The Perils of Non-Hallucinogenic Psychedelics: On the Limits of Translatability

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.

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