As research into psychedelic approaches to traumatic brain injury (TBI) continues to develop, another compound attracting scientific interest is 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT).
Sometimes referred to as “the toad”, due to its natural occurrence in the secretions of the Sonoran Desert toad, 5-MeO-DMT is a powerful, short-acting psychedelic capable of producing profound alterations in consciousness.
Emerging research suggests potential therapeutic benefits for depression and PTSD, alongside possible neurobiological effects relevant to brain injury.
Trauma and Brain injury
Brain injury is often discussed primarily in neurological terms, with attention directed towards memory, attention, processing speed, executive functioning and physical disability. However, the psychological consequences can be equally significant.
Alongside neurological impairment, individuals may experience trauma associated with the injury itself, grief for their previous life, changes in identity, anxiety, depression and difficulties adjusting to circumstances they never anticipated.
Through my work in neurorehabilitation, I have seen how these psychological challenges can become deeply interconnected with the process of recovery.
My personal belief is that unresolved trauma does not necessarily have to arise from a major life event. Even seemingly small experiences can leave an emotional imprint, particularly when the feelings associated with them have never been fully acknowledged or expressed.
I believe that emotions which remain unfelt can continue to affect us through the body and subconscious, creating an underlying sense of unease that may contribute to psychological distress. These unresolved experiences may surface through bodily sensations, dreams or patterns of behaviour that we do not consciously associate with the original experience.
From my perspective, subconscious processes play an important role in shaping how we perceive and respond to the world. Unresolved emotional experiences may therefore continue to influence our relationships, behaviours and emotional wellbeing, even when we are not consciously aware of their origins.
This is what makes somatic approaches to psychological healing particularly interesting to me. Rather than always needing to understand or intellectually analyse an experience, perhaps there are occasions when healing begins by allowing previously suppressed emotions to be felt and expressed.
This raises an interesting possibility for individuals living with brain injury, particularly where difficulties with memory, attention, language or executive functioning can make conventional psychological interventions more challenging.
Could 5-MeO eventually offer an alternative approach to addressing trauma, potentially facilitating emotional processing without requiring the same degree of conscious reflection?
Emerging Clinical Evidence
Research specifically investigating 5-MeO following TBI remains limited. However, clinical studies have begun examining its effects on psychological conditions, including post-traumatic stress disorder (PTSD) and treatment-resistant depression.
Ragnhildstveit et al. (2023) published a longitudinal case report involving a young woman experiencing chronic, treatment-resistant PTSD.
Following a single administration of a preparation containing 5-MeO, the individual experienced clinically significant improvements in PTSD symptoms within 24 hours. These improvements were maintained across follow-up assessments extending to 12 months.
Although encouraging, this was a single uncontrolled case, and the findings cannot establish treatment effectiveness or explain the psychological mechanisms involved.
More substantial evidence has recently emerged from randomised clinical trials investigating treatment-resistant depression.
Cubała et al. (2026) conducted a placebo-controlled trial involving 81 participants receiving inhaled synthetic 5-MeO. The researchers reported significantly greater reductions in depressive symptoms compared with placebo at eight days.
More recently, Feifel et al. (2026) published a randomised clinical trial, involving 193 adults with treatment-resistant depression.
Following a single intranasal administration, approximately 34–35% of participants receiving active treatment demonstrated a clinically meaningful response at 29 days, compared with 12% receiving a very low dose. These findings suggest that 5-MeO may offer rapid and potentially sustained antidepressant effects, despite its relatively short duration of acute psychedelic activity.
Relevance to Traumatic Brain Injury
One of the most relevant studies was conducted by Davis et al. (2023), who investigated consecutive administration of ibogaine and 5-MeO among 86 US Special Operations Forces veterans.
The majority had experienced head injuries, with approximately 81% reporting TBI among their reasons for seeking treatment. Many also experienced overlapping psychological difficulties, including PTSD, depression and anxiety.
The researchers reported significant improvements in PTSD symptoms, depression, anxiety, psychological flexibility, self-reported cognitive functioning and post-concussive symptoms. Improvements remained evident at follow-up assessments extending to six months.
These findings are particularly interesting because they suggest potential benefits across both psychological and cognitive domains relevant to neurorehabilitation.
However, the study was uncontrolled and involved sequential administration of two psychedelic compounds alongside psychological support. Consequently, it is not possible to determine how much of the reported improvement was attributable specifically to 5-MeO.
