We slowly start to understand that the therapeutic power of psychedelics might lie in allowing resilience to emerge in patients. But what is resilience exactly, on the neurobiological level? And what endpoints would be useful to design clinical trials around resilience?
There are different ways to define resilience. Resilience is the capacity to adapt effectively to significant stress or adversity while maintaining, or regaining, functionality. It is a dynamic process, likely not a personality trait: resilience can vary across situations, life stages, and domains of functioning. The main definition is the property of resisting and dealing with potentially damaging stressors. Therefore, one can understand resilience as either 1. The absence of PTSD, or the buffer against PTSD, with the work of Joseph Zohar and Rachel Yehuda. Defining resilience as the absence of PTSD is useful in trauma research because it provides a measurable clinical outcome. Or 2. The absence of demoralization or the capacity to keep motivation intact, with the work of Eric Nestler and Stephen Ross.
These frameworks were laid by two landmark papers: Feder, Nestler & Charney's "Psychobiology and molecular genetics of resilience" (Feder et al., 2009) and its follow-up, Russo, Murrough, Han, Charney & Nestler's "Neurobiology of resilience" (Russo et al., 2012), which defined the field as we know it today. In these publications, the authors argue that resilience is not merely the absence of pathology but an active, adaptive process.
Resilience as the Absence of PTSD
The works of Joseph Zohar and Hagit Cohen use rat models of PTSD (predator scent-stress or PSS) and anxiety-like behavior tests to study the neurobiology of trauma, focusing on the HPA axis and the microglia response in the hippocampus (Cohen & Zohar, 2004; Nahum et al., 2022). Additionally, they also injected the rats with a stress hormone (hydrocortisone) and its blocker (RU486) after the stress exposure. They found that rats highly responding to PSS in the behavioral tests showed activation of microglial cells in the brain, correlated with an augmentation of Iba-1 (a marker of microglial activation) and a decrease of CX3CR1 (a marker of non-activated microglia). They concluded that trauma-like conditions triggered inflammation in the hippocampus. Based on that inflammatory signature, they found that not every rat responded the same to PSS — some carried a long-lasting impact, some did not — and so were able to distinguish two subpopulation phenotypes of rats: resilient vs. vulnerable. It seems that while inflammation is involved in the traumatic processing, it doesn't respond the same way for all, reflecting the fact that only a subpopulation of humans will develop PTSD when exposed to a stressor. Interestingly, Zohar and colleagues found later on that treating patients pharmacologically immediately post-trauma could shift someone from a vulnerable phenotype into a resilient one (Cohen et al., 2008; Zohar et al., 2011). This is how the concept of Golden Hours was born. Golden Hours is a form of secondary prevention: intervening after the trauma but before the disorder has taken hold.
Zohar et al. have used MDMA in some of his experiments (Arluk et al., 2022). His team investigated if administering MDMA could shift the phenotype of his vulnerable rodents into resilient ones. In a nutshell, they found that pairing administration of MDMA with trauma-cue reactivation led to a shift in phenotype: from vulnerable, the rodents shifted to resilient (Arluk et al., 2022).
Resilience as a Buffered HPA Axis
As her title reads: Dr. Yehuda is the Chemers Neustein Family Professor of Trauma and Resilience at Mount Sinai, hence resilience is her main topic and she studies it in humans first. She showed that trauma survivors with PTSD show higher levels of noradrenaline and lower levels of cortisol. This was counterintuitive at first, but Dr. Yehuda explains it by a hypersensitive HPA axis, arguing that PTSD isn't just too much stress hormone, but a dysregulation in how the organism contains the stress response. This hypersensitive, overly efficient negative-feedback loop leaves some individuals unable to properly terminate the stress response after trauma has passed. This finding gave birth to the idea of injecting synthetic cortisol in the ER immediately post-trauma to prevent PTSD from "solidifying," the same secondary-prevention window Zohar was chasing with hydrocortisone, just tested in a human ER setting rather than the rat model — and, notably, Yehuda herself is a co-author on Zohar's foundational animal/clinical Golden Hours paper (Zohar et al., 2011), making this less a parallel and more a direct collaboration. This work parallels the pharmacological logic set by Zohar in his Golden Hours paradigm. But Dr. Yehuda didn't stop there. She went on to show that resilience could extend (or not) across generations. Her work showed that Holocaust survivors and their adult offspring carry epigenetic marks on the same stress-related gene region — the glucocorticoid-responsive gene FKBP5 — hence a role for the parents' trauma history.
