Author: Tharusha Jayasena

Emerging Role of Psychedelics in the Treatment of Post Traumatic Stress Disorder
Axon DAO will be launching its first NFT project in July 2022 to show its commitment to supporting neurological research and promising new treatments in the veteran mental health space with a longer-term vision of establishing as it works towards its vision of establishing a blockchain-based neuro-medical fund. Ongoing research into the role of psychedelics such as ketamine and psilocybin for the benefit of post-traumatic stress disorder (a disabling psychiatric condition affecting both active military members and veterans), has shown promising effects for this disorder. In collaboration with its community of supporters, Axon DAO is aiming to raise over $50,000 to support the work of Thank You Life in making psychedelic-assisted psychotherapy assessable to those in need, including veterans but restricted to access due to financial barriers through providing treatment scholarships at psychedelic centers.

Introduction
Post-traumatic stress disorder (PTSD) is a chronic and disabling psychiatric disorder affecting over 7 million people, with a lifetime prevalence in the United States of approximately 7.8% [1]. In the past, post-traumatic psychopathology has been classified under several labels following wars in America. These include the term soldier’s heart (from the American Civil War), shell shock and traumatic neurosis (WW I), combat fatigue (WW II), and gross stress reaction (Vietnam War) [2]. However, sadly, the condition did not receive the attention it deserved and active research into treatment was mostly neglected and was not formally recognized as a diagnostic entity until 1980 [2].

Post-traumatic stress disorder is identified as the presence of recurrent, intrusive distressing memories, dreams, dissociative reactions (such as flashbacks), and reactions to internal or external cues that symbolize or resemble an aspect of a previously experienced traumatic event (actual or threatened) [1]. In response to these symptoms, individuals often attempt to avoid situations where they may be reminded about the trauma. This is done by controlling thoughts, memories, and emotions or by avoiding people, places, conversations, and situations that may trigger memories. Patients also exhibit changes in memory formation (such as selective amnesia of specific details surrounding the trauma) and other comorbidities such as depression including negative beliefs and expectations, negative emotional states and social withdrawal, chronic pain, and dementia [3, 4]. In addition, patients may experience irritability, self-destructive behavior, hyper-vigilance, sleep disturbance, emotional numbing, and difficulty in concentrating [3, 4]. Symptoms related to re-experiencing the traumatic event are a defining feature of PTSD as well as anxiety and hyperarousal in the absence of trauma-related cues [4]. It is thought that alterations and dysregulation of fear processing and difficulty in learning safety signals are likely involved in the development and/or maintenance of PTSD [4, 5].

Neurobiological Changes Found in PTSD
Although PTSD is still largely regarded as a psychological condition, over the past decades there has been extensive growth in the area of investigating the biological changes found in PTSD. Psychological trauma has been shown to result in brain changes at both cellular and molecular levels, studying these changes may give insights into the pathogenesis of PTSD. One of the earliest and most validated findings from this area of research is that of heightened psychophysiological response (elevated heart rate and skin conductance) to trauma-related stimuli such as combat sounds as well as to internal, mental imagery of traumatic events which correlated with the severity of the disorder [6-8]. In addition, other studies have reported exaggerated startle response to be present in PTSD [9]. Sleep abnormalities have also been reported in PTSD patients, these include higher amounts of stage 1 sleep, less slow-wave sleep, and more rapid-eye-movement density [10]. Sleep difficulties in veterans with PTSD include insomnia, nightmares, and sleep-related breathing and movement disorders [11]. Psychophysiological assessments of treatment outcomes of these biomarkers may provide more objective information than a patient’s report and maybe a more sensitive measure of progress. There is also emerging evidence of elevated levels of oxidative stress and inflammation in PTSD. Oxidative stress occurs when pro-oxidant molecules exceed the capacity of available antioxidants. The brain is particularly susceptible to oxidative stress. Previous studies have reported significant differences in antioxidant concentrations in PTSD [3]. Results from blood biomarker studies have also shown evidence of pro-inflammatory processes in the pathophysiology of PTSD, such as the elevation of cytokines and C-reactive protein [3]. In regards to brain structural and activity abnormalities observed in PTSD, there is some evidence linking PTSD with lower hippocampal volume [12, 13] and hyperactivity in the amygdala [14]. To the extent that diminished volume may underlie diminished function, these findings may indicate a reduced capacity to inhibit fear and other negative emotional responses in PTSD. The hippocampus plays a role in the encoding and recognition of episodic memories and environmental cues, including those that are present during fear conditioning, extinction, and fear renewal [15, 16]. It also plays a role in the regulation of stress hormones [17]. Fear extinction learning refers to the gradual decrease in response to a conditioned stimulus that occurs when the stimulus is presented without reinforcement and in PTSD subjects, failure to recall extinction of fear responses is associated with lower hippocampal activation [16]. Neuroimaging studies have shown altered activity in individuals with PTSD in various areas of the brain including the amygdala which is a key structure for both the recognition of dangerous stimuli and the coordination of the fear response [16, 18]. The amygdala plays a crucial role in the formation of fear-related associations, detection and emotional response to threats, fear learning, and memory of emotional events [4, 18]. Functional neuroimaging studies have reported increased amygdala activation in response to trauma-related stimuli such as combat sounds in patients with PTSD compared to control subjects [14, 19].

