PTSD BIOMARKERS

"In 1980, the American Psychiatric Association (APA) added PTSD to the third edition of its Diagnostic and Statistical Manual of Mental Disorders (DSM-III) nosologic classification scheme. Although controversial when first introduced, the PTSD diagnosis has filled an important gap in psychiatric theory and practice.
https://www.ptsd.va.gov/professional/treat/essentials/history_ptsd.asp#:~:text=In%201980%2C%20the%20American%20Psychiatric,in%20psychiatric%20theory%20and%20practice [2132]

Accounts of PTSD-like symptoms can be found in the Epic of Gilgamesh, the writings of Herodotus and Hippocrates, and in the Indian epic poem Ramayana.

Terms used of the years included shell shock, soldier’s heart, irritable heart, Da Costa's syndrome, combat fatigue or war neurosis. And for a a couple of centuries "nostalgia" - not its present meaning:

"In the late 1600s, Swiss physician Dr. Johannes Hofer coined the term 'nostalgia' to describe Swiss soldiers who suffered from despair and homesickness, as well as classic PTSD symptoms like sleeplessness and anxiety. Around the same time, German, French and Spanish doctors described similar illnesses in their military patients.

"In 1761, Austrian physician Josef Leopold Auenbrugger wrote about nostalgia in trauma-stricken soldiers in his book Inventum Novum. The soldiers, he reported, became listless and solitary, among other things, and efforts could do little to help them out of their torpor.

"PTSD in the Civil War
Nostalgia was a phenomenon noted throughout Europe and the 'disease' reached American soil during the U.S. Civil War (1861–1865). In fact, nostalgia became a common medical diagnosis that spread throughout camps. But some military doctors viewed the illness as a sign of weakness and one that only affected men with a 'feeble will'—and public ridicule was sometimes the recommended 'cure' for nostalgia."
https://www.history.com/topics/inventions/history-of-ptsd-and-shell-shock [2133]

Shivitti is a sort of case study, The author was sufficiently impressed by his psychedelic outcome that he wrote a book about it:

"An autobiographical record of one Holocaust survivor’s triumph over concentration camp syndrome with a regimen of professionally administered LSD.

"Imprisoned in Auschwitz for two years, having eluded death by the narrowest of margins, the man known as Ka-tzetnik 135633 survived the Holocaust to discover that survival alone would not end his torment. For over 30 years, through nightly dreams of terrifying intensity, the writer remained captive to the horrors of Auschwitz. Finally in 1976 he sought help from Professor Jan Bastiaans, the Dutch psychiatrist who first recognized Concentration Camp Syndrome and successfully treated camp survivors with a therapy involving doses of LSD. Shivitti is a memoir of that experience."
https://maps.org/product/shivitti-a-vision/ [3548]

Trauma author Dr David Healy charts the course of its treatment from the Civil War, before and after Freudianism, to the post-Vietnam intervention of the DSM and its gradual generalisation to to the traumas common in life, to today. Slovenia's own slant on all of this is an uncooked omlette.

"The word shellshock essentially rebranded hysteria, which up till WW I had been a disorder of women and people with weaker constitutions. A new name was needed because in WW I officers, no less than the working class men in trenches, were badly affected. Women in contrast were becoming surgeons and running hospitals back at home. The social order was shaken up. There was an uptick of births linked to WW I but not as dramatic as the increase 30 years later.

"Shellshock helped make Freud’s reputation. Paradoxically, Freud came to the fore not because he believed trauma was a factor causing nervous problems but because his position was that trauma, whether War or Sexual Abuse in childhood, was irrelevant. People broke down in War or in Life, because they had pre-existing adjustment difficulties linked to poor prior management of their libidinous impulses. Current difficulties (trauma) played into the prior weakness. See Shipwreck in Maastricht.

"This view excuses the powers that be from causing our nervous breakdowns. It stops us suing governments for drafting us into military or vaccine wars. It lays a basis for pointing to a pre-existing mendacity of women when they claim sexual abuse or rape.

"Thinking on these lines was not unique to Freud. It played a growing part in industrial accidents and ‘mental trauma’ linked to these accidents in American legal cases from the creation of railroads in the 1850s onwards.

"It shaped how the American military dealt with the question of military pensions after the Civil War – ultimately creating in the US what might be called the first single party payer health service anywhere in the world. It colored how Germany and Britain dealt with Shellshock after WW I.

"For WW II the Americans screened men for psychological weakness and excluded them. This did nothing to eliminate the problems. The War and the post War nervous problems entrenched psychoanalytic thinking in the United States. The Europeans went to War armed with high dose barbiturates, which helped in many but not all cases.

"Analysis came out of the War strengthened. This led to claims that it was obvious where the War had come from – the Germans were maladjusted. Democrat voting psychiatrists, unlike Republican voting doctors in general, knew what was wrong with Republican politicians like Goldwater and Reagan – they were latent homosexuals. In an era when Americans put a man on the moon, the shrinks figured it was within reach to prevent Wars by curing our neuroses.

"Data on personality profiles showing that German concentration camp guards were more normal and less psychopathic than the American G.I.s who liberated the camps did nothing to change minds on this."

...and his analysis comes to a frightening conclusion about industrialized medicine.

Today we seek biological explanations - to produce targeted cures.

But PTSD biomarkers remain a topic of some complexity with little opportunity for access to analyses for ordinary patients.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4520791/ [51]

List of potential tests in Table 1

The last biomarker mentioned is lowered endocannabinoids, and reference 64 refers to

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3870889/ [52]

in which AEA and 2-AG were assayed in addition to cortisol in survivors of the WTC collapse, so the patients were all exposed to similar experiences at the same time, increasing its usefulness

"The effect of reduced 2-AG content in PTSD remained significant after controlling for the stress of exposure to the WTC collapse, gender, depression and alcohol abuse. There were no significant group differences for AEA or cortisol levels; however, across the whole sample AEA levels positively correlated with circulating cortisol, and AEA levels exhibited a negative relationship with the degree of intrusive symptoms within the PTSD sample. This report shows that PTSD is associated with a reduction in circulating levels of the eCB 2-AG. Given the role of 2-AG in the regulation of the stress response, these data support the hypothesis that deficient eCB signaling may be a component of the glucocorticoid dysregulation associated with PTSD. The negative association between AEA levels and intrusive symptoms is consistent with animal data indicating that reductions in AEA promote retention of aversive emotional memories."

The ventromedial prefrontal cortex may contribute to conditioned response inhibition via suppression of the amygdala.
https://www.jneurosci.org/content/jneuro/26/37/9503.full.pdf [148]

Hwang et al (2025) relate how...

"Recent studies have begun to detail the molecular biology of PTSD. However, given the array of PTSD-perturbed molecular pathways identified so far, it is implausible that a single cell type is responsible. Here we profile the molecular responses in over two million nuclei from the dorsolateral prefrontal cortex of 111 human brains, collected post-mortem from individuals with and without PTSD and major depressive disorder. We identify neuronal and non-neuronal cell-type clusters, gene expression changes and transcriptional regulators, and map the epigenomic regulome of PTSD in a cell-type-specific manner. Our analysis revealed PTSD-associated gene alterations in inhibitory neurons, endothelial cells and microglia and uncovered genes and pathways associated with glucocorticoid signalling, GABAergic transmission and neuroinflammation."
https://www.nature.com/articles/s41586-025-09083-y [5255]

The locus coeruleus (LC) is a small, bluish nucleus located in the brainstem, specifically in the pons. It is situated in the floor of the fourth ventricle, just under the cerebellum. This tiny structure serves as the brain's primary source of norepinephrine, a neurotransmitter crucial for functions such as attention, arousal, sleep-wake cycles, and memory.

Engborg et al (2025) found "Stress reactivity is modulated by cannabinoid type-1 receptors in norepinephrine and epinephrine neurons in a context-dependent manner":

"Here, we identify a role for CB1R in NE/E neurons in regulating stress-related affective responses using a combination of intersectional genetic, anatomical, behavioral, and physiological approaches. In control mice, Cnr1 mRNA was widely expressed in medullary C1/A1 and C2/A2 nuclei, with more limited expression in LC neurons, highlighting molecular diversity within the central noradrenergic system. Notably, Cnr1 was present in both NE- and E-producing medullary neurons, marking the first cell-type-specific characterization of Cnr1 in brainstem NE/E populations and extending prior work focused primarily on the LC (Luskin et al., 2024, Oropeza et al., 2007, Srivastava et al., 2022, Wyrofsky et al., 2017). In Cnr1cKO-Dbh mice, Cnr1 expression was reduced across all examined NE/E nuclei. Behaviorally, Cnr1cKO-Dbh mice exhibited increased center time following restraint stress, reduced immobility in the forced swim test, heightened active escape responses to a looming visual threat, and diminished rearing and ambulation during the initial threat presentation. In contrast, no genotype differences were observed in the elevated zero maze or light–dark box following foot shock stress, nor in the tail suspension test. Additionally, heart rate dynamics remained unchanged. These findings suggest that CB1R signaling in NE/E neurons modulates behavioral responses to acute stress in a context-dependent manner."
https://www.sciencedirect.com/science/article/pii/S0306452225008942 [5367]

In "Childhood Trauma is Associated with Poorer Cognitive Performance in Older Adults" (2018) Petkus et al say:

"Neurobiological mechanisms involving chronic inflammation, decreased neuroplasticity, and epigenetic modification of stress-related pathways may explain the possible association between early life trauma and poorer cognitive performance in later life. The hypothalamus-pituitary-adrenal (HPA) axis is thought to play a particularly important role in this association. The HPA axis activates under stress, resulting in elevated levels of the cortisol hormone and certain severe and/or chronic stressors, particularly if experienced early in life, may permanently alter HPA axis function. Studying this association is important, as chronically elevated cortisol levels have been associated with worse neuropsychological performance in later life."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959209/ [3583]

"Perceived stress can have long-term physiological and psychological consequences
and has shown to be a modifiable risk factor for Alzheimer disease and related dementias." say Kulshreshtha et al (2023), who compared perceived stress and health indicators:

"The final analytical sample included 24 448 participants (14 646 women [59.9%]; median age, 64 years [range, 45-98 years]; 10 177 Black participants [41.6%] and 14 271 White participants [58.4%]). A total of 5589 participants (22.9%) reported elevated levels of stress. Elevated levels of perceived stress (dichotomized as low stress vs elevated stress) were associated with 1.37 times higher odds of poor cognition after adjustment for sociodemographic variables, cardiovascular risk factors, and depression (adjusted odds ratio [AOR], 1.37; 95% CI, 1.22-1.53). The association of the change in the Perceived Stress Scale score with incident cognitive impairment was significant in both the unadjusted model (OR, 1.62; 95% CI, 1.46-1.80) and after adjustment for sociodemographic variables, cardiovascular risk factors, and depression (AOR, 1.39; 95% CI, 1.22-1.58). There was no interaction with age, race, and sex."
https://doi.org/10.1001/jamanetworkopen.2023.1860 [3584]

The state of knowledge on species differences shows that humanity is at an early stage in the understanding of these processes.
https://www.pnas.org/content/pnas/early/2019/12/17/1902288116.full.pdf [149]

But according to Ney et al at the School of Psychology, University of Tasmania, much of the research as it relates to PTSD and cannabinoids may be gender-skewed:

"Despite men reportedly experiencing more traumatic events than women, lifetime prevalence of PTSD is twice as common in women in Australia (Silove et al., 2017), United Kingdom (Wittchen et al., 2011) and the United States (Kessler et al., 1995; Tolin Foa, 2006). Whilst exposure to different trauma types (and specifically interpersonal and sexual violence in women) makes a substantial contribution, this is insufficient to explain the difference in prevalence between the sexes (Olff, Langeland, Draijer, & Gersons, 2007; Tolin & Foa, 2006). Despite sex hormones being effectors of stress responses critical to PTSD aetiology, the majority of psychological and pharmacological PTSD preclinical research is conducted using males (Lebron-Milad & Milad, 2012). It is therefore possible that treatments developed for PTSD may be insensitive to the specific needs of female patients"

See their Table 3 for an overview of studies on sex differences and endocannabinoid signalling,
https://www.researchgate.net/profile/Luke-Ney-2/publication/326337009_Modulation_of_the_endocannabinoid_system_by_sex_hormones_Implications_for_Posttraumatic_Stress_Disorder/links/5fbd8bfda6fdcc6cc663e25d/Modulation-of-the-endocannabinoid-system-by-sex-hormones-Implications-for-Posttraumatic-Stress-Disorder.pdf [4387]

Maldonado et al in "The endocannabinoid system in modulating fear, anxiety, and stress" (2020) explain more about stress and the ECS:



"Stress is an alteration of homeostasis as a consequence of external or internal threats. Indeed, acute stressors elicit immediate and protracted neuroendocrine responses with protective effects. These responses involve the activation of the sympathetic nervous system and the HPA axis. Within seconds of stress exposure, noradrenaline and adrenaline are released through sympathetic postganglionic neurons and adrenal gland chromaffin cells contributing to fight-or-escape protective responses. In parallel, the HPA axis is activated through CRH release from the hypothalamus, which leads to ACTH release from the pituitary gland. ACTH in the general blood stream reaches adrenal glands that pour glucocorticoids into the blood circulatory system. These corticoids activate glucocorticoid receptors that increase glucose availability and trigger transcriptional changes partly directed to limit inflammation and repair processes that can be postponed.