Rachel Yehuda and her team have used MDMA-Assisted Therapy to treat patients with PTSD. The results are very encouraging and show that PTSD symptoms (measured on the CAPS-5, the Clinician-Administered PTSD Scale for DSM-5) are significantly reduced, more than psychotherapy alone (Mitchell et al., 2021). The VA-affiliated reviews are still questioning the studies about durability, mechanism, and which patients could benefit most, since MDMA-AT doesn't seem to be a "one size fits all" type of therapy.
Resilience and the Reward Circuit Pathway
Eric Nestler's team at Mount Sinai has explored a different facet of the neurobiology of trauma and resilience, tackling it from the Nucleus Accumbens and Ventral Tegmental Area angle, the reward circuit. His lab used a different model than the PSS paradigm used in rats: chronic social defeat stress in mice (CSDS). They showed a different pattern in vulnerable vs. resilient mice: vulnerable mice have an increased firing of VTA dopamine neurons which drives elevated BDNF in the nucleus accumbens and downstream signaling that produces depression-like behavior (Krishnan et al., 2007). Interestingly, resilient mice upregulate their potassium (Kv) channels in the VTA so the VTA-dopamine neurons' firing is attenuated. Here we have a feedback loop that regulates the overactive, chronic-stress-induced VTA firing, allowing us to understand resilience as an active response rather than a passive, structural mechanism, an absence of pathology. Furthermore, pairing CSDS with wheel running, they showed that mice who had chronic voluntary wheel running (VWR) showed resilience to CSDS, whereas mice who did not do wheel-running exercise developed a depressive-like state, characterized by anhedonia and social avoidance (Mul et al., 2018). That behavior was furthermore dependent on the transcription factor ΔFosB, neutralized by viral injection with an inactive mutant of ΔFosB in the Nucleus Accumbens.
The other interesting finding related to resilience from the Nestler Lab is the "chromatin scar." How DNA is folded and packaged into bigger structures (chromatin) is dependent on the activity of certain histones. The Nestler lab found that methylation on the H3K27me1 histone in Nucleus Accumbens neurons was responsible for a certain spatial structure of the chromatin, that would define stress vulnerability on various levels: behavioral, physiological, and transcriptional (Torres-Berrío et al., 2024). They found that this effect on histone methylation would be long-lasting in life, when happening at an early developmental stage. Stress, or trauma, hitting early enough can have a persistent effect on how chromatin is organized, therefore shaping the accessibility of certain gene transcriptions vs. others. Epigenetics shape genetic expression, and here they prove to be stress-dependent. This finding reveals what gets potentially encoded permanently in vulnerable individuals. If a scar is a permanent epigenetic mark, then Nestler proposes to find drugs that could help erase such marks, instead of coping with the complications of PTSD afterwards.
Eric Nestler's team used ketamine in an interesting way: they injected mice prophylactically — prior to the CSDS — and found that the prophylactic ketamine was protecting the animals against the stress (Parise et al., 2021), and that it was a NAc-VTA-dependent effect. They showed that prophylactic ketamine was protecting the reward circuit against the effects of a stressor that hasn't happened yet. This is a distinct category from Zohar's and Yehuda's post-trauma secondary-prevention windows, since here the intervention precedes the trauma itself entirely.