Prevalence of PTSD Amongst Veterans
It is well known that veterans (individuals who have left the military) and military service members (those currently serving) in particular, are exposed to a multitude of operational, occupational, and interpersonal stresses that negatively affect many aspects of their mental health, and this not surprisingly this group is at an increased risk for PTSD, especially those who have experienced military combat or captivity. Rates of PTSD in Vietnam veterans range from 19-30% and are 12-25% for those who served in Iraq and Afghanistan [20]. There is also variation in rates due to military status (active duty or reserve), time period, and location of operations [20]. The military today is all-volunteer based and much smaller compared to periods of history where drafting was undertaken. As a result, military service members face longer and multiple deployments, resulting in an increased exposure to trauma and other stressors causing an increased prevalence of new PTSD cases and thus making this disorder one of the most common mental health disorders among military personnel exposed to combat [20]. As a result, PTSD represents a significant source of disability and morbidity among military and veteran populations. High degrees of disability make it difficult for an individual to maintain employment and social wellness with the devastating and debilitating consequences spreading to their families and society, including poor social, family, and working relationships, lower-income, education, and occupational success. In addition to the disabilities caused by PTSD alone, there are several comorbidities associated with the disorder. Over 90% of individuals with PTSD have at least one other mental disorder [21]. Other disorders that commonly co-occur include depression, suicidal ideation, alcohol use disorder, and anxiety disorders [21]. They are also more likely to experience a variety of preventable lifestyle health problems such as obesity, heart disease, migraines, arthritis, and hypertension [22].

Psychedelics (Ketamine and Psilocybin) and the Treatment of PTSDDespite its prevalence, currently available treatments for PTSD have limitations. While trauma-focused psychotherapies have the most empirical support, they are limited by significant rates of nonresponse, partial response, and treatment dropout. There are few available pharmacotherapies for PTSD, and their efficacy is insufficient. Selective serotonin reuptake inhibitors (SSRIs) are approved by the U.S. Food and Drug Administration (FDA) for PTSD treatment and are the frontline treatment for the disorder [23]. Approximately 60% of patients with PTSD respond to SSRIs, but only 20%−30% achieve complete remission from treatment [23]. Additionally, maximal improvement with available medications can take months. The lack of progress in PTSD pharmacotherapy recently has made it imperative to develop novel therapeutic interventions for chronic and treatment-resistant PTSD.

One such treatment could be via the use of psychedelics. After several decades of hiatus, psychedelics are increasingly being studied for the treatment of a range of psychiatric indications. Within the past 2 years, the US Food and Drug Administration (FDA) has recommended MDMA and psilocybin, which are still on the US Drug Enforcement Administration’s most restrictive schedule, a breakthrough therapy designation, and approved ketamine for treatment-resistant depression. Currently, several psychedelics are being investigated for the treatment of PTSD. Psychedelic drugs refer to a class of compounds that can induce a wide range of psychological, cognitive, emotional, and physical effects. Psychedelics such as ketamine and psilocybin have gained recent popularity for the treatment of depression. They may both also have benefits for PTSD.

