallucinogenic experiences. 

For the intrepid reader, avid for more information: the review by Iyer, Favela, Zhang, and Olson (2021) maps, in a very comprehensive way, the chemistry, receptor pharmacology, and biosynthetic logic of iboga alkaloids and provides the foundation for the rational design of safer, non-hallucinogenic engineered “ibogalogs”. The medicinal chemistry efforts described in this work highlight scaffold simplification, removal of cardiotoxic motifs, and the generation of more drug-like molecules through synthetic redesign rather than minor atomic additions and substitutions. 

Again, Olson Lab and Delix mediated, Tabernanthalog (TBG) has emerged as the leading example of this approach. Reported in the 2021 Nature paper by Cameron et al. paper, TBG is a structurally simplified iboga analogue designed to eliminate cardiotoxicity and reduce hallucinogenic liability while retaining neuroplastic activity. The design strategy replaced the rigid iboga polycyclic system with a water-soluble scaffold while preserving key pharmacophores needed for intracellular signaling. 

At a mechanistic and functional level, TBG increases dendritic spine density and enhances cortical neural plasticity in vitro and in vivo and, in rodents, produces rapid antidepressant-like effects and reduces alcohol intake and heroin-seeking behavior in self-administration paradigms, assays modeling depressive symptoms, and drug compulsive consumption and relapse vulnerability. Crucially, TBG does not induce the mouse HTR, leading the authors to classify it as non-hallucinogenic. Together, the iboga-derived analog program claims that oneirogenic scaffolds can be re-engineered toward safer, plasticity-promoting therapeutics. However, the precise mechanistic contributions of kappa-opioid signaling remain incompletely characterized.

Ketamine and the Search for Non-Dissociative Analogues

But what about ketamine? Why does nobody ever think about the next-generation non-hallucinogenic non-dissociative non-anesthetic arylcyclohexylamines?

Oh yes, you can bet people have been thinking about those, too. Unlike classic psychedelics, ketamine is a dissociative anesthetic that exerts its therapeutic and phenomenological, hallucinogenic-like effects via antagonism at the NMDAR (i.e., preventing its function), and engaging other systems such as the opioidergic, which seemingly critically mediates the antidepressant and anti-suicidal effects of ketamine.  

As of 2026, there are no completely non-hallucinogenic structural analogues of ketamine; the closest option is its enantiomer, (R)-ketamine. However, this compound only slightly differs in its dissociative properties. Instead, the development of non-hallucinogenic “ketalogs” has primarily focused on functionally mimicking ketamine’s downstream mechanisms. This is achieved by modulating NMDAR and related circuits using different molecular scaffolds.

One example is Rapastinel, a positive allosteric modulator of the NMDAR developed by Allergan, a company known for creating and marketing a wide range of branded pharmaceuticals. Rather than blocking the receptor like ketamine, rapastinel enhances its activity, boosting long-term changes in brain prefrontal cortex function, and producing rapid and sustained antidepressant-like effects in rodent forced swim tests, without causing hallucinations. However, despite promising preclinical data, rapastinel ultimately failed to meet its primary efficacy endpoint in Phase 3 trials as adjunctive treatment for major depressive disorder. The same company developed Zelquistinel as a next-generation, significantly more potent NMDAR modulator that promotes activity-dependent synaptic plasticity in the hippocampus and prefrontal cortex and produces rapid, sustained antidepressant-like effects in both the forced swim test and the chronic social-defeat rodent model, without causing hallucinations. 

Accordingly, following the idea that selective enhancement of hippocampal excitability may be sufficient for rapid antidepressant responses, it has also been shown that downstream modulation of hippocampal circuitry can recapitulate ketamine-like antidepressant effects, independent of NMDAR activation and dissociative or psychotomimetic side effects. For instance, when L-655,708, a negative allosteric modulator of GABA-A receptors preferentially expressed in the hippocampus, was administered systemically to rats, it resulted in sustained antidepressant-like effects in the forced swim test. Additionally, there was no HTR or self-administration liability, indicating a lack of abuse potential.

How Far We’ve Come, and What’s Next

Taken together, these programs illustrate how far the field has come in attempting to separate neuroplasticity from hallucinogenic experience. At the same time, they also point to many assumptions that still underlie this work.

In Part II, we will take a closer look at those assumptions, examining the limitations of current assays, the challenges of translatability of psychedelic and therapeutic effects, and the medical models and clinical realities that might shape the future of these compounds.