"The endocannabinoid system present in the HPA axis and the sympathetic nervous system plays a crucial role in regulating stress responses (Figure 3). Early studies showed that repeated THC modified dopamine b-hydroxylase activity in rodent serum, a measure of sympathetic system activation. This effect was different depending on the basal status of exposed subjects revealing a complex modulatory role of the endocannabinoid system: THC alleviated sympathetic activation in naive mice but potentiated this response in rodents subjected to immobilization stress. CB1R controls peripheral and central adrenaline, and noradrenaline release involved in stress-induced memory impairment, and the sympathetic nervous system partly mediates the anxiety-like effects observed after CB1R blockade. In regard to the HPA axis, pharmacological and knockout studies demonstrate that CB1R activity limits hypothalamic CRH release. CB1R is also present in the pituitary gland and adrenal cortex cells, where it restricts ACTH and glucocorticoid release, respectively. On the contrary, glucocorticoids induce fast increases in endocannabinoid synthesis in brain areas that shape the perception of psychological stressors. These regions include areas involved in cognitive processes such as PFC and hippocampus, and areas related with affective responses such as the amygdala. Glucocorticoids released after acute stressors activate G-protein membrane receptors in the BLA, promoting a rapid increase in retrograde 2-AG signaling that leads to suppression of GABAergic synaptic inputs onto BLA principal neurons, inducing fast increases in anxiety-like behavior. These limbic areas are further connected with the hypothalamus to modulate stress responses (Figure 3). CB1R located in these structures represent a unique opportunity for pharmacological modulation. However, the use of exogenous CB1R ligands has been associated with serious health problems, from THC effects promoting addictive behaviors and anxiety disorders to the psychiatric alterations (anxiety, depression, or suicidal behaviors) related to the CB1R inverse agonist rimonabant. Therefore, a great deal of research has focused on the pharmacological modulation of endogenous cannabinoids as an alternative approach for the treatment of stress-induced alterations. In this context, the enzymes involved in the synthesis and degradation of endocannabinoids represent potential effective targets with possible better safety profiles than drugs directly acting on CB1R."

And

"Local CB1R activity has also been associated with anxiogenesis in certain circuits. Thus, the amygdala sends CB1R -positive projections to the bed nucleus of the stria terminalis (BNST), a brain region closely involved in anxiety. This area is connected with midbrain structures, including the ventral tegmental area and the locus coeruleus. Glutamatergic and GABAergic projections from the amygdala to BNST are each sufficient for the development of anxious responses to unpredictable stimuli. CB1R activity in these projections seems essential for the shift from phasic to sustained fear responses in fear conditioning chambers, interpreted as a reminiscence of the human anxiety against unpredictable threats. In the context of an established anxiogenic response, blocking cannabinoid activity in the BNST facilitates the transition from persistent to phasic freezing responses, a switch that could allow earlier reinstatement of normal anxious behavior."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605023/ [2942]

New data keeps pouring in on THC and it all tends to support the notion that THC is a fear-reducing substance. More precisely, one which inhibits the system by which learned fear is retained. Reporting the "Influence of Δ9-tetrahydrocannabinol on long-term neural correlates of threat extinction memory retention in humans" (2019) Hammoud et al say:

"...our results are the first to examine the long-term impact of a single dose administration of THC on the functional activation of the threat extinction network. Our findings show a significant effect on the functional connectivity of threat-detection network that emerged after a week from engagement. These data highlight the need to further investigate the long-term influence of THC on threat and anxiety circuitry. Specifically, THC, or compounds with comparable impact on CB1 receptors (e.g., cannabidiol) could be used as adjuncts to extinction-based therapies for PTSD and anxiety disorders. This is especially relevant to PTSD treatment given that threat extinction learning and extinction memory retention has been shown to be deficient in PTSD patients. Moreover, the neural correlates related to PTSD psychopathology are comparable to those engaged by THC in the present study."
https://www.nature.com/articles/s41386-019-0416-6.pdf [150]

Among a series of studies of fear extinction involving Irit Akirev [3987], is "Neuropeptide Y and cannabinoids interaction in the amygdala after exposure to shock and reminders model of PTSD" from Mayman et al (2020):

"Modulation of cannabinoid and neuropeptide Y (NPY) receptors may offer therapeutic benefits for post-traumatic stress disorder (PTSD). In this study, we aimed to investigate the functional interaction between these systems in the basolateral amygdala (BLA) in a rat model of PTSD.

"Rats were exposed to the shock and reminders model of PTSD and tested for hyper arousal/PTSD- and depression-like behaviors 3 weeks later. Immediately after shock exposure rats were microinjected into the BLA with URB597, a selective inhibitor of fatty acid amide hydrolase (FAAH) that increases the levels of the endocannabinoid anandamide or with the NPY1 receptor agonist Leu31,Pro34-NPY (Leu).

"Intra-BLA URB597 prevented the shock/reminders-induced PTSD- behaviors (extinction, startle) and depression-behaviors (despair, social impairments). These preventing effects of URB597 on PTSD- and depression-like behaviors were shown to be mostly mediated by cannabinoid CB1 and NPY1 receptors, as they were blocked when URB597 was co-administered with a low dose of a CB1 or NPY1 receptor antagonist. Similarly, intra-BLA Leu prevented development of all the behaviors. Interestingly, a CB1 antagonist prevented the effects of Leu on despair and social behavior, but not the effects on extinction and startle. Moreover, exposure to shock and reminders upregulated CB1 and NPY1 receptors in the BLA and infralimbic prefrontal cortex and this upregulation was restored to normal with intra-BLA URB597 or Leu.

"The findings suggest that the functional interaction between the eCB and NPY1 systems is complex and provide a rationale for exploring novel therapeutic strategies that target the cannabinoid and NPY systems for stress-related diseases."
https://www.sciencedirect.com/science/article/abs/pii/S0028390819303661 [3989]

In 2025, 100 years since General Smuts got his way at the Opium Convention, Xue et al were happy to reveal "An Amygdala-hippocampus Circuit for Endocannabinoid Modulation of Anxiety Avoidance":

"Recent studies indicate a therapeutic potential of increased brain endocannabinoids (eCBs) in anxiety disorders, but the underlying brain circuits are still elusive. Here, it is observed that optogenetic inhibition and activation of anterior basolateral amygdala (aBLA) - ventral hippocampus (vHPC) glutamatergic projections respectively decrease and increase anxiety avoidance behaviors. Then, the contributions of eCBs in aBLA–vHPC projections to anxiety avoidance are investigated by employing three newly developed synapse- and circuit-specific eCB-targeted viral strategies to achieve real-time monitoring of eCB release, in vivo optogenetic activation of CB1 receptors, and CRISPR-Cas9 gene knockdown of eCB biosynthesis enzymes. Prominent eCB release are surprisingly found at aBLA–vHPC glutamatergic synapses during anxiety avoidance, suggesting inhibitory effects of increased eCBs in aBLA–vHPC projections on anxiety avoidance. This idea is further supported by findings that specific activation of CB1 receptors at aBLA–vHPC synapses inhibit presynaptic glutamate release and reduce anxiety avoidance. In contrast, specific knockdown of eCB biosynthesis enzymes at aBLA–vHPC synapses reduce eCB levels at aBLA–vHPC glutamatergic synapses and increase anxiety avoidance. Additionally, inhibition of aBLA-innervated vHPC glutamatergic neurons alleviates anxiety avoidance. Together, these findings reveal counteracting effects of increased eCB signaling in aBLA–vHPC circuits on anxiety avoidance."
https://advanced.onlinelibrary.wiley.com/doi/pdfdirect/10.1002/advs.202505121 [5521]

Nobuo Masataka (2025) frightened some naive cats with fake thunderstorms. CBD helped:

"In humans, cannabidiol (CBD), the primary non-addictive component of cannabis, is known to possess considerable therapeutic potential. The purpose of this study was to investigate the effects of CBD administration on reducing sound-induced fear in healthy domestic cats in a laboratory model of thunderstorm simulation. A total of 40 cats, each naïve to the current testing, were randomly assigned into either of two administration groups (CBD and placebo). Each group was then exposed to the thunderstorm test twice; once at the beginning of the administration (the administration of CBD at 4.0 mg/kg/day over a 2-week-period or the administration of the same amount of sunflower oil as a placebo) and once after the end of the administration. When undesirable urination was observed, occurrences of this behaviour were found to decrease significantly when CBD was administered. However, no such changes were recorded when the placebo was administered. These results indicate that CBD could be an effective option for the treatment of noise-induced fear."
https://www.mdpi.com/2076-2615/15/11/1642 [5341]

For "Cannabidiol Treatment in a Predator-Based Animal Model of PTSD: Assessing Oxidative Stress and Memory Performance" Jîtcă et al (2025) found:

"CBD exhibited a tendency to reduce anxiety, a common symptom of PTSD, although this effect was not statistically significant. However, it demonstrated protective effects on memory, as evidenced by the MWM test. Likewise, CBD also showed a reduction in MDA levels, which implies that an improvement in PTSD symptomatology may also target a reduction in oxidative stress. Since there are several models used to induce PTSD, we cannot consider that one is better than the other, because each brings an advantage, which allows us to create a picture of the mechanisms involved in the occurrence of PTSD and how the symptoms can be improved. An important direction of this topic could be the investigation of the molecular mechanisms by which CBD influences PTSD symptoms, including the analysis of the expression of genes and proteins involved in the stress response, neuroinflammation and neuroplasticity (BDNF) and inflammatory markers (IL-6, TNF-α) in order to provide additional information about the mode of action of CBD."
https://www.mdpi.com/1422-0067/26/10/4491/pdf?version=1746705743 [5034]

Then there was Sultan et al (2025) "Controlled Inhalation of Tetrahydrocannabinol-Predominant Cannabis Flos Mitigates Severity of Post-Traumatic Stress Disorder Symptoms and Improves Quality of Sleep and General Mood in Cannabis-Experienced UK Civilians: A Real-World, Observational Study". Beginning with the observation that "Approximately 4% of the UK population experiences PTSD", this study of 58 victims is outlined in Figure 1, showing improvements in global PTSD score, intrusion, avoidance, cognition and mood, and hyperreactivity/hyperarousal:


https://karger.com/mca/article-pdf/7/1/149/4282163/000540978.pdf [5106]

"Endocannabinoids inhibit contextual fear memory generalization via hippocampal GABAergic synaptic transmission" report Ge et al (2025):

"Memory generalization allows an organism to adapt to new conditions, but overgeneralization of fear or traumatic experiences can be detrimental to survival and contributes to the development of various mental disorders. However, the cellular and molecular mechanisms underlying fear memory generalization, especially in the hippocampus, remain largely unknown. In this study, utilizing a well-established mouse model of fear memory generalization, we investigated the role of endocannabinoids (eCBs)-mediated GABAergic synaptic inputs to hippocampal pyramidal neurons in regulating contextual fear memory generalization. Our results revealed that pharmacological or genetic blockade of CB1R in hippocampal CA1 resulted in overgeneralization of contextual fear memory but not fear memory expression. Subsequent investigations in conditional knockout mice revealed the involvement of CB1R in GABAergic neurons, but not those in glutamatergic neurons or astrocytes, in this overgeneralization. In addition, activation of GABAA receptors on pyramidal neurons was required for inducing overgeneralization via AM281, a CB1R antagonist. Neural mechanistic studies showed that eCBs/CB1R signaling regulates both the activity and plasticity of inhibitory synapses during generalization, highlighting the prominence of the disinhibition of CB1R in interneurons during this process. Subsequently, we delved into the downstream effects and found that eCB-dependent long-term potentiation (LTP) in CA1 pyramidal neurons was regulated by the aforementioned mechanisms. Our findings illustrate that the eCBs/CB1R signaling pathway modulates the balance between fear memory discrimination and generalization by controlling inhibitory inputs to hippocampal pyramidal neurons, accompanied by alterations in excitatory plasticity within this region."
https://www.pnas.org/doi/10.1073/pnas.2423974122 [5254]

"Medical Cannabis Improved PTSD Symptoms, Anxiety, and Quality of Life Over an 18-Month Period" say Datta et al (2025):

"In 269 patients, significant improvements in PTSD symptoms, anxiety, sleep quality, and HRQoL were observed at all follow-up points (p < 0.001). On multivariate logistic regression, male gender (OR = 0.51; 95% CI:0.28–0.94; p = 0.034) was associated with a reduced chance of reporting improvements in IES-R. Adverse events were reported by 70 (26.02%) patients, with insomnia (n = 42, 15.61%) and fatigue (n = 40, 14.87%) being the most common."

Nevertheless sleep quality scale (SQS) improved significantly, along with nearly all other parameters: avoidance, intrusions, hyperarousal, self-care, usual activities, pain and discomfort, anxiety and depression, generalized anxiety disorder‐7 (GAD-7), patient global impression of change (PGIC) and impact of event scale – revised (IES-R) total score at all follow-up points: 1, 3, 6, 12 and 18 months.

https://www.tandfonline.com/doi/full/10.1080/14737175.2025.2490539#d1e649 [5179]

Diurnal variations in endocannabinoids
https://pubmed.ncbi.nlm.nih.gov/31610409/ [53]

Shows daily variation in endocannabinoids, the effect of circadian rhythms, on AEA, 2-AG and congeners OEA and PEA.

"Congeners of AEA, the structural analogs oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) were simultaneously assayed. Prior to 24-h blood sampling, each participant was exposed to two nights of normal (8.5 h) or restricted sleep (4.5 h). The two sleep conditions were separated by at least one month. In both sleep conditions, during the period of blood sampling, each individual ate the same high-carbohydrate meal at 0900, 1400, and 1900.

"Results: Mean 24-h concentrations of AEA were 0.697 ± 0.11 pmol/ml. A reproducible biphasic 24-h profile of AEA was observed with a first peak occurring during early sleep (0200) and a second peak in the mid-afternoon (1500) while a nadir was detected in the mid-morning (1000). The 24-h profiles for both OEA and PEA followed a similar pattern to that observed for AEA. AEA, OEA, and PEA levels were not affected by sleep restriction at any time of day, contrasting with the elevation of early afternoon levels previously observed for 2-AG.