Ketamine, first approved by the FDA as an anesthetic agent in 1970, is a non-competitive glutamate N-methyl-D-aspartate (NMDA) receptor antagonist, with a lower affinity for serotonin, dopamine, opioid, and other receptors [24]. After decades of use for anesthesia, analgesia, and sedation, the efficacy of single-dose intravenous ketamine infusion for treatment-resistant depression is now well established, and repeated infusions demonstrate prolonged improvement [25]. Given the treatment-resistant nature of PTSD for many patients, the potential benefit of developing a safe ketamine protocol may be warranted in a similar manner to that of its use for depression. Further controversy for ketamine is based on the fact that it may cause transient dissociation. Even though there is currently only limited data available, ketamine has been shown to result in a near-complete resolution of symptoms over the short term and seems to have similar findings to the use of ketamine in depression [24, 26]. It has also been shown to increase synaptic plasticity, improve the ability to process traumatic memories and facilitate fear extinction and block memory reconsolidation [26, 27]. These clinical improvements are immediate and last well beyond the half-life of ketamine but unfortunately are transient lasting 1–2 weeks thus repeated infusions are required for maintenance. It is thought that upregulating brain-derived neurotrophic factor levels and antagonizing NMDA result in a reversal of some of the damage caused by chronic stress. With ongoing clinical trials and more investigation, ketamine may prove to be an important tool in treating PTSD for those who fail more conventional treatments.

Although there is limited empirical evidence for mechanisms through which ketamine might reduce PTSD symptoms, several neurobiological mechanisms have been proposed. One hypothesis is that the therapeutic effects of psychedelic drugs like ketamine might be partially explained by their ability to rapidly increase synaptic and neuronal plasticity [24, 26]. Ketamine could also target PTSD symptoms by its effects on glutamate signaling [28]. The glutamate system has been shown to play an essential role in several memory processes, such as reconsolidation and extinction learning [26, 28]. Ketamine’s effects on these memory processes suggest a potential role for its use within a substance-assisted psychotherapy framework. Some researchers suggest that the symptoms experienced in PTSD may be caused by a loss of synaptic connectivity [24]. The stress experienced in PTSD may impair the functioning of synaptic connectivity, which is mostly mediated by glutamate. As glutamate synapses play a crucial role in these neuronal circuits, it is possible that the use of ketamine may enhance synaptic connectivity in these circuits, ultimately reversing the effects of stress [24, 26]. Due to its plasticity-enhancing effects, ketamine may also increase the receptiveness to psychotherapeutic interventions in the days following administration.

Administration of a subanesthetic dose of ketamine could then be considered an augmentation strategy for trauma-focused psychotherapy, suggesting that the integration of ketamine within a psychotherapeutic treatment could result in long-term remission of PTSD symptoms. Within a substance-assisted psychotherapy approach, the acute psychoactive effects of ketamine—ranging from sensory distortions and hallucinations to transformations in emotional attitudes to aspects of self and others, and changes in life values and purposes, could catalyze, deepen, or increase engagement in a psychotherapeutic process. As with the use of ketamine for depression, research suggests that the therapeutic effects of ketamine on PTSD can be enhanced—both in strength and duration—with repeated infusions. In a study by Albott et al, 6 ketamine infusions (0.5 mg/kg) over a 12-day period in 15 military veterans with comorbid PTSD and treatment-resistant depression resulted in a remission rate of 80%, with a median time to relapse of 41 days [29]. In another study, Pradhan et al combined the administration of ketamine with a mindfulness-based cognitive therapy protocol in patients with PTSD and found Patients in the ketamine group showed a significantly more durable reduction in PTSD symptoms than patients in the placebo group [30]. Feder et al reported a 5-times increase in the duration of response compared with a single administration of ketamine without any psychotherapy, however, improvement in PTSD symptoms was still relatively short-lived [31].

