A new class of compounds aims to harness brain plasticity without hallucinogenic effects. Justin Ray, MSN, PMHNP-BC of South Chesapeake Psychiatry examines psychoplastogens and what they could mean for the future of depression treatment for patients in Chesapeake, VA and across Hampton Roads.
If you follow this newsletter, you know that I tend to start with foundations. Not to simplify complex science, but to clarify the language and assumptions we carry into it. Before we talk about what is new, we need to understand what problem we are trying to solve.
In recent years, the conversation around rapid acting antidepressants has accelerated. Ketamine and esketamine changed the tempo of treatment. The idea that mood could shift within hours rather than weeks forced psychiatry to reconsider long held assumptions about latency and mechanism. But with that shift came operational realities. In clinic administration. Monitoring. Infrastructure. Delivery models that look less like a traditional antidepressant prescription and more like an interventional procedure.
I have written previously about GM 2505, now belonging to AbbVie and known as Bretisilocin (Gilgamesh Pharmaceuticals, 2025). In its Phase 2a trials, it was administered intravenously on Day 1 and again on Day 15. Much like Spravato, there is an acute psychoactive effect that lasts roughly an hour. It is time limited, monitored, and occurs in a controlled clinical setting.
In that Phase 2a study of 40 participants, those receiving GM 2505 demonstrated an 18.5 point reduction in MADRS scores within 24 hours of the first infusion. By Day 14, that reduction deepened to 21.6 points, with 70 percent achieving remission. By Day 29, remission rates were reported at 94 percent, and the antidepressant effect persisted through Day 74 without additional treatment. (Gilgamesh Pharmaceuticals, 2025).
On paper, those numbers command attention. Rapid response. High remission rates. Durability after limited dosing. But the real world friction is not only about whether a drug works. It is about how it works in practice.
If an intervention requires in clinic administration, monitoring, and potentially a REMS style framework, access narrows immediately. Add an intravenous catheter and the cost of implementation rises again. Staffing. Chair time. Infusion logistics. Clinical infrastructure that many outpatient practices simply do not have. The science may be compelling, but the delivery model determines whether that science ever reaches a client sitting across from you.
This is where the fork in the road becomes clear. What if we could capture the same rapid and durable antidepressant signal without the psychedelic experience and without the clinic bound administration model? What if plasticity could be driven without perceptual disruption?
That is the question behind psychoplastogens (Olson, 2018).
At the center of this debate sits the 5 HT2A receptor and how it signals. Each 5 HT2A receptor is capable of coupling to more than one intracellular pathway. Classically, it couples to Gq 11, activating phospholipase C, increasing intracellular calcium, and driving downstream cortical excitation. It can also recruit beta arrestin, once thought to terminate signaling but now understood to initiate distinct signaling cascades of its own. (Vargas et al., 2023).
This is where the concept of biased agonism enters the conversation.
A receptor is not a simple on or off switch. It is a dynamic protein capable of adopting multiple conformations. When a ligand binds, it stabilizes a particular shape. Different shapes preferentially activate different intracellular programs. One ligand may favor Gq 11 signaling. Another may preferentially recruit beta arrestin. A third may activate both in varying proportions.
Traditional psychedelics such as psilocybin and LSD are believed to strongly activate Gq 11 signaling in cortical pyramidal neurons, particularly in layer V of the prefrontal cortex. This cascade increases glutamatergic output and disrupts hierarchical sensory processing, correlating with perceptual distortion and hallucinations. While the biology continues to be clarified, Gq dominant signaling is widely associated with the acute psychedelic phenotype. (Vargas et al., 2023).
The provocative question is whether therapeutic effects can be dissociated from hallucinogenic effects by shifting signaling bias away from Gq 11 and toward beta arrestin.
Beta arrestin is not merely a shutdown protein. It scaffolds signaling complexes, including MAP kinase pathways, and can promote transcriptional and plasticity related changes. In theory, a beta arrestin biased 5 HT2A ligand might promote synaptic remodeling and antidepressant effects without triggering the high amplitude cortical excitation linked to hallucinations.