"Conclusions: The 24-h rhythm of AEA is markedly different from that of 2-AG, being of lesser amplitude and biphasic, rather than monophasic. These observations suggest distinct regulatory pathways of the two eCB and indicate that time of day needs to be carefully controlled in studies attempting to delineate their relative roles. Moreover, unlike 2-AG, AEA is not altered by sleep restriction, suggesting that physiological perturbations may affect AEA and 2-AG differently. Similar 24-h profiles were observed for OEA and PEA following normal and restricted sleep, further corroborating the validity of the wave-shape and lack of response to sleep loss observed for the AEA profile. Therapeutic approaches involving agonism or antagonism of peripheral eCB signaling will likely need to be tailored according to time of day."

These two papers tell us that a) reduced EC is a reliable marker of PTSD; b) more AEA correlates with less symptoms of PTSD; c) AEA behaves differently in its diurnal behaviour; and d) any perceived need for exogenous supplementation of EC is likely to be time of day dependent.

"In a study of the effects of THC on fear extinction, Compared to subjects who received placebo, participants who received THC showed increased vmPFC and HIPP activation to a previously extinguished conditioned stimulus (CS+E) during extinction memory recall."
https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC3960373&blobtype=pdf [146]

Another study using MRI and a well-established threat-processing paradigm found that low doses of ∆9-tetrahydrocannabinol (THC) can produce anxiolytic effects, reduce threat-related amygdala activation, and enhance functional coupling between the amygdala and medial prefrontal cortex and adjacent rostral cingulate cortex (mPFC/rACC) during threat processing in healthy adults. https://pubmed.ncbi.nlm.nih.gov/32162103/ [147]

Recognising the cannabis (but not its illegality) sometimes produces anxiety, in 2015 Komaki et al of the Neurophysiology Research Center, Hamadan University of Medical Sciences, Iran, evaluated anxiety and CB1 effects:

"Previous studies have shown that [the] cannabinoidergic system is involved in anxiety. However, there are controversial reports in the experimental studies. The aim of this study is to evaluate the effect of pharmacological stimulation or blocking of CB1 receptors and inhibition of endocannabinoid degradation in anxiety like behavior in elevated plus-maze (EPM) test in rat. The EPM is one of the most widely used animal models of anxiety.

"Male Wistar rats were randomly allocated to ten groups. Different groups of animals intraperitoneally received Win-55212 (0.3, 1 and 5 mg/kg) as CB1 receptor agonist, AM-251 (0.3, 1 and 5 mg/kg) as CB1 receptor antagonist, URB-597 (0.03, 0.1 and 0.3 mg/kg) as endocannabinoid breakdown inhibitor or saline (as control group) 30 min before submitting into EPM test.

"The results showed that compared to the control group, Win-55212 (1 and 5 mg/kg) and URB-597 (0.1 and 0.3 mg/kg) significantly increased both of the time and percentage of entries into open arms. AM-251 (1 and 5 mg/kg) significantly decreased the time and percentage of entries into open arms in the EPM test. These substances have no effects on the total distance covered by animals and number of closed arm entries.

"It is concluded that activation of cannabinoid receptor exert anxiolytic effect while blocking of cannabinoid receptor resulted in anxiety behavior. The locomotor activity was not significantly changed by cannabinoid system. It is suggested that potentiation of cannabinoid system may be therapeutic strategy for the anxiety behavior."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4656987/ [2108]

In 2010 El-Alfy et al at the University of Mississippi had tried some different anxiety tests:

"The antidepressant action of cannabis as well as the interaction between antidepressants and the endocannabinoid system has been reported. This study was conducted to assess the antidepressant-like activity of Δ9-THC and other cannabinoids. Cannabinoids were initially evaluated in the mouse tetrad assay to determine doses that do not induce hypothermia or catalepsy [a neurological finding of prolonged muscular rigidity and immobility with decreased response to external stimuli and reduced sensitivity to pain]. The automated mouse forced swim (FST) and tail suspension (TST) tests were used to determine antidepressant action. At doses lacking hypothermic and cataleptic effects (1.25, 2.5, and 5 mg/kg, i.p.), both Δ9-THC and Δ8-THC showed a U-shaped dose response with only Δ9-THC showing significant antidepressant-like effects at 2.5 mg/kg (p < 0.05) in the FST. The cannabinoids cannabigerol (CBG) and cannabinol (CBN) did not produce antidepressant-like actions up to 80 mg/kg in the mouse FST, while cannabichromene (CBC) and cannabidiol (CBD) exhibited significant effect at 20 and 200 mg/kg, respectively (p < 0.01). The antidepressant-like action of Δ9-THC and CBC was further confirmed in the TST. Δ9 -THC exhibited the same U-shaped dose response with significant antidepressant-like action at 2.5 mg/kg (p < 0.05) while CBC resulted in a significant dose dependent decrease in immobility at 40 and 80 mg/kg doses (p < 0.01). Results of this study show that Δ9-THC and other cannabinoids exert antidepressant-like actions, and thus may contribute to the overall mood-elevating properties of cannabis."
https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC2866040&blobtype=pdf [2109]

Akirav (2013) summarised the resilience-promoting properties of cannabinoids thus:

"Glucocorticoid and endocannabinoid systems cross-talk after stress.
Exogenous cannabinoid agonists decrease HPA axis activity after stress.
Stress and glucocorticoids modulate endocannabinoid levels in limbic areas.
Cannabinoid receptor agonists ameliorate the effects of stress on emotional memory.
Cannabinoids decrease HPA axis activity in the amygdala via the GABAergic system."

She proposed the involvement of the amygdala:

"Enhancing cannabinoids signaling using exogenous CB1 receptor agonists prevent the effects of acute stress on emotional memory. I propose a model suggesting that the ameliorating effects of exogenously administered cannabinoids on emotional learning after acute stress are mediated by the decrease in the activity of the HPA axis via GABAergic mechanisms in the amygdala."

... which we shall see was later confirmed below.
https://www.sciencedirect.com/science/article/abs/pii/S0149763413001929?via%3Dihub [3986]

On "Neuroplasticity in Posttraumatic Stress Disorder" López-López and Crespo (2025) (machine translated from Spanish) tell us:

"Resilience, understood as the dynamic adaptation following trauma, is a determining factor in the vulnerability to develop PTSD that may be associated with myelination. It has been described that contextual fear memory, like other memories, requires the generation of new myelin; therefore, the use of promyelinating drugs such as clemastine fumarate in mice improves remote memory recall and favors fear generalization. In war veterans with and without PTSD, estimating the degree of myelination through T1/T2-weighted magnetic resonance imaging, a positive correlation has been observed between the total index of the Clinician-Administered PTSD Scale (CAPS) and myelination in the hippocampus. Furthermore, this same correlation is observed regarding the severity of depressive symptoms.

"A recent translational study focusing on the hippocampus, amygdala and corpus callosum described similar results in rats and humans. In rodents, analysis of myelination in the gray matter of the hippocampal dentate gyrus shows a positive correlation between oligodendrocyte density and myelin basic protein, a protein that is translated only in mature myelinating oligodendrocytes, and the avoidance and anxiety phenotype, while in the amygdala and cornu ammonis (CA) regions of the hippocampus this positive correlation occurs with contextual fear learning. This corroborates data from a previous study using this same protein, together with specific oligodendrocytes of the hippocampal dentate gyrus, showing that they are associated with hypervigilance, avoidance and escape in the face of stress from two weeks after its onset."
https://pmc-ncbi-nlm-nih-gov.translate.goog/articles/PMC12326437/?_x_tr_sl=auto&_x_tr_tl=en&_x_tr_hl=sl [5246]

Zhu et al (2025) add that:

"The bed nucleus of stria terminalis (BNST) acts as a crucial hub for assessing vigilant threats, with the oval subnucleus (ovBNST) being enriched in endocannabinoid ligands and receptors. The endocannabinoid system (ECS) is well recognized for its role in stress responses. However, the molecular and circuitry mechanisms through which the ovBNST ECS mediates chronic stress induced depressive phenotypes remain unclear.

"Methods and results: The chronic unpredictable mild stress (CUMS) was optimized to model the depression-like behaviors and body weight loss in mice. By utilizing the endocannabinoid sensor, an increased release of endocannabinoid in the ovBNST was probed in response to acute stress. Local blockage of ovBNST cannabinoid type 1 receptor (CB1R) with NESS0327 induced both anhedonia and despair depressive phenotypes in naïve mice. In contrast, intra-ovBNST infusion of either CB1R agonist or cannabinoid hydrolase inhibitor JZL-184 ameliorated despair-like behaviors while merely changed anhedonia in CUMS mice. By combining viral tracing with RNAscope and western blotting, the reduction in CB1R transcriptional and translational level was found to be associated with the CUMS induced depressive disorders. This reduction may be attributed to the changes in ovBNST located presynaptic CB1R that originates from the medial prefrontal cortex (mPFC).

"Discussion: Overall, these results suggest that chronic stress may restructure the ovBNST ECS to result in depressive phenotypes. This study may extend the comprehension of ECS in the ovBNST, specifically its role in modulating the pathogenesis of depressive disorders induced by chronic stress."
https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2025.1629351/full [5271]

According to Forsythe and Boileau in "Use of cannabinoids for the treatment of patients with post-traumatic stress disorder" (2021):

"Numerous treatment options have been developed for the disorder, including psychotherapeutic approaches such as exposure therapy, virtual reality therapy, cognitive behavioral therapies and eye movement desensitization and reprocessing. Around 40–70% of individuals receiving these treatments briefly have noticed significant improvement in symptoms and extinction of the learned fear. Not all individuals are ideal candidates for these treatments, however. High rates of suicidality, dissociation, destructive impulsivity, and chaotic life problems are indications that the patients may not respond well to treatment, causing clinicians to become more likely to forgo attempting these therapies. This exposes a need for developing other therapy options."
https://www.degruyter.com/document/doi/10.1515/jbcpp-2020-0279/html [3546]

"SSRIs have long been considered first-line pharmacological treatment for PTSD; however, only about 60% of patients respond to it with only 20–30% reaching full remission. The most promising agents to aid in the process of improving PTSD symptoms were found to target receptors such as the N-methyl-D-aspartic acid (NMDA) receptor, the receptors targeted by 3,4-methylenedioxyN-methylamphetamine (MDMA), such as the 5HT2 receptor, and the endocannabinoid CB1 receptor."

Ten studies THC, CBD or synthetic cannabinoids are summarised in Table 1.

"A common, and expected, limitation of these studies is small sample size."
https://www.degruyter.com/document/doi/10.1515/jbcpp-2020-0279/pdf [297]

As Rabinak et al (2020) reported in "Cannabinoid modulation of corticolimbic activation to threat in trauma-exposed adults: a preliminary study":

"In adults with PTSD, THC lowered threat-related amygdala reactivity, increased mPFC activation during threat, and increased mPFC-amygdala functional coupling." said Wayne State University Detroit researchers Rabinak et al in "Cannabinoid modulation of corticolimbic activation to threat in trauma-exposed adults: a preliminary study" (2020). "During fMRI scanning, participants completed an emotional face processing task developed by Hariri and colleagues (Hariri et al. 2002) that has been shown to reliably elicit threat-related amygdala responses."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244361/ [4558]

"In adults with PTSD, THC lowered threat-related amygdala reactivity, increased mPFC activation during threat, and increased mPFC-amygdala functional coupling." said Wayne State University Detroit researchers Rabinak et al in "Cannabinoid modulation of corticolimbic activation to threat in trauma-exposed adults: a preliminary study" (2020). "During fMRI scanning, participants completed an emotional face processing task developed by Hariri and colleagues (Hariri et al. 2002) that has been shown to reliably elicit threat-related amygdala responses."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244361/ [4558]

In 2019, Lake et al of the British Columbia Centre on Substance Use asked "Does cannabis use modify the effect of post-traumatic stress disorder on severe depression and suicidal ideation? Evidence from a population-based cross-sectional study of Canadians". And the answer was yes.

"Among 24,089 eligible respondents, 420 (1.7%) reported a current clinical diagnosis of post-traumatic stress disorder. In total, 106 (28.2%) people with post-traumatic stress disorder reported past-year cannabis use, compared to 11.2% of those without post-traumatic stress disorder (p < 0.001). In multivariable analyses, post-traumatic stress disorder was significantly associated with recent major depressive episode (adjusted odds ratio = 7.18, 95% confidence interval: 4.32–11.91) and suicidal ideation (adjusted odds ratio = 4.76, 95% confidence interval: 2.39–9.47) among cannabis non-users. post-traumatic stress disorder was not associated with either outcome among cannabis-using respondents (both p > 0.05)."
https://journals.sagepub.com/doi/abs/10.1177/0269881119882806 [4560]

Nacasch et al (2022) targeted the endocannabinoid system in treatment-resistant combat PTSD:

"In this retrospective naturalistic study, we followed 14 relatively mature (32-68 years of age), treatment-resistant, chronic combat post-traumatic patients who remained severely symptomatic despite treatment with many lines of conventional treatment prior to receiving medicinal cannabis. Our findings show that total sleep score, subjective sleep quality, and sleep duration significantly improved (p < 0.01). Total PTSD symptom score and its subdomains (intrusiveness, avoidance, and alertness) showed improvement (p < 0.05). However, there was no improvement in the frequency of nightmares (p = 0.27). The mean follow-up time was 1.1 ± 0.8 years (range of 0.5 to 3 years)."
https://www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2022.1014630/full [4559]

In "Self-reported Medicinal Cannabis Use as an Alternative to Prescription and Over-the-counter Medication Use Among US Military Veterans" (2023) McNabb et al examined a mostly RML-friendly Massachusetts-based cohort of ex-armed forces personnel, reporting in Clinical Therapeutics.