Another psychedelic compound that has also shown promising results for PTSD treatment and has long-lasting effects compared to ketamine, is the active psychoactive compound of “magic mushrooms”, psilocybin. As with ketamine, psilocybin induces several neurobiological changes that may be relevant for the psychotherapeutic application. Psilocybin has been shown to facilitate fear extinction in animal studies and to promote neural plasticity by increasing neurogenesis and synaptogenesis [32]. It has also been shown to decrease amygdala reactivity during emotional processing resulting in the increased positive mood [33]. As patients with PTSD often show elevated amygdala reactivity this may be an important target area to increase the ability to process traumatic memories. Other beneficial effects that validate the potential therapeutic role of psilocybin in the treatment of PTSD include increases in emotional empathy, creative divergent thinking, enhanced mindfulness capacities, and insightfulness, reduced avoidance and increases in acceptance and connectedness, and increases in openness and emotional breakthrough experiences [26]. Psilocybin has also been shown to induce strong mystical experiences which have been shown to correlate with positive psychological change and importantly, it has been shown that some of these benefits can last months to years even with a single administration of the compound [34].

Most of the currently used psychotherapies for the treatment of PTSD are exposure-based therapies, which are individual cognitive-behavioral therapy that focuses on reducing symptoms through extended contact with feared or avoided trauma-related stimuli including thoughts, objects, events, or people [35]. The goal is to extinguish conditioned fear to cues associated with trauma by desensitization to fearful stimuli. Many patients experience a reduction in PTSD symptoms after psychotherapy, however, 40–60% of patients do not respond adequately [26, 35]. The processing of traumatic memories typically can be an emotionally challenging experience for PTSD patients. For some patients, emotional detachment, fragmentation of trauma memories, or an inability to complete sessions due to the inability to tolerate re-experiencing traumatic memories can lead to nonresponse and treatment dropout. The integration of the targeted use of certain psychoactive substances within a psychotherapeutic treatment may have the potential to address some of these challenges. The psychoactive properties of psychedelic drugs may be of particular interest within such a substance-assisted psychotherapy approach and this approach has shown efficacy in previous studies [26, 36]. The rationale behind this approach is that These substances may increase engagement with and the effectiveness of psychotherapeutic interventions due to a variety of psychological and neurobiological effects, such as an increased capacity for emotional and cognitive processing through pharmacologically diminished fear and arousal, increased insightfulness, and introspection strengthened therapeutic alliance through increased trust and rapport, increases in synaptic plasticity, or by targeting processes of fear extinction and memory consolidation [26, 36].

When properly applied, new models of substance-assisted psychotherapy may offer a valuable contribution to the spectrum of existing pharmacological and psychotherapeutic treatments for PTSD. These interventions may not easily become a first-line treatment as they require specific expertise and environments, but they may boost explorations to implementing novel approaches to mental health infrastructures. For a large number of patients for whom PTSD has become a chronic illness, these approaches can be of immense value. If successfully implemented, many patients with PTSD could potentially recover, and the availability of psychedelics could herald a new era in the evidence-based care options that are available to patients with PTSD.

Axon DAO will be launching its first NFT project in July 2022 to show its commitment to neurological research, treatments, technology, and medicines, as it works towards its vision of establishing a neuro-medical fund. The genesis project will be supporting Thank You Life which is a charity organization providing scholarship funds to those in need of psychedelic-assisted psychotherapy at psychedelic centers but cannot access treatment due to financial barriers to this expensive treatment. Specifically, they take donations to grant access to treatments with ketamine. Once MDMA, and psilocybin are legal, they will provide the same assistance. Proceeds for the NFT project will go directly to support their mission of making psychedelic-assisted psychotherapy assessable to all who need it, including veterans suffering from PTSD. Thank You Life dedicates its financial and human capital to both for-profit and not-for-profit initiatives, that support the evolution of human consciousness and aspire to be one of the catalyzers of a movement that will positively and materially impact the lives of billions in the span of a generation.