Stay tuned!

References

1. The Subjective Effects of Psychedelics Are Necessary for Their Enduring Therapeutic Effects: Yaden DB, Griffiths RR. The Subjective Effects of Psychedelics Are Necessary for Their Enduring Therapeutic Effects. ACS Pharmacol Transl Sci. 2020 Dec 10;4(2):568-572. doi: 10.1021/acsptsci.0c00194. PMID: 33861219; PMCID: PMC8033615.
2. The Subjective Effects of Psychedelics May Not Be Necessary for Their Enduring Therapeutic Effects: Olson DE. The Subjective Effects of Psychedelics May Not Be Necessary for Their Enduring Therapeutic Effects. ACS Pharmacol Transl Sci. 2020 Dec 10;4(2):563-567. doi: 10.1021/acsptsci.0c00192. PMID: 33861218; PMCID: PMC8033607.
3. Psychedelics: Nichols DE. Psychedelics. Pharmacol Rev. 2016 Apr;68(2):264-355. doi: 10.1124/pr.115.011478. Erratum in: Pharmacol Rev. 2016 Apr;68(2):356. doi: 10.1124/pr.114.011478err. PMID: 26841800; PMCID: PMC4813425.
4. Psychoplastogens: A Promising Class of Plasticity-Promoting Neurotherapeutics: Olson DE. Psychoplastogens: A Promising Class of Plasticity-Promoting Neurotherapeutics. J Exp Neurosci. 2018 Sep 19;12:1179069518800508. doi: 10.1177/1179069518800508. PMID: 30262987; PMCID: PMC6149016.
5. A Non-Hallucinogenic LSD analog with Therapeutic Potential for Mood Disorders: Lewis V, Bonniwell EM, Lanham JK, Ghaffari A, Sheshbaradaran H, Cao AB, Calkins MM, Bautista-Carro MA, Arsenault E, Telfer A, Taghavi-Abkuh FF, Malcolm NJ, El Sayegh F, Abizaid A, Schmid Y, Morton K, Halberstadt AL, Aguilar-Valles A, McCorvy JD. A non-hallucinogenic LSD analog with therapeutic potential for mood disorders. Cell Rep. 2023 Mar 28;42(3):112203. doi: 10.1016/j.celrep.2023.112203. Epub 2023 Mar 6. PMID: 36884348; PMCID: PMC10112881.
6. A non-hallucinogenic psychedelic analogue with therapeutic potential: Cameron LP, Tombari RJ, Lu J, Pell AJ, Hurley ZQ, Ehinger Y, Vargas MV, McCarroll MN, Taylor JC, Myers-Turnbull D, Liu T, Yaghoobi B, Laskowski LJ, Anderson EI, Zhang G, Viswanathan J, Brown BM, Tjia M, Dunlap LE, Rabow ZT, Fiehn O, Wulff H, McCorvy JD, Lein PJ, Kokel D, Ron D, Peters J, Zuo Y, Olson DE. A non-hallucinogenic psychedelic analogue with therapeutic potential. Nature. 2021 Jan;589(7842):474-479. doi: 10.1038/s41586-020-3008-z. Epub 2020 Dec 9. PMID: 33299186; PMCID: PMC7874389.
7. Zalsupindole is a Nondissociative, Nonhallucinogenic Neuroplastogen with Therapeutic Effects Comparable to Ketamine and Psychedelics: Agrawal R, Gillie D, Mungenast A, Chytil M, Engel S, Wu MC, et al. (October 2025). “Zalsupindole is a Nondissociative, Nonhallucinogenic Neuroplastogen with Therapeutic Effects Comparable to Ketamine and Psychedelics”. ACS Chem Neurosci acschemneuro.5c00667.
8. Molecular design of a therapeutic LSD analogue with reduced hallucinogenic potential: J.R. Tuck, L.E. Dunlap, Y.A. Khatib, C.J. Hatzipantelis, S. Weiser Novak, R.M. Rahn, A.R. Davis, A. Mosswood, A.M.M. Vernier, E.M. Fenton, I.K. Aarrestad, R.J. Tombari, S.J. Carter, Z. Deane, Y. Wang, A. Sheridan, M.A. Gonzalez, A.A. Avanes, N.A. Powell, M. Chytil, S. Engel, J.C. Fettinger, A.R. Jenkins, W.A. Carlezon, A.S. Nord, B.D. Kangas, K. Rasmussen, C. Liston, U. Manor, & D.E. Olson, Molecular design of a therapeutic LSD analogue with reduced hallucinogenic potential, Proc. Natl. Acad. Sci. U.S.A. 122 (16) e2416106122, https://doi.org/10.1073/pnas.2416106122 (2025).