Resilience and Demoralization in Terminal Cancer Patients
Stephen Ross at NYU Langone published a seminal study in 2016 about the effect of psilocybin on 29 terminally ill cancer patients via a double-blind, placebo-controlled (niacin), randomized, and crossover (everybody gets psilocybin at one point) design, using a single dose of psilocybin (0.3 mg/kg) (Ross et al., 2016). They used the Hospital Anxiety and Depression Scale (HADS), the Beck Depression Inventory (BDI), and the State-Trait Anxiety Inventory (STAI) as primary outcome measures for assessing the antidepressant effect of psilocybin in conjunction with psychotherapy. They also used a Demoralization Scale as a secondary endpoint to measure the impact of the psychedelic on hopelessness, spiritual wellbeing, loss of meaning, and other categories of demoralization. The results showed that after 2 weeks, the improvement in demoralization and hopelessness was already significant, alongside gains in spiritual wellbeing and quality of life. These benefits, together with the antidepressant and anxiolytic effects, remained durable at the 6.5-month follow-up, with roughly 60 to 80% of participants continuing to show a clinically significant response. The remission was significant for depression and anxiety as well as for demoralization, all improving together over the same follow-up window.
In 2021, Stephen Ross and his team performed a secondary analysis on 11 of the original 29 patients from the 2016 study (Ross et al., 2021). They looked at certain categories of demoralization, such as Loss of Meaning (LoM), and compared them to a composite suicidal-ideation (SI) score, built from single items on two depression-related scales. On the between-group comparison against placebo, LoM reached statistical significance at 2 weeks, while the SI comparison did not — though both showed large within-group improvement. This is a small and, by the authors' own account, underpowered analysis, but it points toward an interesting property of psilocybin: it might be better suited to treat demoralization than depression, which involves more vegetative symptoms. We can interpret this as a recovery of resilience, understanding demoralization as the opposite end of the resilience spectrum.
Conclusion
By investigating MDMA, ketamine, and psilocybin in trauma and in existential distress, these four teams are demonstrating that psychedelic-assisted interventions may alter the trajectory of trauma-related responses, or of the demoralization that can follow a terminal diagnosis, whether administered prophylactically or after exposure to a stressor. As the field moves closer to broader regulatory acceptance, this work signals a decisive shift: adversity, whether traumatic or existential, may no longer be viewed solely as an injury to be managed after the fact, but as a dynamic neurobiological process that can be actively shaped, interrupted, and potentially reversed. With all the regulatory tailwinds, bringing the possibility of recovery closer becomes a practical and accessible reality.
Now that a resilience–demoralization continuum is better characterized, including at the neurobiological level, the question that follows is what endpoints might reasonably anchor a clinical trial. The material reviewed here suggests several candidate domains, none of which is yet established, but each of which seems worth considering. Molecular and cellular markers as potential biomarkers offer one avenue: inflammatory indices such as Iba-1 and CX3CR1, HPA-axis reactivity profiles, epigenetic signatures including FKBP5 methylation, and reward-circuit correlates such as BDNF and ΔFosB expression. These would presumably be paired with conventional clinical assessment scales such as the original version of the Demoralization Scale (Kissane et al., 2004), which has a Loss of Meaning domain, or CAPS-5, or MADRS. A second, more speculative possibility — incorporating the Loss of Meaning factor from the Demoralization Scale directly alongside MADRS in depression, or CAPS-5 in PTSD, on the reasoning that despair and hopelessness may not be fully captured by either instrument — is not attempted here, since no precedent for such a composite exists and it would likely face regulatory skepticism. It is worth being explicit about what such a proposal would require. It is worth noting that the Demoralization Scale has been validated only in medical populations, and a subscale extracted from it would need content validity work in the target indication, evidence of reliability and construct validity, and an anchor-based estimate of within-patient meaningful change before it could support anything beyond exploratory analysis. Any claim intended for labeling may need to be negotiated as a fit-for-purpose measure in the context of a specific development program. That burden is substantial but not disqualifying, and it is the kind of work that is best begun early. Whether the effort could establish demoralization as a discrete and tractable state of vulnerability, and therefore a legitimate target for resilience-building interventions, remains an open question for the near future.
References
- Arluk, S., Matar, M. A., Carmi, L., Arbel, O., Zohar, J., Todder, D., & Cohen, H. (2022). MDMA treatment paired with a trauma-cue promotes adaptive stress responses in a translational model of PTSD in rats. Translational Psychiatry, 12(1), 181.
- Cohen, H., & Zohar, J. (2004). An animal model of posttraumatic stress disorder: the use of cut-off behavioral criteria. Annals of the New York Academy of Sciences, 1032, 167–178.