More information about Thank You Life and the work they do can be found on their website: https://thankyoulife.org/

Axon DAO’s team has discovered a passionate community in the web3 space that's committed to helping and educating others at its core. Combining art, healing, and technology - the Axon DAO Genesis NFT - will launch a series of charitable projects that benefit the patient, neurological research, the artists involved, and Axon DAO itself, in equal parts. Axon DAO is working with its reputable advisor network and contributors to launch this project in partnership with Desci World, Thank you Life, and (the University of Texas Dell Medical School) and will continue to build a coalition with other DAOs, participants, and experts alike in relatable fields. Axon DAO will always seek contributors, accredited capital investors, and advisors in neurology, blockchain, medical tech, IP/data, private equity, venture capital, lawyers, patients, researchers, and any other interested individuals who want to be part of this new field. Make sure to follow Axon DAO on social media to stay up to date on our genesis drop and future projects:

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References

1. Kirkpatrick, H.A. and G.M. Heller, Post-traumatic stress disorder: theory and treatment
   update. Int J Psychiatry Med, 2014. 47(4): p. 337-46.
2. Crocq, M.A. and L. Crocq, From shell shock and war neurosis to posttraumatic stress disorder:
   a history of psychotraumatology. Dialogues Clin Neurosci, 2000. 2(1): p. 47-55.
3. Miller, M.W., et al., Oxidative Stress, Inflammation, and Neuroprogression in Chronic PTSD.
   Harv Rev Psychiatry, 2018. 26(2): p. 57-69.
4. Pitman, R.K., et al., Biological studies of post-traumatic stress disorder. Nat Rev Neurosci,
5. 13(11): p. 769-87.
6. Maeng, L.Y. and M.R. Milad, Post-Traumatic Stress Disorder: The Relationship Between the
   Fear Response and Chronic Stress. Chronic Stress (Thousand Oaks), 2017. 1: p.
   2470547017713297.
7. Keane, T.M., et al., Utility of psychophysiological measurement in the diagnosis of
   posttraumatic stress disorder: results from a Department of Veterans Affairs Cooperative
   Study. J Consult Clin Psychol, 1998. 66(6): p. 914-23.
8. Pitman, R.K., et al., Psychophysiologic responses to combat imagery of Vietnam veterans
   with posttraumatic stress disorder versus other anxiety disorders. J Abnorm Psychol, 1990.
   99(1): p. 49-54.
9. Pitman, R.K., S.P. Orr, and G.S. Steketee, Psychophysiological investigations of posttraumatic
   stress disorder imagery. Psychopharmacol Bull, 1989. 25(3): p. 426-31.
10. Pole, N., The psychophysiology of posttraumatic stress disorder: a meta-analysis. Psychol
    Bull, 2007. 133(5): p. 725-46.
11. Kobayashi, I., J.M. Boarts, and D.L. Delahanty, Polysomnographically measured sleep
    abnormalities in PTSD: a meta-analytic review. Psychophysiology, 2007. 44(4): p. 660-9.
12. Khazaie, H., M.R. Ghadami, and M. Masoudi, Sleep disturbances in veterans with chronic
    war-induced PTSD. J Inj Violence Res, 2016. 8(2): p. 99-107.
13. Bremner, J.D., et al., The environment contributes more than genetics to smaller
    hippocampal volume in Posttraumatic Stress Disorder (PTSD). J Psychiatr Res, 2021. 137: p.
    579-588.
14. Cobb, A.R., et al., Hippocampal volume and volume asymmetry prospectively predict PTSD
    symptom emergence among Iraq-deployed soldiers. Psychol Med, 2021: p. 1-8.
15. Etkin, A. and T.D. Wager, Functional neuroimaging of anxiety: a meta-analysis of emotional
    processing in PTSD, social anxiety disorder, and specific phobia. Am J Psychiatry, 2007.
    164(10): p. 1476-88.
16. Logue, M.W., et al., Smaller Hippocampal Volume in Posttraumatic Stress Disorder: A
    Multisite ENIGMA-PGC Study: Subcortical Volumetry Results From Posttraumatic Stress