"A total of 510 veterans of US military service participated in the survey, which was administered between March 3 and December 31, 2019. The participants reported experiencing a variety of mental and other physical health conditions. Primary health conditions reported included chronic pain (196; 38%), PTSD (131; 26%), anxiety (47; 9%), and depression (26; 5%). Most participants (343; 67%) reported using cannabis daily. Many reported using cannabis to reduce the use of over-the-counter medications (151; 30%) including antidepressants (130; 25%), anti-inflammatories (89; 17%), and other prescription medications. Additionally, 463 veterans (91% of respondents) reported that medical cannabis helped them to experience a greater quality of life and 105 (21%) reported using fewer opioids as a result of their medical cannabis use. Veterans who were Black, who were female, who served in active combat, and who were living with chronic pain were more likely to report a desire to reduce the number of prescription medications they were taking (odds ratios = 2.92, 2.29, 1.79, and 2.30, respectively). Women and individuals who used cannabis daily were more likely to report active use of cannabis to reduce prescription medication use (odds ratios = 3.05 and 2.26)."
https://www.clinicaltherapeutics.com/article/S0149-2918(23)00133-9/fulltext [2859]

Another survey of 52 veterans, all with chronic pain, found that cannabis was the most frequently used natural products, followed by magnesium and turmeric (or curcumin) and vitamins.

https://escholarship.org/content/qt4896q9pd/qt4896q9pd_noSplash_62d21e2a7124ce26aee1df003cbcfb0f.pdf?t=ssqyzq [4841]

In the USA Bonn-Miller et al (2022)

"...assessed PTSD symptoms and functioning every 3 months over the course of a year in two samples of participants diagnosed with PTSD: (1) those with PTSD using dispensary-obtained cannabis (cannabis users) and (2) those with PTSD, who do not use cannabis (controls). Linear mixed-effects models and generalized estimating equations tested whether trajectories of symptoms differed between the two subsamples.

"Results: A total of 150 participants (mean [standard deviation] age, 50.67 [15.26] years; 73% male) were enrolled in the study. Over the course of 1 year, the cannabis users reported a greater decrease in PTSD symptom severity over time compared to controls [group×time interaction=−0.32 (95% confidence interval [CI]=−0.59 to −0.05, R2=0.13; t=−2.35, p=0.02). Participants who used cannabis were 2.57 times more likely to no longer meet DSM-5 criteria for PTSD at the end of the study observation period compared to participants who did not use cannabis (95% CI=1.12–6.07; p=0.03)."

and

"Adjusting for age and veteran status, cannabis users showed a significantly greater rate of decline for hyperarousal symptoms compared to controls."



https://www.ptsd.va.gov/professional/articles/article-pdf/id1563675.pdf [2104]

In Israel, Nasach et al examined "Medical cannabis for treatment-resistant combat PTSD" (2023).

"In this retrospective naturalistic study, we followed 14 relatively mature (32-68 years of age), treatment-resistant, chronic combat post-traumatic patients who remained severely symptomatic despite treatment with many lines of conventional treatment prior to receiving medicinal cannabis. Our findings show that total sleep score, subjective sleep quality, and sleep duration significantly improved (p < 0.01). Total PTSD symptom score and its subdomains (intrusiveness, avoidance, and alertness) showed improvement (p < 0.05). However, there was no improvement in the frequency of nightmares (p = 0.27). The mean follow-up time was 1.1 ± 0.8 years (range of 0.5 to 3 years)."

 
https://www.frontiersin.org/articles/10.3389/fpsyt.2022.1014630 [2359]

McNabb et al examined "Self-reported Medicinal Cannabis Use as an Alternative to Prescription and Over-the-counter Medication Use Among US Military Veterans" (2023):

"A total of 510 veterans of US military service participated in the survey, which was administered between March 3 and December 31, 2019. The participants reported experiencing a variety of mental and other physical health conditions. Primary health conditions reported included chronic pain (196; 38%), PTSD (131; 26%), anxiety (47; 9%), and depression (26; 5%). Most participants (343; 67%) reported using cannabis daily. Many reported using cannabis to reduce the use of over-the-counter medications (151; 30%) including antidepressants (130; 25%), anti-inflammatories (89; 17%), and other prescription medications. Additionally, 463 veterans (91% of respondents) reported that medical cannabis helped them to experience a greater quality of life and 105 (21%) reported using fewer opioids as a result of their medical cannabis use. Veterans who were Black, who were female, who served in active combat, and who were living with chronic pain were more likely to report a desire to reduce the number of prescription medications they were taking (odds ratios = 2.92, 2.29, 1.79, and 2.30, respectively). Women and individuals who used cannabis daily were more likely to report active use of cannabis to reduce prescription medication use (odds ratios = 3.05 and 2.26)."

and

In line with previous research and VA statistics, the participants in this study experienced several mental and other physical health concerns. Many reported experiences with PTSD, exposure to occupational environmental hazards (eg, agent orange, asbestos, burn pits), chronic pain, anxiety, and depression, among other conditions. Study findings also revealed that participants' cannabis use positively affected the treatment or management of several health conditions and symptoms. Many of the respondents reported that medicinal cannabis treatment helped them to experience a greater quality of life, fewer psychological symptoms, fewer physical symptoms, and to use less alcohol, fewer medications, less tobacco, and fewer opioids.
https://www.clinicaltherapeutics.com/article/S0149-2918(23)00133-9/fulltext#seccesectitle0001 [2823]

According to Lynskey et al (2024):

"Background
Cannabis-based medicinal products (CBMPs) are increasingly being used to treat post-traumatic stress disorder (PTSD), despite limited evidence of their efficacy. PTSD is often comorbid with major depression, and little is known about whether comorbid depression alters the effectiveness of CBMPs.

"Aims
To document the prevalence of depression among individuals seeking CBMPs to treat PTSD and to examine whether the effectiveness of CBMPs varies by depression status.

"Method
Data were available for 238 people with PTSD seeking CBMP treatment (5.9% of the treatment-seeking sample) and 3-month follow-up data were available for 116 of these. Self-reported PTSD symptoms were assessed at treatment entry and at 3-month follow-up using the PTSD Checklist – Civilian Version (PCL-C). The probable presence of comorbid depression at treatment entry was assessed using the nine-item Patient Health Questionnaire (PHQ-9). Additional data included sociodemographic characteristics and self-reported quality of life.

"Results
In total, 77% met screening criteria for depression, which was associated with higher levels of PTSD symptomatology (mean 67.8 v. 48.4, F(1,236) = 118.5, P < 0.001) and poorer general health, quality of life and sleep. PTSD symptomatology reduced substantially 3 months after commencing treatment (mean 58.0 v. 47.0, F(1,112) = 14.5, P < 0.001), with a significant interaction (F(1,112) = 6.2, P < 0.05) indicating greater improvement in those with depression (mean difference 15.3) than in those without (mean difference 7).

"Conclusions
Depression is common among individuals seeking CBMPs to treat PTSD and is associated with greater symptom severity and poorer quality of life. Effectiveness of CBMPs for treating PTSD does not appear to be impaired in people with comorbid depression."
https://www.cambridge.org/core/journals/bjpsych-open/article/medicinal-cannabis-for-treating-posttraumatic-stress-disorder-and-comorbid-depression-realworld-evidence/F88B15F3E00576E757ADF4915F9874A6 [4483]

In a larger study "Suicidal Ideation in Medicinal Cannabis Patients: A 12-Month Prospective Study" (2024) the objective of Lynskey et al was...

"Objective
To document the prevalence and correlates of suicidal ideation (SI) among individuals seeking cannabis-based medicinal products (CBMPs); to test whether SI declines or intensifies after three months of CBMP treatment and to document 12-month trajectories of depression in those reporting SI and other patients.

"Method
Observational data were available for 3781 patients at entry to treatment, 2112 at three months and 777 for 12 months. Self-reported depressed mood and SI were assessed using items from the PHQ-9. Additional data included sociodemographic characteristics and self-reported well-being.

"Results
25% of the sample reported SI at treatment entry and those with SI had higher levels of depressed mood (mean = 17.4 vs. 11.3; F(1,3533) = 716.5, p < .001) and disturbed sleep (mean = 13.8 vs. 12.2, F(1,3533) = 125.9, p < .001), poorer general health (mean = 43.6 vs. 52.2, F(1,3533) = 118.3, p < .001) and lower quality of life (mean = 0.44 vs. 0.56 (F(1,3533) = 118.3, p < .001). The prevalence of SI reduced from 23.6% to 17.6% (z = 6.5, p < .001) at 3 months. Twelve-month follow-up indicated a substantial reduction in depressed mood with this reduction being more pronounced in those reporting SI (mean (baseline) = 17.7 vs. mean (12 months) = 10.3) than in other patients (mean (baseline) = 11.1 vs. mean (12 months) = 7.0).

"Conclusions
SI is common among individuals seeking CBMPs to treat a range of chronic conditions and is associated with higher levels of depressed mood and poorer quality of life. Treatment with CBMPs reduced the prevalence and intensity of suicidal ideation."
https://www.tandfonline.com/doi/10.1080/13811118.2024.2356615?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed [3866]

In "Controlled Inhalation of Tetrahydrocannabinol-Predominant Cannabis Flos Mitigates Severity of Post-Traumatic Stress Disorder Symptoms and Improves Quality of Sleep and General Mood in Cannabis-Experienced UK Civilians: A Real-World, Observational Study" from Sultan et al (2024):

"Results from this observational study suggest an association between treatment with THC-predominant cannabis flowers and symptomatic improvement for up to 6 months in a cohort of UK civilians diagnosed with PTSD. The treatment was safe and well tolerated and characterized by marked effects on quality of sleep, general mood, and severity of PTSD-associated symptoms. Despite previous exposure to cannabis, participants continued to report benefits after initiating treatment with THC-predominant cannabis flowers."

https://karger.com/mca/article/7/1/149/912500/Controlled-Inhalation-of-Tetrahydrocannabinol [3858]

In "The Effectiveness and Adverse Events of Cannabidiol and Tetrahydrocannabinol Used in the Treatment of Anxiety Disorders in a PTSD Subpopulation" (2023) from Stack et al of the University of Sydney's School of Pharmacology and Applied Cannabis Research in Sydney, NSW, Australia:

"The median doses taken were 50.0 mg/day for CBD and 4.4 mg/day for THC. The total participant sample reported significantly improved anxiety, depression, fatigue, and ability to take part in social roles and activities. Those who were diagnosed with PTSD (n = 57) reported significantly improved anxiety, depression, fatigue, and social abilities. The most common AEs reported across the whole participant cohort were dry mouth (32.6%), somnolence (31.3%), and fatigue (18.5%), but incidence varied with different cannabis formulations. The inclusion of THC in a formulation was significantly associated with experiencing gastrointestinal AEs; specifically dry mouth and nausea. Conclusions: Formulations of cannabis significantly improved anxiety, depression, fatigue, and the ability to participate in social activities in participants with anxiety disorders. The AEs experienced by participants are consistent with those in other studies."

And of special note:

"Participants who took a THC-dominant formulation reported a significant decrease in their anxiety levels. Those same participants also represented the highest proportion of participants that were classified as having clinical improvement (61.1%, n = 11), compared with participants who were prescribed other formulation types. This was unexpected as the median THC dose for this participant group was 33.8 mg/day, and it has been suggested that doses higher than 30 mg/day could be anxiogenic. A study reported that doses of CBD ranging from 15 to 60 mg/day could offset the anxiogenic properties of THC, which is reflected in our data; however, with lower doses of CBD (median = 6.0 mg/day CBD)."
https://journals.sagepub.com/doi/pdf/10.1177/87551225231180796 [4557]

As assessed by Sultan et al (2024), "Controlled Inhalation of Tetrahydrocannabinol-Predominant Cannabis Flos Mitigates Severity of Post-Traumatic Stress Disorder Symptoms and Improves Quality of Sleep and General Mood in Cannabis-Experienced UK Civilians: A Real-World, Observational Study"

"Participants were asked to complete the PTSD checklist for civilians (PCL-C). The PCL-C is a 17-item self-report measure of the 17 DSM-IV symptoms of PTSD. The PCL-C has a variety of purposes, including screening individuals for PTSD, diagnosing PTSD, and/or monitoring symptom change during and after treatment. The PCL-C asks about symptoms in relation to “stressful experiences” and can be used with any population. The symptoms endorsed may not be specific to just one event, which can be helpful when assessing survivors who have symptoms due to multiple events. Furthermore, the 17 items within the PCL-C can be grouped into the four clusters of symptoms that characterize PTSD: items 1–5 refer to symptoms of intrusion, questions 6 and 7 capture symptoms of avoidance, questions 8–12 correspond to symptoms of altered mood, and finally questions 13–17 report symptoms of altered reactivity. Evidence suggests that a 5–10-point change represents reliable change (i.e., change not due to chance) and a 10–20-point change represents clinically significant change. Therefore, it is recommended to use 5 points as a threshold for determining whether an individual has responded to treatment and 10 points as a threshold for determining whether the improvement is clinically meaningful."

And...

"Fifty-eight patients were included, 34 of which also had PROMs [patient-reported outcome measures] recorded at 6 months. Most were males (65.5%) with an average age of 39.2 years who had previously used cannabis illicitly (95.6%). At 3 months, participants reported significant improvements in overall health, mood, and sleep quality (p < 0.001) but not in the proxy for HRQoL (p = 0.052). Similarly, participants reported substantial benefits in managing intrusion symptoms (p < 0.001), mood alterations (p < 0.001), and reactivity alterations (p = 0.002), which were sustained or further improved at 6 months. Participants did not report any side effects associated with CBMPs."
https://pmc.ncbi.nlm.nih.gov/articles/PMC11521486/ [4906]

Ma et al (2025) looked at "Involvement of endocannabinoid receptor 1 in oxidative and inflammatory responses underlying anxiety-like behavior in SPS&S-exposed mice":

"This study employed the single prolonged stress and shock (SPS&S) model, a validated rodent paradigm of PTSD, to evaluate the expression of key eCB system proteins within the medial preftontal cortex (mPFC), Hip, and Amy – brain regions critically implicated in PTSD pathophysiology (Ressler et al., 2022). Furthermore, using the systemic administration of the CB1 receptor agonist WIN 55,212-2, we investigated the modulation of CB1 receptor activation on oxidative stress products, inflammatory responses and PTSD-related behaviors."

...