Rather than blocking the receptor, as atypical antipsychotics do through 5 HT2A antagonism, or fully activating all pathways, as classic psychedelics do, a biased ligand attempts something more selective. It attempts to stabilize the therapeutic signaling pathway while minimizing the psychedelic one
Biology rarely cooperates perfectly. Hallucinations are unlikely to be driven solely by one pathway. Signaling cross talk occurs. Regional receptor density varies. Intracellular scaffolding proteins differ across brain regions. What appears clean in a cell culture system becomes complex in a cortex. But conceptually, biased agonism represents a shift. We are no longer asking whether a drug occupies a receptor. We are asking how it shapes intracellular signaling and which programs it prioritizes.
This is where Tabernanthalog, ITI 1549, DLX 001, DLX 159, and DLX 007 enter the picture.
Tabernanthalog is a synthetic analog of ibogaine that was designed to retain ibogaine’s neuroplastic and potential antidepressant or antiaddictive properties while minimizing its hallucinogenic and cardiotoxic effects. (Cameron et al., 2021).
It functions primarily as a psychoplastogen, meaning it promotes structural and functional neural plasticity, including dendritic growth and synaptogenesis, through mechanisms that involve serotonergic signaling pathways such as 5-HT2A. Unlike ibogaine, which is psychoactive and associated with QT prolongation risk, tabernanthalog was engineered to be non-hallucinogenic and to avoid significant cardiac ion channel blockade in preclinical models. (Olson, 2018; Ly et al., 2018; Ly et al., 2021).
ITI 1549 is Intra Cellular Therapies’, now Johnson and Johnson’s entry into the psychoplastogen space, another investigational serotonergic compound positioned within the psychoplastogen framework. The premise is similar. Engage 5 HT2A related plasticity pathways. Drive structural remodeling without inducing a psychedelic state.
DLX 001, also known as zalsupindole, is Delix’s lead clinical candidate. It is designed to be a non hallucinogenic, non dissociative neuroplastogen, often described as an isotryptamine and an analog of 5 MeO DMT engineered to avoid classic psychedelic liabilities. Its target indication is major depressive disorder. (Agrawal et al., 2025).
In Phase 1 studies involving 106 healthy volunteers, primary aims included safety, pharmacokinetics, and pharmacodynamic markers. No psychotomimetic, hallucinatory, or dissociative effects were reported across dose levels according to public reporting
The Phase 1b program in patients with major depressive disorder focused on early target engagement and neuroplastic effects, using portable EEG and repeated cognitive and neurophysiology measures through the Cumulus NeuLogiq platform to identify scalable biomarkers. Company reported data described rapid, robust, and durable antidepressant effects along with signals on potential markers of plasticity. Operationally, one of the most striking aspects is that the FDA cleared a Phase II design that includes at home self administration
If a compound truly avoids acute perceptual and behavioral impairment, it can be developed more like a conventional outpatient antidepressant rather than a clinic bound psychedelic session. That distinction is not trivial. It determines scalability.
DLX 159 is described as another non hallucinogenic, non dissociative tryptamine neuroplastogen for major depressive disorder and other neuropsychiatric conditions, currently in IND enabling stages. DLX 007 has been positioned toward substance use disorders as a non hallucinogenic, non cardiotoxic ibogaine analog with NIH and NIDA support, having completed IND enabling studies and slated for clinical testing per company reporting
Across this space, the unifying biological theme is plasticity. Preclinical literature consistently describes serotonergic psychedelics as rapidly promoting neuritogenesis, spinogenesis, and synaptogenesis, effects that appear to involve 5 HT2A signaling along with TrkB and mTOR pathways (Ly et al., 2018; Ly et al., 2021; Vargas et al., 2023).
A practical way to conceptualize this is through the AMPA BDNF TrkB mTOR axis. AMPA mediated excitatory throughput acts as a signal that plasticity can proceed. BDNF binding to TrkB promotes growth and synaptic strengthening. mTOR functions as a protein synthesis and synapse building hub. The psychoplastogen framework aims not at daily symptomatic nudging but at structural and functional remodeling after one or a few doses. This is where the language of research becomes critical. (Olson, 2018; Ly et al., 2018).
Psychiatry has historically relied on receptor blockade as its blunt instrument. Dopamine antagonism. Serotonin antagonism. Occupancy as proxy for efficacy. The psychoplastogen movement suggests a different strategy. Not simply occupying receptors, but engineering signal bias and downstream plasticity.