    Disorder Consortia. Biol Psychiatry, 2018. 83(3): p. 244-253.
17. Milad, M.R., et al., Neurobiological basis of failure to recall extinction memory in
    posttraumatic stress disorder. Biol Psychiatry, 2009. 66(12): p. 1075-82.
18. Jacobson, L. and R. Sapolsky, The role of the hippocampus in feedback regulation of the
    hypothalamic-pituitary-adrenocortical axis. Endocr Rev, 1991. 12(2): p. 118-34.
19. Harnett, N.G., A.M. Goodman, and D.C. Knight, PTSD-related neuroimaging abnormalities in
    brain function, structure, and biochemistry. Exp Neurol, 2020. 330: p. 113331.
20. Liberzon, I., et al., Brain activation in PTSD in response to trauma-related stimuli. Biol
    Psychiatry, 1999. 45(7): p. 817-26.
21. Inoue, C., et al., Veteran and Military Mental Health Issues, in StatPearls. 2022: Treasure
    Island (FL).
22. Sareen, J., Posttraumatic stress disorder in adults: impact, comorbidity, risk factors, and
    treatment. Can J Psychiatry, 2014. 59(9): p. 460-7.
23. Nichter, B., et al., Physical health burden of PTSD, depression, and their comorbidity in the
    U.S. veteran population: Morbidity, functioning, and disability. J Psychosom Res, 2019. 124:
    p. 109744.
24. Alexander, W., Pharmacotherapy for Post-traumatic Stress Disorder In Combat Veterans:
    Focus on Antidepressants and Atypical Antipsychotic Agents. P T, 2012. 37(1): p. 32-8.
25. Feder, A., et al., The emergence of ketamine as a novel treatment for posttraumatic stress
    disorder. Adv Pharmacol, 2020. 89: p. 261-286.
26. Marcantoni, W.S., et al., A systematic review and meta-analysis of the efficacy of intravenous
    ketamine infusion for treatment resistant depression: January 2009 - January 2019. J Affect
    Disord, 2020. 277: p. 831-841.
27. Krediet, E., et al., Reviewing the Potential of Psychedelics for the Treatment of PTSD. Int J
    Neuropsychopharmacol, 2020. 23(6): p. 385-400.
28. Ly, C., et al., Psychedelics Promote Structural and Functional Neural Plasticity. Cell Rep, 2018.
    23(11): p. 3170-3182.
29. Asim, M., et al., Ketamine attenuates the PTSD-like effect via regulation of glutamatergic
    signaling in the nucleus accumbens of mice. Mol Cell Neurosci, 2022. 120: p. 103723.
30. Albott, C.S., et al., Efficacy, Safety, and Durability of Repeated Ketamine Infusions for
    Comorbid Posttraumatic Stress Disorder and Treatment-Resistant Depression. J Clin
    Psychiatry, 2018. 79(3).
31. Pradhan, B., et al., d-Serine is a potential biomarker for clinical response in treatment of post-
    traumatic stress disorder using (R,S)-ketamine infusion and TIMBER psychotherapy: A pilot
    study. Biochim Biophys Acta Proteins Proteom, 2018. 1866(7): p. 831-839.
32. Feder, A., et al., Efficacy of intravenous ketamine for treatment of chronic posttraumatic
    stress disorder: a randomized clinical trial. JAMA Psychiatry, 2014. 71(6): p. 681-8.
33. de Vos, C.M.H., N.L. Mason, and K.P.C. Kuypers, Psychedelics and Neuroplasticity: A
    Systematic Review Unraveling the Biological Underpinnings of Psychedelics. Front Psychiatry,
34. 12: p. 724606.
35. Kraehenmann, R., et al., Psilocybin-Induced Decrease in Amygdala Reactivity Correlates with
    Enhanced Positive Mood in Healthy Volunteers. Biol Psychiatry, 2015. 78(8): p. 572-81.
36. McCulloch, D.E., et al., Psilocybin-Induced Mystical-Type Experiences are Related to
    Persisting Positive Effects: A Quantitative and Qualitative Report. Front Pharmacol, 2022. 13:
    p. 841648.
37. Henslee, A.M. and S.F. Coffey, Exposure therapy for posttraumatic stress disorder in a
    residential substance use treatment facility. Prof Psychol Res Pr, 2010. 41(1): p. 34-40.
38. Luoma, J.B., et al., A Meta-Analysis of Placebo-Controlled Trials of Psychedelic-Assisted
    Therapy. J Psychoactive Drugs, 2020. 52(4): p. 289-299.