"SPS&S exposure induced significant anxiety-like behaviors and increased freezing in fear tests. It decreased CB1 receptor and NAPE-PLD expression while increasing FAAH and MAGL levels in all examined brain regions, alongside elevated IL-1β and caspase-1. Plasma oxidative stress and inflammatory cytokines were also elevated. WIN 55,212-2 administration mitigated anxiety-like behaviors but not conditioned fear responses. Crucially, it normalized the elevated plasma oxidative stress and inflammatory cytokine levels."
https://www.sciencedirect.com/science/article/abs/pii/S0014299925008143?via%3Dihub [5306]

Of THC's endogenous homologue anandamide, Ney and Matthews (2025) say:

"Posttraumatic stress disorder (PTSD) is characterized by profound changes to stress systems and impairments in fear extinction, the process believed to underlie recovery from a traumatic experience. This chapter reviews the contribution of anandamide—an important endocannabinoid—to human and animal stress responding as well as fear conditioning with relevance to PTSD. Anandamide is critical to the activation of the stress response and is differentially expressed following exposure to trauma. It is also critical to the extinction of conditional fear and may present a feasible target for treatment by increasing the capacity for patients to consolidate extinction memories during exposure therapy."
https://www.sciencedirect.com/science/article/abs/pii/B9780443190810000160 [3859]

Mederos et al (2024) elaborate on the role of the ECS in "Overwriting an instinct: visual cortex instructs learning to suppress fear responses":

"Fast instinctive responses to environmental stimuli can be crucial for survival but are not always optimal. Animals can adapt their behavior and suppress instinctive reactions, but the neural pathways mediating such ethologically relevant forms of learning remain unclear. We found that posterolateral higher visual areas (plHVAs) are crucial for learning to suppress escapes from innate visual threats through a top-down pathway to the ventrolateral geniculate nucleus (vLGN). plHVAs are no longer necessary after learning; instead, the learned behavior relies on plasticity within vLGN populations that exert inhibitory control over escape responses. vLGN neurons receiving input from plHVAs enhance their responses to visual threat stimuli during learning through endocannabinoid-mediated long-term suppression of their inhibitory inputs. We thus reveal the detailed circuit, cellular, and synaptic mechanisms underlying experience-dependent suppression of fear responses."

They explain:

"The model exhibited depression of inhibitory synapses onto vLGN neurons that receive input from plHVAs during learning. Such a form of synaptic plasticity, called long-term depression of inhibition (iLTD), has been previously described in multiple brain areas in vitro and is dependent on endocannabinoid (eCB) signaling. Heterosynaptic iLTD can be triggered by activation of group I metabotropic glutamate receptors (mGluR1 or mGluR5) in postsynaptic neurons. This causes release of eCBs which act as retrograde messengers, activating eCB receptors (CB1R) on nearby presynaptic inhibitory terminals which can induce a long-lasting reduction of presynaptic GABA release probability. Allen Institute gene expression data showed that eCB receptor CB1R and mGluR5 are highly expressed in vLGN (Fig. S7A-B). We therefore investigated if eCB-dependent iLTD in vLGN could mediate learned suppression of escape."
https://www.biorxiv.org/content/10.1101/2024.07.31.605567v1.full.pdf [4738]

In "Association of the HTR2A 102T/C polymorphism with attempted suicide: a meta-analysis" Wang et al (2015) concluded:

"Our meta-analysis does not support the previously suggested association between HTR2A 102T/C and attempted suicide in the general population. However, in patients with schizophrenia, the C/C genotype of 5-HT2A receptor 102T/C may increase the risk of attempted suicide."
https://pubmed.ncbi.nlm.nih.gov/26075944/ [4742]

Turiaco et al (2024) ask about the "Genetics of suicide ideation. A role for inflammation and neuroplasticity?" in the European Archives of Psychiatry and Clinical Neuroscience:

"Exposure to suicide or suicide attempts increases the risk of suicidal behavior. One of the strongest clinical predictors of SB is the non-suicidal self-injury. SI and SB are favored by predisposing risk factors such as loneliness, hopelessness, demoralization, economics factors, cultural factors, or social isolation due to belonging to a social minority."

Single-gene theories are now generally debunked.

"SCZ patients with SI have over a six-fold increase of suicide, while people who had at least one lifetime psychotic event has double odds of experiencing SI, triple odds of a future suicide attempt, and four times the odds of dying by suicide. Given those data, the importance of identifying biological and genetic biomarkers emerges. Our study tried to reach this aim using a classic GWAS approach, a molecular pathway analysis and modelling the polygenic risk score with the clinical predictors in a model through machine learning. No SNP alone reached a GWAS significance in identifying the genetic risk for SI."

However...

"B3GALTL gene product codes for a protein that is implicated in synaptogenesis. Quite interestingly, B3GALTL is expressed in the brain by neurons and astrocytes (proteinatlas.org). It is also expressed in T cells. This finding is then of particular relevance: Microglia are the primary immune system cells in the central nervous system, and they function like peripheral macrophages, releasing a multitude of pro-inflammatory cytokines and chemokines. Post-mortem examination of suicide patients shows an increased density of microglia in anterior cingulate cortex, dorsolateral prefrontal cortex, and mediodorsal thalamus regions. An increased microglial activation is identified by PET in patients with SI. Microglial cells affect the tryptophan-kynurenine pathway, increasing the production of neurotoxic metabolites such as quinolinic acid, a NMDA agonist and creating an imbalance in the glutamatergic system. Glutamate neurotransmission is the background of a normal cognitive and emotional processing, so its disruption can lead to increased impulsivity, depressed mood, and suicidality. Consistently with this finding, another important molecule involved in neuroinflammation is the 18-kDa Translocator Protein (TSPO), whose expression was significantly increased in patients with SI, most robustly in the regions of the anterior cingulate cortex. Refer to Table 5, for previous relevant studies about schizophrenia, neuroinflammation and SI."
https://pmc.ncbi.nlm.nih.gov/articles/PMC11422468/ [4743]

Several lines of evidence indicate that abnormalities in the functioning of the central serotonergic system are involved in the pathogenesis of depressive illness and suicidal behavior.

https://pubmed.ncbi.nlm.nih.gov/19224112/ [298]
https://pubmed.ncbi.nlm.nih.gov/29526601/ [299]
https://pubmed.ncbi.nlm.nih.gov/11727894/ [300]

Research does not seek to eliminate environmental influences in favour of genetic disposition in depression, suicidal ideation and completed suicide. But there are only two hypotheses for the high incidence in Slovenia, both of which may be right, namely that some are genetically predisposed to snap when stress is prolonged or reaches a certain level, or that living conditions for some, according to the rules constructed by their own society, are relentlessly sub-optimal.

Slovenia is an ideal candidate for psychedelic therapy. Slovenia ruminates endlessly about the past. Millions of tonnes of CO2 are expended generating hot air about long-dead regimes and ideologies, because they have affected people in this area. But arguing about what Tito wrote about Stalin in 1940 won't bring your dead relatives back or make you happy and strong today. To ignore the past and bury the hatchet seems like a cop-out. But the past is getting in the way of the present, and the future.

"In 1976, a man known as Ka-Tzetnik 135633 (original name: Yehiel De-Nur) underwent LSD-assisted psychotherapy. At the time, he was under the supervision of Prof. Jan Bastiaans at the State University of Leiden in the Netherlands. Bastiaans was the psychiatrist who had first identified concentration camp syndrome, also known as survivor syndrome. This syndrome is a form of what we would now call post-traumatic stress disorder (PTSD). Its characteristics include social withdrawal, sleep disturbance, anxiety, and depression. Bastiaans had also successfully treated this syndrome with LSD-assisted psychotherapy. Ka-Tzetnik 135633 was a survivor of Auschwitz, where he was a prisoner for two years. This trauma was followed by three decades of torment, in which he relived the horror of those two years at night. Through LSD-assisted psychotherapy, however, Ka-Tzetnik 135633 found healing.

"Almost a half century after Bastiaans' successful trials, the regulation of psychedelics for treating PTSD is finally underway. Think of the Holocaust survivors who might have found healing through these medicines, but couldn't because of a politically-motivated ban on psychedelics. This realization brings home the horrific impact of the failed war on drugs.'"
https://realitysandwich.com/psychedelics-and-judaism/ [1092]

Many diagnosed with PTSD are unimpressed by the medical response. Modlin et al (2025) report on self-treatment strategies: cannabis and psychedelics were the two most preferred, with MDMA a close third:

"An online survey recruited individuals with self-reported trauma symptoms or a formal diagnosis of post-traumatic stress disorder (PTSD)/complex post-traumatic stress disorder (CPTSD). Participants were asked about their treatment history, satisfaction with current treatments, and use of illicit substances for symptom management. Further, after receiving psychoeducation on 3,4-methylenedioxymethamphetamine (MDMA) and psilocybin therapies, participants’ perceptions and willingness to participate in these treatments were assessed.

"Results: Of the 873 respondents, 94.8% reported experiencing psychological trauma, with 73.4% diagnosed with PTSD or CPTSD. Many had attempted multiple treatments, predominantly medications and various psychotherapies, but reported high dissatisfaction. Significant rates of marijuana, psychedelics, and MDMA use for self-management of trauma symptoms were reported, with minimal physical and psychological complications. Willingness to try MDMA and psilocybin therapies was high (0.81 and 0.83, respectively). Notably, women and heterosexual individuals showed lower willingness, while younger respondents and those with higher education levels showed greater willingness to try these treatments.

"Conclusion: High willingness to try MDMA and psilocybin therapies among trauma-exposed individuals highlights the need for further research and clinical trials. Understanding demographic variations in willingness can guide the development of accessible and effective treatment options for PTSD and CPTSD. Public education about potential risks and harm reduction strategies is crucial to promote safe and informed use of these emerging therapies."
https://psychiatry-psychopharmacology.com/Content/files/sayilar/142/S3-S19.pdf [5365]

Psychedelics break the rumination cycle by disrupting - in a good way - brain activities which perpetuate habitual thinking and behaviour.

The most abundant 5-HT receptors expressed in the medial prefrontal cortex (mPFC) are 5-HT1AR and 5-HT2AR. The 5-HT2AR pathway is enhanced by 5-HT2AR-agonist psychedelics.
https://pubmed.ncbi.nlm.nih.gov/28858536/ [301]

In mice, given a single dose of psilocybin or LSD, and using the social reward conditioned place preference (sCPP) assay Nardou et al have made an important step forward in understanding the mechanism by which psychedelics can override cultural log-jams retarding progress and societal happiness, such as we see in Slovenia. "Psychedelics reopen the social reward learning critical period" (2023) finds:

"Psychedelics are a broad class of drugs defined by their ability to induce an altered state of consciousness. These drugs have been used for millennia in both spiritual and medicinal contexts, and a number of recent clinical successes have spurred a renewed interest in developing psychedelic therapies. Nevertheless, a unifying mechanism that can account for these shared phenomenological and therapeutic properties remains unknown. Here we demonstrate in mice that the ability to reopen the social reward learning critical period is a shared property across psychedelic drugs. Notably, the time course of critical period reopening is proportional to the duration of acute subjective effects reported in humans. Furthermore, the ability to reinstate social reward learning in adulthood is paralleled by metaplastic restoration of oxytocin-mediated long-term depression in the nucleus accumbens. Finally, identification of differentially expressed genes in the ‘open state’ versus the ‘closed state’ provides evidence that reorganization of the extracellular matrix is a common downstream mechanism underlying psychedelic drug-mediated critical period reopening. Together these results have important implications for the implementation of psychedelics in clinical practice, as well as the design of novel compounds for the treatment of neuropsychiatric disease."
https://www.nature.com/articles/s41586-023-06204-3 [2825]

But we do not need to rely on mice when there are real-life mass traumas going on. A special opportunity came along on 7 October 2023 in the Hamas attack on Supernova. "Trauma Under Psychedelics: MDMA Shows Protective Effects During the Peritraumatic Period" say Netzer et al (2024):

"Traumatic events (TEs) play a causal role in the etiology of psychopathologies such as depression and posttraumatic stress disorder (PTSD). Recent research has highlighted the therapeutic potential of psychoactive substances and especially 3,4-methylenedioxymethamphetamine (MDMA), in alleviating trauma symptoms in chronic patients. However, little is known regarding the consequences of trauma that is acutely experienced under the influence of psychoactive substances. Here we investigated the acute experiences and peritraumatic processing of 657 survivors from the high-casualty terror attack at the Supernova music festival in Israel on October 7th, 2023. Data were collected four to twelve weeks following the TE. Approximately two-thirds of survivors were under the influence of psychoactive substances at the time of the TE, offering a tragic and unique natural experiment on the impact of psychoactive compounds on TE processing. Our findings reveal that individuals who experienced the trauma while under the influence of MDMA demonstrated significantly improved intermediate outcomes compared to those who were under the influence of other substances or no substances at all. Specifically, the MDMA group reported increased feelings of social support, more social interactions and enhanced quality of sleep during the peritraumatic period, yielding reduced levels of mental distress and reduced PTSD symptom severity. These novel findings suggest that the influence of MDMA during the TE may carry protective effects into the peritraumatic period, possibly mediated through the known effects of MDMA in reducing negative emotions and elevating prosociality. These protective effects in turn may mitigate the development of early psychopathology-related symptoms. Current preliminary results underscore the need for further understanding of the cognitive and physiological processes by which psychedelic substances intersect with trauma recovery processes."
https://www.biorxiv.org/content/10.1101/2024.03.28.587237v1 [3174]


With "Facing trauma under the influence of psychedelics: A phenomenological study with Nova rave survivors" psychedelic research found a new angle. Two thirds of the Israeli festivalgoers attacked On 7 October 2023 were under the influence of LSD, mushrooms, ketamine or MDMA, say Simon et al (2025):



"Participants’ awareness and knowledge about their substance use created an 'epistemic container,' which may have facilitated real-time containment of traumatic input while complicating later meaning-making. A neurophenomenological pattern emerged wherein psychedelic subjective effects appeared suppressed during the acute trauma exposure, resurging after the threat was over. Quantitative analysis showed a predominantly positive subjective impact of substance use on immediate survival (75%–79%) and emotional coping (83%–84%) but mixed outcomes in aftermath processing (42%–53% positive and 25%–26% negative).