Ibogaine has also been investigated independently in veterans with TBI. Cherian et al. (2024) reported substantial improvements in disability, psychological symptoms and aspects of cognitive functioning following a magnesium–ibogaine treatment programme.
An important question, therefore, is whether 5-MeO might provide additional therapeutic benefits, particularly in relation to trauma-related symptoms, or whether its effects could be investigated independently.
Potential Neurobiological Mechanisms
Beyond its possible psychological benefits, researchers have also begun exploring whether 5-MeO might influence biological processes involved in brain injury recovery.
Plummer et al. (2025) reviewed the potential of psilocybin and 5-MeO as therapeutics for TBI, examining their possible effects on several mechanisms associated with neurological injury.
Following brain injury, secondary injury processes can involve neuroinflammation, oxidative stress, neuronal damage and disruption to neuroplasticity. These processes may contribute to persistent cognitive and neurological difficulties.
The authors highlight the pharmacological activity of 5-MeO at serotonin receptors, alongside its proposed interaction with sigma-1 receptors, which have been associated with cellular stress responses and neuroprotective mechanisms. These interactions raise the possibility that 5-MeO could influence inflammation, neuronal survival and the brain's capacity for structural adaptation.
Supporting this broader hypothesis, Jefferson et al. (2023) investigated 5-MeO in mice and identified increased dendritic spine density within the frontal cortex, with changes persisting for approximately one month. Dendritic spines play an important role in communication between neurons, and changes in their formation are associated with mechanisms of neuroplasticity.
However, these findings remain preclinical. Whether 5-MeO produces comparable effects in the injured human brain, or whether such changes translate into meaningful improvements in cognition and everyday functioning, has yet to be established.
A Different Approach
One of the most interesting features of 5-MeO-DMT is its relatively short duration.
Not everybody may want or need the prolonged psychedelic experience associated with compounds such as ibogaine. If 5-MeO could facilitate meaningful trauma relief without requiring extensive conscious reflection or a lengthy psychedelic experience, it could offer a valuable alternative for individuals living with the psychological consequences of brain injury.
The sequential administration of ibogaine and 5-MeO, as investigated by Davis et al. (2023), also raises some interesting questions. I can see the potential benefits of combining the two, with ibogaine perhaps allowing for more extensive psychological exploration and 5-MeO offering a different, potentially more somatic approach to trauma. However, I also question whether administering them in close succession allows sufficient time to process and integrate an experience as profound as ibogaine.
These compounds may complement one another, although they could also be better suited to individual therapeutic approaches. I think further research is needed to understand their respective contributions and whether combining them provides additional benefits.
I feel the most interesting possibility is that 5-MeO could offer a relatively brief, direct approach to trauma relief following brain injury, particularly for individuals who may not need, or wish to undergo, a more prolonged psychedelic intervention.
References
Cherian, K.N. et al. (2024). ‘Magnesium–ibogaine therapy in veterans with traumatic brain injuries’. Nature Medicine, 30, pp. 373–381.
Cubała, W.J. et al. (2026). ‘GH001 vs placebo in patients with treatment-resistant depression: A randomized clinical trial’. JAMA Psychiatry, 83(6), pp. 561–569.
Davis, A.K. et al. (2023). ‘Open-label study of consecutive ibogaine and 5-MeO-DMT assisted-therapy for trauma-exposed male Special Operations Forces Veterans: Prospective data from a clinical program in Mexico’. The American Journal of Drug and Alcohol Abuse, 49(5), pp. 587–596.
Feifel, D. et al. (2026). ‘Single intranasal administration of the psychedelic mebufotenin for treatment-resistant depression: A randomized clinical trial’. JAMA. Published online 26 October 2026.
Jefferson, S.J. et al. (2023). ‘5-MeO-DMT modifies innate behaviors and promotes structural neural plasticity in mice’. Neuropsychopharmacology, 48, pp. 1257–1266.
Plummer, Z. et al. (2025). ‘Examining the potential of psilocybin and 5-MeO-DMT as therapeutics for traumatic brain injury’. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 141, 111448.
Ragnhildstveit, A. et al. (2023). ‘5-MeO-DMT for post-traumatic stress disorder: A real-world longitudinal case study’. Frontiers in Psychiatry, 14, 1271152.