Whether that promise translates into durable, scalable, and safe clinical outcomes remains to be seen. Phase II and Phase III trials will determine whether early signals hold under larger and more rigorous conditions. But conceptually, the shift is significant.
This conversation is not simply about psychedelics. It is about whether psychiatry can move from receptor occupancy to signal engineering, from acute symptom suppression to network recalibration, and from clinic bound procedures to outpatient plasticity.
Plasticity without psychedelia is an ambitious goal. If achieved, it would represent not just a new class of antidepressants, but a new way of thinking about how we intervene in the brain.
Agrawal, R., Gillie, D., Mungenast, A., Chytil, M., Engel, S., Wu, M. C., Rasmussen, K., Salinas, E., & Olson, D. E. (2025). Zalsupindole is a nondissociative, nonhallucinogenic neuroplastogen with therapeutic effects comparable to ketamine and psychedelics. ACS Chemical Neuroscience, 16(22), 4388–4399. https://doi.org/10.1021/acschemneuro.5c00667
Gilgamesh Pharmaceuticals. (2025, May 15). Gilgamesh Pharmaceuticals announces positive topline Phase 2a results for GM-2505 in major depressive disorder (MDD). PR Newswire. https://www.prnewswire.com/news-releases/gilgamesh-pharmaceuticals-announces-positive-topline-phase-2a-results-for-gm-2505-in-major-depressive-disorder-mdd-302465404.html
Vargas, M. V., Dunlap, L. E., Dong, C., Carter, S. J., Tombari, R. J., Jami, S. A., Cameron, L. P., Patel, S. D., Hennessey, J. J., Saeger, H. N., McCorvy, J. D., Gray, J. A., Tian, L., & Olson, D. E. (2023). Psychedelics promote neuroplasticity through activation of intracellular 5-HT2A receptors. Science, 379(6633), 700–706.
https://doi.org/10.1126/science.adf0435.
Olson, D. E. (2018). Psychoplastogens: A promising class of plasticity-promoting neurotherapeutics. Journal of Experimental Neuroscience, 12, 1179069518800508. https://doi.org/10.1177/1179069518800508
Cameron, L. P., Tombari, R. J., Lu, J., Rodriguez, A. J., Naik, A. K., Hertood, H. J., Dunlap, L. E., West, B. V., Vargas, M. V., Pangala, S. P., Hussein, A., Yourish, J., Lim, H. E., Parent, J. S., Sorrell, M. E., Sanchez, M. S., Moore, H. N., Zuo, Y., & Olson, D. E. (2021). A non-hallucinogenic psychedelic analogue with therapeutic potential. Nature, 589(7842), 474–479. https://doi.org/10.1038/s41586-020-3008-z
Ly, C., Greb, A. C., Cameron, L. P., Wong, J. M., Barragan, E. V., Wilson, P. C., Burbach, K. F., Soltanzadeh Zarandi, S., Sood, A., Paddy, M. R., Duim, W. C., Dennis, M. Y., & Olson, D. E. (2018). Psychedelics promote structural and functional neural plasticity. Cell Reports, 23(11), 3170–3182. https://doi.org/10.1016/j.celrep.2018.05.022
Ly, C., et al. (2021). Transient stimulation with psychoplastogens is sufficient to initiate neuronal growth. ACS Pharmacology & Translational Science, 4(2), 452–460. https://doi.org/10.1021/acsptsci.0c00065
Psychoplastogens are compounds that promote neural plasticity - the brain's ability to form new connections - and are being studied as rapid-acting treatments for depression and related conditions.
South Chesapeake Psychiatry provides depression treatment, psychiatric evaluation, and medication management in Chesapeake, VA, with in-person and telepsychiatry options across Hampton Roads.
Yes. Telehealth medication management and virtual psychiatric care in VA are available for many patients across Hampton Roads.
South Chesapeake Psychiatry provides expert psychiatric care and medication management in Chesapeake, VA, with in-person visits and secure telepsychiatry for patients across Hampton Roads and throughout Virginia. To request an appointment for depression treatment, contact South Chesapeake Psychiatry today.
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This article is for educational purposes only and is not medical advice. Always consult a qualified clinician about your individual care.
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