"Conclusions:
Psychedelic-induced dissociation during trauma exposure may confer acute adaptive benefits while causing integration challenges a paradox with significant implications on trauma research. This singular perspective on the psychedelic–trauma interface invites further research into these complex neuropsychological interactions. Psychedelics may serve as epistemological instruments, revealing cognitive processes and unique prisms through which trauma response, psychopathology, resilience, and the adaptive capacities of the human mind under extreme conditions can be re-examined."

Unfortunately evaded in this "unique interaction between psychedelic states and extreme stress" (a description suggesting the authors have not studied tripping in Lincoln on a Saturday night) was the opportunity to include a control group.

So the chances of comparing survival rates and other parameters between users and non-users have been lost.

With this methodology there was no danger of demonstrating evolutionary advantages of elevated consciousness, although the authors findings suggest exactly this: psychedelics use "seems to have created a distinct form of psychological protection that both aided immediate survival and posed challenges for later integration".

"Optimistic detachment" helped users to cope with the threat and being sharp enabled them to act smart.

How to help never-users understand this? In support of the Defence claim that the ZPPPD as it applies to psychedelics (excluding ketamine and MDMA) is an unconstitutional restriction of evolutionary advantage, the Defendant compares the value of psychedelics amid stressful conditions to the "unconscious competence" of driving a vehicle normally (second-nature behaviour, background-task capable), as opposed to sweating neurotically over every control movement.

As for any increased difficulties in the aftermath, you remember the last book you read, but are unlikely to recall any specific text. You won't have to worry about PTSD recovery later if you are dead. If you have more information to integrate, chances are the result will be more integrated.

Once again, the opportunity to compare recovery patterns between psychedelic and non-users with controls was eluded rather than elucidated in this, perhaps the ultimate survivor-biased study. Perhaps the other third of the festivalgoers couldn't be found.
https://journals.sagepub.com/doi/10.1177/02698811251372508?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed [5651]

As of 2025 no comparison of survival by drug type at Supernova pertains. However, the Court must hear that it is more bad news for any followers of Slovenian culture who find themselves under attack as, following a study by Nacasch et al (2025):

"The team hypothesised that survivors who were on drugs at the time would have been more hyper-aware of the event and their surroundings, thereby experiencing more post/trauma from the attack overall. However, they were wrong."

Unfortunately for Slovenia's majority drug-choosers:

"'It was the alcohol,' [Professor Mark Weiser] told Health Policy Watch. 'These people were the ones who had more severe post-traumatic symptoms.'"
https://healthpolicy-watch.news/study-alcohol-not-psychedelics-linked-to-heightened-trauma-in-survivors-of-attack-on-israeli-festival-goers/ [5652]

Note: this was one of those occasions when alcohol wasn't a "drug".

"Seventy-one of them (57.7%) reported using psychoactive drugs at the festival – 12 only alcohol, nine only lysergic acid (LSD), seven only 3,4-methylenedioxymethamphetamine (MDMA), six only cannabis, three only methylmethcathinone (MMC), 15 various drug combinations including alcohol, and 19 various drug combinations excluding alcohol."

Despite all the harmful illegality adding to the background stress, the pro-alcohol researchers had to admit defeat:

"The multiple regression analysis of the PDEQ [Peritraumatic Dissociative Experiences Questionnaire] dissociation score with VAS-A [Visual Analog Scale for Anxiety], GAD-7 [Generalized Anxiety Disorder-7], PHQ-9 [(Patient Health Questionnaire-9], and PDS-5 [Posttraumatic Diagnostic Scale] subscale scores, including gender and age, was statistically significant (p=0.0001)."

Each of the component scores were also statistically significant except VAS-A. In more great news for the nation's psychiatrists and pharma concerns...

"...in marked contrast to our expectations, we found that only pre-trauma alcohol consumption, with or without other drugs, significantly increased the risk of peri-traumatic dissociation, anxiety,depression, and ASD [acute stress disorder] symptoms."
https://onlinelibrary.wiley.com/doi/pdf/10.1002/wps.21254 [5653]

Another alternative to mice is "Human pluripotent stem cells as a translational toolkit in psychedelic research in vitro". As Salerno and Rehan explain:

"PSCs can differentiate into various brain cell types, mirroring endogenous expression patterns and cell identities to recreate disease phenotypes. Brain organoids derived from PSCs resemble cell diversity and patterning, while region-specific organoids simulate circuit-level phenotypes. PSC-based models hold significant promise to illuminate the cellular and molecular substrates of psychedelic-induced phenotypic recovery in neuropsychiatric disorders."

and

"The identities of the signaling pathways responsible for psychedelics’ hallucinogenic and therapeutic properties and whether these are distinct or overlapping pathways are some of the questions still under debate.

"The Gq or β-arrestin-2 recruitment paradigm represents a glimpse into the extensive network of pathways regulated by 5-HT2AR activation via psychedelics. For example, distinct psychedelics activate phospholipase A2 and phospholipase D via ADP-ribosylation factor 1. The activation of 5-HT2AR, triggered by various agonists including DOI and LSD, can lead to the heterodimerization of the receptor with metabotropic glutamate receptor 2 and dopamine D2 receptor, both of which are Gi-coupled receptors. This transactivation blocks the cAMP’s synthesis by adenylate cyclase and prompts heterotrimeric Gi/o proteins to trigger Src-mediated downstream events.

"A burst of glutamate also follows psychedelic administration, mainly in the cortical layer V of the neocortex, which is a 5-HT2AR-enriched area.8,23 High glutamate levels activate the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), boosting the secretion of brain-derived neurotrophic factor (BDNF), which in turn signals through the tyrosine receptor kinase B (TrkB) and mammalian target of rapamycin (mTOR) pathways, sustaining both the AMPAR activation and BDNF secretion in a positive feedback loop of neural plasticity.

"Furthermore, the hallucinogenic properties of different psychedelics are also proposed to be influenced by other 5-HTRs, and not all 5-HT2AR agonists have hallucinogenic properties. For instance, human studies also provide evidence supporting the involvement of the 5-HT1AR in the effects of psilocybin. Competition binding studies on rodent brains and primary cells revealed a lack of pronounced selectivity of psilocin for 5-HT2AR over 5-HT1AR. Nevertheless, the role of the 5-HT2AR remains the subject of more extensive study and investigation. Ketanserin, a selective antagonist of the 5-HT2Rs, effectively eliminates head-twitch behavioral responses in mice; however, it does not attenuate psilocybin-induced structural modifications in the prefrontal cortex. As a result, uncertainties remain about whether and how the neuroplastic effects on rescuing disease phenotypes relate to behavioral responses, especially in humans. Moreover, human studies investigating the molecular mechanisms of psychedelic-induced plasticity rely on global parameters such as peripheral BDNF levels, which may not correlate with the molecular mechanisms occurring in brain cells. For in-depth cellular and molecular insights into the role of 5-HT2AR, in vitro investigations are required."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11019282/ [3173]

Using PSCs Schmidt et al (2024) of the University of Heidelberg showed that psilocin causes 5-HT2A receptor internalization and redistribution in human cortical neurons, induces BDNF expression and downstream signaling in human neurons in a dose-dependent manner, induces gene expression changes associated with axonal and synaptic plasticity, increases dendritic complexity, and increases synaptic strength and synaptogenesis.
https://www.researchgate.net/publication/381253376_Psilocin_fosters_neuroplasticity_in_iPSC-derived_human_cortical_neurons [3175]

Blest-Hopley et al (2025) found "improved mental health outcomes and normalised spontaneous EEG activity in veterans reporting a history of traumatic brain injuries following participation in a psilocybin retreat":

"This study investigates the effects of psilocybin administered in retreat settings on veterans with a history of TBI, focusing on mental health outcomes and changes in brain connectivity as measured by EEG.

"Methods: A total of 21 participants were recruited through the Heroic Hearts Project, which facilitated access to two six-day psilocybin retreats in Jamaica. Before the retreat, participants underwent three individual and three group coaching sessions to prepare for the experience. During the retreat, two psilocybin ceremonies were held, spaced 48 hours apart. Participants received an initial dose of 1.5g to 3.5g of dried psilocybin mushrooms, with the option to increase the second dose up to 5g. Psilocybin was administered in a tea format, under the supervision of experienced facilitators. Psychological outcomes were assessed using validated questionnaires (PCL-5, PHQ-9, STAI) at baseline (four weeks pre-retreat) and four weeks post-retreat. Electroencephalography (EEG) was used to measure brainwave activity pre- and post-treatment. Paired t-tests were used to analyze changes in psychological scores, while EEG frequency band analysis assessed changes in brain function and connectivity.

"Results: Improvements were observed across several mental health measures: PTSD (PCL-5 scores decreased by 50%, p=0.010), depression (PHQ-9 scores decreased by 65%, p<0.001), and anxiety (STAI) scores decreased by 28%, p<0.001). EEG data showed decreased delta and theta power in frontal and temporal regions, indicating potential improvements in cognitive control and emotional processing. Enhanced coherence in alpha and beta bands suggested improved neural communication."
https://www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2025.1594307/full [5324]



Administration of psychedelics to a relatively small number of people could bring the paralysing stand-off over Slovenia's past to a quick and elegant halt. The participants would see the damage they are doing - to themselves and the country - by perpetuating hostilities against groups and against individuals long dead. They would be able to more accurately gauge the importance of the historical against the challenges of the present and future. They would be less susceptible to fearmongering and superstition. Their nightmares would be put into perspective.

The Slovenians who stand to gain the most from ranting on about the past for political purposes are the least likely to have taken them. Among them you will find the most enthusiastic opponents of the benefits of psychedelics, about which their ignorance resembles what the average villager in Radenci knows of Tito in the 1940s, i.e. what they have been told, not what they have experienced.

Unnecessary and counterproductive rigidity are legal and mental constructs that can be ameliorated by mind-expanding drugs. They offer a sideways view, and offer users the opportunity to invite unnecessary and counterproductive rigidity to get lost. And this is why the anti-drug religion, prohibition, doesn't like them.

Oblivion from alcohol, often associated with violence, is a legally approved coping mechanism, but is solipsistic and does nothing to solve the underlying malaises. Drugs other than alcohol, which can give rise to creative solutions to life stresses or at least relief by way of euphoria are legally disapproved, and the users accused of escapism. A drug user is not concerned with his or her genetic predisposition. They can't change that.

What Slovenia's warring factions need is not more press stories about what the communists did, but consolation now. Now does not contain the grudges of the past, nor the anxieties of the future. Now is not a popular concept for political manipulators. "Now" suggests something should be done, rather than talked about. "Now" cannot play on people's resentments and fears. Dealing with "Now" may be financially expensive compared to promises and grumbling.

Although it is not necessary to understand the mechanisms of the human brain by which consolation takes place, and psychedelic people have managed without this so far, it's good to know the scientists are finally being allowed to fill in the details, and the activation of 5-HT1A receptors in the anterior cingulate cortex was sufficient to reverse consolation and sociability deficits in Chinese mandarin voles.
https://elifesciences.org/articles/67638 [302]

I think it might work in Slovenians too.

From "The Role of Nutrients in Protecting Mitochondrial Function and
Neurotransmitter Signaling: Implications for the Treatment of
Depression, PTSD, and Suicidal Behaviors" by Du et al (2016):

"Drugs, which lower the cholesterol levels, are able to cause the depressive symptoms (Tatley and Savage, 2007). In addition, fish-intake (rich in EPA or DHA) directly protects against the onset of major depressive disorder (Weidner et.al., 1992). Moreover, chronic stress induced an inhibition to the respiratory chain in the mitochondria in the brain (Madrigal et al., 2001). Mitochondrial dysfunction caused by changes in biochemical cascade or the damage to the mitochondrial electron transport chain has been suggested to be an important pathogenic factor for the psychiatric disorders, particularly in bipolar disorders and depression (Rezin et al., 2009). Moreover, food supplements, such as B12 or folate, which protects mitochondrial functions are effective as an adjunctive therapy for the treatment of depression (Papakostas et al., 2005). All these studies imply that mitochondrial dysfunction and reduced formation of lipid raft may be involved in the etiology of depression and suicidal behavior (Figure 1). These stress-induced neuronal dysfunctions interact with the other genetic and environmental factors, including adverse childhood events, exposure to trauma, drug abuse, smoking, alcohol usage, sleep, diet, and exercise levels, to precipitate mood disorders in genetically and/or physiologically vulnerable or predisposed individuals (Figure 1)."