9. DLX-159: A Novel, Next Generation, Non-Hallucinogenic Neuroplastogen With the Potential for Treating Neuropsychiatric Diseases: Rasmussen K, Agrawal R, Felts A, Leach P, Gillie D, Mungenast A, et al. (2024). “ACNP 63rd Annual Meeting: Poster Abstracts P1-P304: P252. DLX-159: A Novel, Next Generation, Non-Hallucinogenic Neuroplastogen With the Potential for Treating Neuropsychiatric Diseases” (PDF). Neuropsychopharmacology. 49 (S1): 65–235 (207–207). doi:10.1038/s41386-024-02011-0
10. The iboga enigma: the chemistry and neuropharmacology of iboga alkaloids and related analogs: Iyer RN, Favela D, Zhang G, Olson DE. The iboga enigma: the chemistry and neuropharmacology of iboga alkaloids and related analogs. Nat Prod Rep. 2021 Mar 4;38(2):307-329. doi: 10.1039/d0np00033g. PMID: 32794540; PMCID: PMC7882011.
11. Attenuation of antidepressant and antisuicidal effects of ketamine by opioid receptor antagonism: Williams NR, Heifets BD, Bentzley BS, Blasey C, Sudheimer KD, Hawkins J, Lyons DM, Schatzberg AF. Attenuation of antidepressant and antisuicidal effects of ketamine by opioid receptor antagonism. Mol Psychiatry. 2019 Dec;24(12):1779-1786. doi: 10.1038/s41380-019-0503-4. Epub 2019 Aug 29. PMID: 31467392.
12. Rapastinel mechanism (NMDAR PAM): Moskal JR, Burch R, Burgdorf J, et al. GLYX-13, an NMDA receptor glycine-site functional partial agonist, induces antidepressant-like effects without ketamine-like side effects. Pharmacology & Therapeutics, 2014. (PMID: 30544218)
13. GLYX-13, a NMDA Receptor Glycine-Site Functional Partial Agonist, Induces Antidepressant-Like Effects Without Ketamine-Like Side Effects: Burgdorf J, Zhang XL, Nicholson KL, Balster RL, Leander JD, Stanton PK, Gross AL, Kroes RA, Moskal JR. GLYX-13, a NMDA receptor glycine-site functional partial agonist, induces antidepressant-like effects without ketamine-like side effects. Neuropsychopharmacology. 2013 Apr;38(5):729-42. doi: 10.1038/npp.2012.246. Epub 2012 Dec 5. PMID: 23303054; PMCID: PMC3671991.
14. Allergan Announces Phase 3 Results for Rapastinel as an Adjunctive Treatment of Major Depressive Disorder (MDD). PR Newswire, 2019.
15. Zelquistinel Is an Orally Bioavailable Novel NMDA Receptor Allosteric Modulator That Exhibits Rapid and Sustained Antidepressant-Like Effects: Burgdorf JS, Zhang XL, Stanton PK, Moskal JR, Donello JE. Zelquistinel Is an Orally Bioavailable Novel NMDA Receptor Allosteric Modulator That Exhibits Rapid and Sustained Antidepressant-Like Effects. Int J Neuropsychopharmacol. 2022 Dec 12;25(12):979-991. doi:10.1093/ijnp/pyac043. PMID: 35882204; PMCID: PMC9743962.
16. Selective Pharmacological Augmentation of Hippocampal Activity Produces a Sustained Antidepressant-Like Response without Abuse-Related or Psychotomimetic Effects: Carreno FR, Collins GT, Frazer A, Lodge DJ. Selective Pharmacological Augmentation of Hippocampal Activity Produces a Sustained Antidepressant-Like Response without Abuse-Related or Psychotomimetic Effects. Int J Neuropsychopharmacol. 2017 Jun 1;20(6):504-509. doi: 10.1093/ijnp/pyx003. PMID: 28339593; PMCID: PMC5458335.

AUTHOR