- Cohen, H., Matar, M. A., Buskila, D., Kaplan, Z., & Zohar, J. (2008). Early post-stressor intervention with high-dose corticosterone attenuates posttraumatic stress response in an animal model of posttraumatic stress disorder. Biological Psychiatry, 64(8), 708–717.
- Feder, A., Nestler, E. J., & Charney, D. S. (2009). Psychobiology and molecular genetics of resilience. Nature Reviews Neuroscience, 10, 446–457.
- Kissane, D. W., Wein, S., Love, A., Lee, X. Q., Kee, P. L., & Clarke, D. M. (2004). The Demoralization Scale: a report of its development and preliminary validation. Journal of Palliative Care, 20(4), 269–276.
- Krishnan, V., Han, M. H., Graham, D. L., Berton, O., Renthal, W., Russo, S. J., et al. (2007). Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell, 131(2), 391–404.
- Mitchell, J. M., Bogenschutz, M., Lilienstein, A., et al. (2021). MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study. Nature Medicine, 27, 1025–1033.
- Mul, J. D., Soto, M., Cahill, M. E., Ryan, R. E., Takahashi, H., So, K., Zheng, J., Croote, D. E., Hirshman, M. F., la Fleur, S. E., Nestler, E. J., & Goodyear, L. J. (2018). Voluntary wheel running promotes resilience to chronic social defeat stress in mice: a role for nucleus accumbens ΔFosB. Neuropsychopharmacology, 43, 1934–1942.
- Nahum, K., Todder, D., Zohar, J., & Cohen, H. (2022). The Role of Microglia in the (Mal)adaptive Response to Traumatic Experience in an Animal Model of PTSD. International Journal of Molecular Sciences, 23(13), 7185.
- Parise, E. M., Parise, L. F., Sial, O. K., Cardona-Acosta, A. M., Gyles, T. M., Juarez, B., et al. (2021). The resilient phenotype induced by prophylactic ketamine exposure during adolescence is mediated by the ventral tegmental area–nucleus accumbens pathway. Biological Psychiatry, 90(7), 482–493.
- Ross, S., Bossis, A., Guss, J., Agin-Liebes, G., Malone, T., Cohen, B., Mennenga, S. E., Belser, A., Kalliontzi, K., Babb, J., Su, Z., Corby, P., & Schmidt, B. L. (2016). Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial. Journal of Psychopharmacology, 30(12), 1165–1180.
- Ross, S., Agin-Liebes, G., Lo, S., Zeifman, R. J., Ghazal, L., Benville, J., Franco Corso, S., Bjerre Real, C., Guss, J., Bossis, A., & Mennenga, S. E. (2021). Acute and Sustained Reductions in Loss of Meaning and Suicidal Ideation Following Psilocybin-Assisted Psychotherapy for Psychiatric and Existential Distress in Life-Threatening Cancer. ACS Pharmacology & Translational Science, 4(2), 553–562.
- Russo, S. J., Murrough, J. W., Han, M. H., Charney, D. S., & Nestler, E. J. (2012). Neurobiology of resilience. Nature Neuroscience, 15, 1475–1484.
- Torres-Berrío, A., Estill, M., Patel, V., Ramakrishnan, A., Kronman, H., Minier-Toribio, A., Issler, O., Browne, C. J., Parise, E. M., van der Zee, Y. Y., Walker, D. M., Martínez-Rivera, F. J., Lardner, C. K., Durand-de Cuttoli, R., Russo, S. J., Shen, L., Sidoli, S., & Nestler, E. J. (2024). Mono-methylation of lysine 27 at histone 3 confers lifelong susceptibility to stress. Neuron, 112(17), 2973–2989.
- Zohar, J., Yahalom, H., Kozlovsky, N., Cwikel-Hamzany, S., Matar, M. A., Kaplan, Z., Yehuda, R., & Cohen, H. (2011). High dose hydrocortisone immediately after trauma may alter the trajectory of PTSD: interplay between clinical and animal studies. European Neuropsychopharmacology, 21(11), 796–809.