As for suicide:

"Epidemiological studies have identified low fish (high in ω-3 fatty acid) consumption as a risk factor for mortality from suicide (Hibbeln and Salem, 1995, Hirayama, 1990, Sublette et al., 2006, Tanskanen et al., 2001). One study noted that frequent fish consumption (twice per week or more) significantly reduced the risk of depressive symptoms and of self-reported suicidal ideation (Tanskanen et al., 2001). A 17-year follow-up study of over 250,000 Japanese subjects showed that people who ate fish daily had a lower risk of death from suicide (Hirayama 1990). In addition, several reports indicate that lower ω3-fatty-acid levels, including lower plasma EPA, and DHA, or EPA in red blood cells, predicted greater risk of suicide attempt (Hibbeln and Salem, 1995, Huan et al., 2004, Sublette et al., 2006). Because both cholesterol and DHA are major components of the lipid raft, it is possible that reduced cholesterol and ω3-fatty-acid levels may affect the formation of lipid rafts in the CNS, and subsequently reduce neurotransmitter signaling (Czysz and Rasenick, 2013). Notably, increased formation of lipid rafts in the membrane would facilitate serotonergic (Donati et al., 2008, Renner et al., 2007), dopaminergic (Villar et al., 2009), and glutamatergic (Francesconi et al., 2009, Ponce et al., 2008) neurotransmitter signaling; all of these play important roles in the pathophysiology and treatment of psychiatric disorders. Studies have noted that low cholesterol levels are associated with increased risk of suicide (Neaton et al., 1992) and that this association shows an inverse relationship with baseline total serum cholesterol (Lester, 2002, Lindberg et al., 1992). Other studies found that individuals who attempted suicide had significantly lower cholesterol levels than controls (Atmaca et al., 2002, Boston et al., 1996, Kim et al., 2002, Kunugi et al., 1997, Maes et al., 1997a, Modai et al., 1994, Rabe-Jablonska and Poprawska, 2000, Sarchiapone et al., 2001, Takei et al., 1994). A postmortem study found that the brains of violent suicide completers had a lower grey-matter cholesterol content (Lalovic et al., 2007), and that a family history of suicidal behavior was more frequent among carriers of Smith–Lemli–Opitz syndrome, an autosomal recessive disorder characterized by abnormally low cholesterol levels (Lalovic et al., 2004)."

https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC4417658&blobtype=pdf [1817]

By 2023, Song et al's highlights were

"Mitochondrial dysfunction plays a vital role in the etiology of depression.

Dysregulation of the mitochondrial quality control system exacerbates the pathophysiology of depression.

Mitochondrial energy metabolism disorders fail to provide physiological support for neuroplasticity in depression.

The interaction between defective mitochondria and neuroinflammation worsens depression.

Mitochondria represent a potential target for pharmacological intervention of depression."



We are reminded:

"BDNF, a substance released by the nerve growth factor family, known as neurotrophins, controls neuronal survival, preserves neuronal function and synaptic plasticity, and promotes the synthesis and release of neurotransmitters . BDNF plays a neuroprotective role by increasing the respiratory control index via the mitogen-activated protein kinase (MEK)/Bcl2. Therefore, suppression of the Bcl2-related signaling pathway reduces BDNF levels, which consequently affects mitochondrial function, resulting in the impairment of plasticity and initiation of apoptosis. In addition to manufacturing oxygen and nitrogen species for synaptic plasticity, mitochondria trigger caspases in dendrites to eliminate postsynaptic spines associated with chronic depression. In line with mitochondrial function, BDNF enhances the utilization ratio of oxidation to enable neuronal plasticity."
https://www.sciencedirect.com/science/article/pii/S0753332223014506 [3998]

According to a 2020 review in BMC Psychiatry by Raymundi et al at the Federal University of Parana in Brazil:

"At low doses, THC can enhance the extinction rate and reduce anxiety responses. Both effects involve the activation of cannabinoid type-1 receptors in discrete components of the corticolimbic circuitry, which could counterbalance the low 'endocannabinoid tonus' reported in PTSD patients. The advantage of associating CBD with THC to attenuate anxiety while minimizing the potential psychotic or anxiogenic effect produced by high doses of THC has been reported. The effects of THC either alone or combined with CBD on aversive memory reconsolidation, however, are still unknown.

"Conclusions: Current evidence from healthy humans and PTSD patients supports the THC value to suppress anxiety and aversive memory expression without producing significant adverse effects if used in low doses or when associated with CBD. Future studies are guaranteed to address open questions related to their dose ratios, administration routes, pharmacokinetic interactions, sex-dependent differences, and prolonged efficacy."



"As reviewed here, low doses of THC attenuate aversive memory expression through anxiety reduction, extinction facilitation, and reconsolidation impairment (currently shown in laboratory animals only."
https://bmcpsychiatry.biomedcentral.com/counter/pdf/10.1186/s12888-020-02813-8.pdf [1506]

By 1985 Howlett had shown "Cannabinoid inhibition of adenylate cyclase. Biochemistry of the response in neuroblastoma cell membranes". The fight-or-flight response, which is triggered by adrenaline, relies on cAMP signaling to increase heart rate and mobilize energy stores. This system is hyperactive and triggered too easily in PTSD. Inhibiting adenylyl cyclase would impair this response.
https://chemport-n.cas.org//chemport-n/?APP=ftslink&action=reflink&origin=npg&version=1.0&coi=1%3ACAS%3A528%3ADyaL2MXhvFOqsL0%3D&md5=49106efb644a6fc89de96c071d7d766b [3731]

By 1997 Glass et al had shown using receptor audioradiography that

"...cannabinoid receptor binding sites in the human brain are localized mainly in: forebrain areas associated with higher cognitive functions; forebrain, midbrain and hindbrain areas associated with the control of movement; and in hindbrain areas associated with the control of motor and sensory functions of the autonomic nervous system."
https://pubmed.ncbi.nlm.nih.gov/9472392/ [3729]

Marsicano et al published "The endogenous cannabinoid system controls extinction of aversive memories" in 2002:

"Acquisition and storage of aversive memories is one of the basic principles of central nervous systems throughout the animal kingdom. In the absence of reinforcement, the resulting behavioural response will gradually diminish to be finally extinct. Despite the importance of extinction, its cellular mechanisms are largely unknown. The cannabinoid receptor 1 (CB1) and endocannabinoids are present in memory-related brain areas and modulate memory. Here we show that the endogenous cannabinoid system has a central function in extinction of aversive memories. CB1-deficient mice showed strongly impaired short-term and long-term extinction in auditory fear-conditioning tests, with unaffected memory acquisition and consolidation. Treatment of wild-type mice with the CB1 antagonist SR141716A mimicked the phenotype of CB1-deficient mice, revealing that CB1 is required at the moment of memory extinction. Consistently, tone presentation during extinction trials resulted in elevated levels of endocannabinoids in the basolateral amygdala complex, a region known to control extinction of aversive memories. In the basolateral amygdala, endocannabinoids and CB1 were crucially involved in long-term depression of GABA (gamma-aminobutyric acid)-mediated inhibitory currents. We propose that endocannabinoids facilitate extinction of aversive memories through their selective inhibitory effects on local inhibitory networks in the amygdala."
https://pubmed.ncbi.nlm.nih.gov/12152079/ [3730]

With understanding of the glucocorticoid mechanism in mammals somewhat stuck, in 2003 Di et al revealed "Nongenomic Glucocorticoid Inhibition via Endocannabinoid
Release in the Hypothalamus: A Fast Feedback Mechanism":

"The glucocorticoid effect was not blocked by the nitric oxide synthesis antagonist NG -nitro-L-arginine methyl ester hydrochloride or by hemoglobin but was blocked completely by the CB1 cannabinoid receptor antagonists AM251 [N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)- 4-methyl-1H-pyrazole-3-carboxamide] and AM281 [1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-4-morpholinyl-1H-pyrazole3-carboxamide] and mimicked and occluded by the cannabinoid receptor agonist WIN55,212-2 [( )-( )-[2,3-dihydro-5-methyl-3-(4- morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate], indicating that it was mediated by retrograde endocannabinoid release."
https://www.jneurosci.org/content/jneuro/23/12/4850.full.pdf [3733]

In 2009 new light was shed on the rapid effects of glucocorticoids in mammals by revealing a putative nongenomic role of glucocorticoids in regulating emotional learning in rodents through a coordinated induction of endocannabinoid signaling. Campolongo et al showed "Endocannabinoids in the rat basolateral amygdala enhance memory consolidation and enable glucocorticoid modulation of memory":

"Extensive evidence indicates that the basolateral complex of the amygdala (BLA) modulates the consolidation of memories for emotionally arousing experiences, an effect that involves the activation of the glucocorticoid system. Because the BLA expresses high densities of cannabinoid CB1 receptors, the present experiments investigated whether the endocannabinoid system in the BLA influences memory consolidation and whether glucocorticoids interact with this system. The CB1 receptor agonist WIN55,212-2 (5–50 ng per 0.2 μL per side), infused bilaterally into the BLA of male Sprague–Dawley rats immediately after inhibitory avoidance training, induced dose-dependent enhancement of 48-h retention. Conversely, the CB1 receptor antagonist AM251 (0.07–0.28 ng per 0.2 μL per side) administered after training into the BLA induced inhibitory avoidance retention impairment. Furthermore, intra-BLA infusions of a low and nonimpairing dose of AM251 (0.14 ng per 0.2 μL per side) blocked the memory enhancement induced by concurrent administration of WIN55,212-2. Delayed infusions of WIN55,212-2 or AM251 administered into the BLA 3 h after training or immediate posttraining infusions of these drugs into the adjacent central amygdala did not significantly alter retention performance. Last, intra-BLA infusions of a low and otherwise nonimpairing dose of AM251 (0.14 ng per 0.2 μL per side) blocked the memory-enhancing effect induced by systemic administration of corticosterone (3 mg/kg, s.c.). These findings indicate that endocannabinoids in the BLA enhance memory consolidation and suggest that CB1 activity within this brain region is required for enabling glucocorticoid effects on memory consolidation enhancement."

https://www.pnas.org/doi/10.1073/pnas.0900835106 [3732]

In "Cannabinoid modulation of corticolimbic activation to threat in trauma-exposed adults: a preliminary study" (2020) Rabinak et al at Wayne State University in Detroit, explained:

"Excessive fear and anxiety, coupled with corticolimbic dysfunction, are core features of stress- and trauma-related psychopathology, such as posttraumatic stress disorder (PTSD). Interestingly, low doses of Δ9-tetrahydrocannabinol (THC) can produce anxiolytic effects, reduce threat-related amygdala activation, and enhance functional coupling between the amygdala and medial prefrontal cortex and adjacent rostral cingulate cortex (mPFC/rACC) during threat processing in healthy adults. Together, these findings suggest the cannabinoid system as a potential pharmacological target in the treatment of excess fear and anxiety. However, the effects of THC on corticolimbic functioning in response to threat have not be investigated in adults with trauma-related psychopathology."

The results of their fMRI study of 71 human subjects undergoing a well-established threat processing paradigm demonstrated that:

"In adults with PTSD, THC lowered threat-related amygdala reactivity, increased mPFC activation during threat, and increased mPFC-amygdala functional coupling."

...which suggests that

"THC modulates threat-related processing in trauma-exposed individuals with PTSD..."

Taking fear and happiness as opposing states, the Defence applauds the astonishing diligence with which scientists are working towards the discovery of what cannabis users already know: it helps you relax, reduces rumination, and makes you happy. These detailed, tiny steps are important. But the backstory does not predate the legally relevant ordinances of international cannabis control. This provides no useful result today for the PTSD victim or recreational user, for whom these effects are as intuitively obvious as those of coffee and do not require scientific proof or peer review.

"Interestingly, CB1Rs are highly abundant in these regions of the corticolimbic system (Tsou et al. 1998; Marsicano and Lutz 1999; Patel et al. 2017) and recent neuroimaging studies in healthy adults show that THC modulates activity in the amygdala and mPFC/rACC. Specifically, an acute oral low dose of THC (7.5 mg) reduced amygdala reactivity, but enhanced coupling between the amygdala and mPFC/rACC, to social threat (i.e., fearful and angry facial expressions), as compared to placebo (PBO; Phan et al. 2008; Gorka et al. 2015a). These findings suggest that pharmacological enhancement of ECB signaling may help to address corticolimbic dysfunction in PTSD and other stress-related disorders. However, it should be noted that others have reported that administration of THC, particularly at a higher dose (10 mg) increases amygdala activation (Bhattacharyya et al. 2010, 2017), and modulates activation in frontal and parietal regions (Crippa et al. 2009), while increasing levels of anxiety and autonomic arousal to fearful faces (Crippa et al. 2009; Bhattacharyya et al. 2010, 2017). These divergent findings highlight the complexity of THC’s effect on threat responding that may be bimodal, such that low doses of THC may be anxiolytic (Wachtel et al. 2002), whereas higher doses of THC are typically anxiogenic (D’Souza et al. 2004; Genn et al. 2004; Viveros et al. 2005b; Bhattacharyya et al. 2015, 2017). To-date, the effects of THC on corticolimbic responses to threat have only been conducted in healthy individuals. Thus, it is unclear whether the observed effects of THC on corticolimbic function and functional connectivity would replicate in individuals with trauma exposure who are at risk for developing PTSD and/or meet criteria for PTSD."

and with reckless abandon as to how their findings might be applied in law to the anti-happy brigade who profit from the miseries of prohibition, they conclude:

"Consistent with previous findings in healthy adults, we found that, within the PTSD group, THC attenuated amygdala activation, increased mPFC/rACC activation, and increased corticolimbic functional connectivity to threat compared to PBO (Phan et al. 2008; Gorka et al. 2015)."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244361/ [1507]

In "The Long-Term, Prospective, Therapeutic Impact of Cannabis on Post-Traumatic Stress Disorder" by Bonn-Miller et al (2022) decided:

"Given the increasing availability and use of cannabis among individuals with post-traumatic stress disorder (PTSD) and the addition of PTSD as an eligible diagnosis in several U.S. medical cannabis programs [24 states as of 2020], the efficacy of dispensary-obtained cannabis needs to be thoroughly examined."

and to the extent that they were able to do so...

"This prospective study [see 2362 page 332 for definition] assessed PTSD symptoms and functioning every 3 months over the course of a year in two samples of participants diagnosed with PTSD: (1) those with PTSD using dispensary-obtained cannabis (cannabis users) and (2) those with PTSD, who do not use cannabis (controls). Linear mixed-effects models and generalized estimating equations tested whether trajectories of symptoms differed between the two subsamples."

And so

"A total of 150 participants (mean [standard deviation] age, 50.67 [15.26] years; 73% male) were enrolled in the study. Over the course of 1 year, the cannabis users reported a greater decrease in PTSD symptom severity over time compared to controls [group×time interaction=−0.32 (95% confidence interval [CI]=−0.59 to −0.05, R2=0.13; t=−2.35, p=0.02). Participants who used cannabis were 2.57 times more likely to no longer meet DSM-5 criteria for PTSD at the end of the study observation period compared to participants who did not use cannabis (95% CI=1.12–6.07; p=0.03)."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9070744/ [1509]

In "Anxiety severity and prescription medication utilization in first-time marijuana users" from Dugosh et al (2023):

"The study sample was comprised of 108 adults with anxiety or PTSD as a referring condition; they were enrolled in a longitudinal study evaluating biopsychosocial outcomes in new MM patients. Consenting participants completed an assessment battery at baseline and Month 3 (n = 94, 87 % follow-up rate) that included a measure of anxiety severity and questions about current anxiety medication prescription and desired (baseline) and actual (Month 3) reductions in medication use.

"Results
Findings indicated that 59 % of participants reported prescription medications for anxiety, with 70 % reporting at least a moderate desire to reduce medication use. Overall and within the medication sub-sample, participants displayed significant reductions in anxiety severity from baseline to Month 3 (p’s <0.0001). Furthermore, 32 % reported actual reductions in medication use at Month 3, and reductions were more likely among patients prescribed benzodiazepines than other drug classes.

"Conclusions
Results suggest that a significant number of MM patients with anxiety and/or PTSD diagnoses are currently being prescribed antianxiety medications and that MM may help to reduce their use of these medications.

"Limitations
Limitations include the observational study design and the lack of a PTSD-specific measure. More controlled longitudinal studies are necessary to better understand the role of MM in the treatment of anxiety and PTSD."
https://www.cannabisclinicians.org/2023/10/27/anxiety-severity-and-prescription-medication-utilization-in-first-time-medical-marijuana-users-2/ [4190]

Again, in 2023, Vaddiparti et al found

"PTSD symptom severity as measured by total PCL-5 score improved significantly at 30- and 70-day follow-ups. Similarly, statistically significant reductions in nightmares were reported at 30- and 70-day follow-ups. Corresponding improvements in sleep were noticed with participants reporting increased duration of sleep hours, sleep quality, sleep efficiency, and total PSQI score. Likewise, negative affect and global mental health improved significantly at follow-up. According to the post hoc analyses, the most statistically significant changes occurred between baseline and 30-day follow-up. The exception to this pattern was nightmares, which did not show significant improvement until day 70."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10642978/ [4254]

In 162 patients with PTSD identified from the UK Medical Cannabis Registry, tested with Impact of Events Scale-Revised (IES-R), EQ-5D-5L, Single-Item Sleep Quality Scale (SQS), Generalized Anxiety Disorder-7 (GAD-7) and Patient Global Impression of Change (PGIC), Pillai et al (2022) found that:

"Statistically significant improvements were seen in all domains of the IES-R, and both GAD7 and SQS, at all lengths of follow-up (p < 0.050). The EQ-5D-5L index score and both ‘usual activities’ and ‘anxiety and/or depression’ subscales also improved significantly at all follow-ups (p < 0.050). Significant improvements in the ‘self-care’ and ‘pain and discomfort’ subscales were seen at 1- and 3-month follow-up and the ‘mobility’ subscale at 3-months only (p < 0.050). There was a large effect size (r = 0.50) for the IES-R hyperarousal score at 3-month follow-up. All other IES-R and GAD7 scores had medium effect sizes. PGIC1 median scores were consistently 6.00 (5.00–6.00) at 1-, 3-, and 6-month follow-up, whilst median PGIC2 was 3.00 (2.00–3.00) at 1- and 3-month follow-up, and 2 (1.00–3.00) at 6-months (n = 128, 93, and 51 respectively)."
https://www.tandfonline.com/doi/full/10.1080/14737175.2022.2155139  [4694]

Mayo et al, reviewing the issue of "Targeting the Endocannabinoid System in the Treatment of Posttraumatic Stress Disorder: A Promising Case of Preclinical-Clinical Translation?" in 2022, say:

"Preclinical research shows that eCB activity influences functional connectivity between the prefrontal cortex and amygdala and thereby influences an organism’s ability to cope with threats and stressful experiences. Animal studies show that CB1 receptor activation within the amygdala is essential for extinction of fear memories. Failure to extinguish traumatic memories is a core symptom of posttraumatic stress disorder, suggesting that potentiating eCB signaling may have a therapeutic potential in this condition. However, it has been unknown whether animal findings in this domain translate to humans. Data to inform this critical question are now emerging and are the focus of this review."

Under the headling "Fear" they say

"The loss-of-function FAAH 385A allele was inserted into mice, resulting in decreased FAAH activity and concomitantly increased AEA levels. In mice and humans, carriers of the A-allele had enhanced fronto-amygdala connectivity and fear extinction. We subsequently reported similar effects in humans, including a gene dose–dependent effect of the A-allele on peripheral AEA levels. Individuals homozygous for the A-allele showed enhanced fear extinction and recall of extinction learning when tested 24 hours later. These findings have since been replicated by others, showing that fear extinction is related to peripheral AEA levels."

And the latest scientists to discover cannabis think...

"The available human data consistently support a translation of animal findings on fear memories and stress reactivity and suggest a potential therapeutic utility in humans."

Their Figure 1 shows the approaches to ECS pathways from a drug manufacturing perspective

https://www.sciencedirect.com/science/article/pii/S0006322321014724

 [4010]

Taking another overview of the evidence in 2023, Marchetta et al

"...describe the three fear memory phases (e.g., consolidation, reconsolidation and extinction) that are most significantly altered in PTSD patients, and...review data from both human and animal studies on the effects of repeated exposure to trauma reminders on fear memory retention and extinction combined with pharmacological intervention."

Highlights include

"Based on preclinical studies, the monoamine hypothesis of PTSD has been enlarged with a more complex neurochemical and neuroplasticity hypothesis that highlights the role of the glutamatergic system in trauma and stress psychopathology."

"The mechanisms sustaining systems consolidation have not been fully elucidated."

As for reconsolidation

"...differently to what the name might suggest, it is not a simple replication of the consolidation phase, although overlaps between the underlying mechanisms of these two phases exist. Studies in rodents have demonstrated that memory may be disrupted via inhibition of new gene expression or protein synthesis in the hippocampus immediately after retrieval of a consolidated memory, whereas the same manipulations into the hippocampus long after retrieval had no effect on memory. This indicates that these manipulations are effective only when given soon after reactivation but not when given after a delay. In addition, consolidated memories that are not retrieved, and therefore do not become labile, cannot be disrupted by the inhibition of gene expression or protein synthesis. Hence, if a consolidated memory could turn back to its labile state and be disrupted by external interventions, some authors argue that there might be the chance that the disruption of the original traumatic memories could be an efficacious approach to treat PTSD patients."

Memory extinction was first commented upon by Pavlov in 1927. Today...

"Extinction training is not the same as forgetting, but it is considered as new learning because it leaves the CS as having two meanings: 'fear' if coupled with the US or 'safe' if it is not coupled with US. When memory is extinguished, it means that the 'safe' prevails over the 'fear' meaning. Many studies have provided evidence demonstrating that extinction consists of a new learning process. Specifically, without extinction training, the fear response lasts months or even years, and extinguished fear responses return naturally with the passage of time (spontaneous recovery), after using a different context compared with the one in which extinction training took place (renewal), or as a consequence of the re-exposure to the US (reinstatement)"



The authors'

"Literature search was conducted in March, 2021 by comprehensive searches in two online databases (PubMed and Scopus). The keywords used for the search of animal studies were: D-cycloserine, yohimbine, methylene blue, glucocorticoids or corticosterone or methyrapone, cannabinoids or endocannabinoids, MDMA or 3-4, methylenedioxymethamphetamine, ketamine, psychedelics and/in post traumatic stress disorder or posttraumatic stress disorder or posttraumatic stress disorder or fear memory or memory extinction or memory reconsolidation. Results were limited to rodents studies. The keywords used for the search of human studies were: D-cycloserine, yohimbine, methylene blue, glucocorticoids or cortisol, cannabinoids or endocannabinoids, MDMA or 3-4, methylenedioxymethamphetamine, ketamine, psychedelics and/in post traumatic stress disorder or posttraumatic stress disorder or post-traumatic stress disorder. For both the 1st (i.e., titles and abstracts) and the 2nd (i.e., full-text articles) screening phases, the following exclusion criteria were used: (1) papers written in a language other than English; (2) non-original researches (e.g., reviews, commentaries, editorials, book chapters); (3) no full-text articles (e.g., meeting abstracts); (4) studies in vitro; (5) studies in non-human animals other than rodents; (6) drugs administration not associated with an animal model of PTSD or psychological intervention in humans; (7) absence of control groups in the studies."

As for cannabinoids:

"The eCBs AEA and 2-AG are mainly degraded by two enzymes fatty-acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively. Increasing number of animal studies suggests that eCB signaling is critically involved in the extinction phase of fear memory. Several reports have demonstrated that increased AEA signaling, through inhibition of FAAH activity, induced an enhancement of fear memory extinction. On the contrary, the administration of CB1 receptor antagonists impaired the extinction and reconsolidation of fear memory. In accordance with these results, CB1 KO mice or mice bearing the FAAH C385A polymorphism, which impairs the activity of FAAH, showed reduced and enhanced fear memory extinction, respectively, thus, supporting the hypothesis that strengthening AEA signaling at CB1 receptors enhances fear extinction. In a PTSD-like rat model, we have recently demonstrated that the FAAH inhibitor URB597 or the direct cannabinoid receptor agonist WIN55,212-2 (Fig. 1) enhanced fear extinction tested 16 days post-trauma, when administered after three spaced extinction sessions, 7, 10 and 13 days after trauma exposure. Both drugs showed beneficial effects, but only URB597 (0.1 mg/kg, i.p.) induced the best improvements by enhancing extinction consolidation and restoring normal social behavior in traumatized rats through indirect activation of CB1 receptors tested up to 36-37 days post-trauma. Further, another recent study has confirmed these findings in male rodents showing beneficial effects on fear extinction of the FAAH inhibitor URB597. Contrarily to what has been found and described above in males, increased AEA signaling at CB1 receptors (Fig. 1), 60 min prior to extinction training in an auditory fear conditioning paradigm, did not alter fear memory extinction in female rats. However, when AEA signaling was increased at the transient potential receptor of vanilloid type-1 channel (TRPV1R, another target of AEA beyond CB1 receptors), it augmented freezing behavior at extinction training and extinction retrieval. Increased 2- AG signaling at CB1 receptors reduced freezing at extinction training in females, without altering fear responses in males."

But in humans, they believe:

"Rigorous clinical studies regarding the efficacy of cannabinoids for PTSD in conjunction with psychotherapy are still lacking."

As for psychedelics Marchetta et al say:

"Psylocibin, lysergic acid diethylamide (LSD) and dimethyltryptamine share a common mechanism of agonism at serotonergic 5-HT2A receptor. Although few studies have indicated possible use of these psychedelics for depression and obsessive-compulsive disorder, no other study has yet been reported regarding a potential treatment for PTSD. However, the effects on empathy, mindfulness related capacities, avoidance, acceptance and connectedness, long-term openness, and emotional break-through experiences along with preclinical studies, demonstrating an enhancing effect on fear memory extinction, should determine a renewed interest on these compounds."
https://pmc.ncbi.nlm.nih.gov/articles/PMC10207915/ [2490]

But were those clinical studies really "still lacking" in 2023?

The Prosecution should have been fully aware, by the early 2000s, of the implications of taking away phytocannabinoids it said had no medical utility:

"Seminal research in the early 2000s revealed that, in vitro, the glucocorticoid-based inhibition of paraventricular nucleus neurons and the subsequent inhibition of corticotropin-releasing hormone synthesis depended on retrograde endocannabinoid signalling. Research in the early 2000s also found that corticotropin-releasing hormone was found to be highly co-expressed with CB1 receptors in the forebrain. It was, therefore, suspected that endocannabinoids could be involved in the regulation of the hypothalamic–pituitary–adrenal (HPA) axis response to stress. Subsequent research confirmed this hypothesis, as it was discovered that a reduction in AEA in the basolateral amygdala is required for HPA axis activation, suggesting that AEA tonically gates the HPA response. Research further explored the mechanisms involved in HPA gating by AEA and found that CRH-mediated increases in FAAH expression is responsible for the decrease in amygdala AEA prior to HPA onset.

"While AEA is believed to tonically gate the HPA stress response, 2-AG is believed to be involved in the termination of the response through the facilitation of glucocorticoid-mediated negative feedback. Research that supports this hypothesis has shown that 2-AG levels increase in the hippocampus 30 to 60 min following stress, while the inhibition of CB1 in the frontal areas of the brain prevents negative feedback of the HPA axis. Likewise, the inhibition of MAGL, but not FAAH, maintains increased corticosterone expression after stress onset. Given the evidence described above, it has therefore been widely hypothesised that endocannabinoids are involved in both the initiation and termination of the HPA axis response to stress." [5126]

The Court is invited to evaluate the validity of the statement that "no other study has yet been reported regarding a potential treatment for PTSD" [2490] with psychedelics. No one has scientifically proved that I will cheer up if I have a cup of tea. But that doesn't mean that I won't.

Then, in September 2023, Cell Reports published a study. Here are some key facts, as reported by neurosciencenews.com:

"Summary: A recent study illuminates the brain’s unique response to stress: releasing its own cannabinoid molecules akin to THC from cannabis plants.

"Centered in the amygdala, these molecules counteract stress alarms originating from the hippocampus, an integral memory and emotion region. This hints at the body’s intrinsic mechanism for stress management.

"Disruption in this system might escalate risks for stress-induced psychiatric conditions.

"Key Facts:

"The amygdala, an emotional brain center, releases endogenous cannabinoids to mitigate stress, interacting with the same receptors as THC.

"When the target cannabinoid receptor was removed in mice, there was a noticeable decline in their ability to handle stress and a diminished inclination towards rewarding experiences.

"This study further supports the endocannabinoid system’s role as a potential drug-development candidate for stress-related disorders."
https://neurosciencenews.com/endocannabinoids-stress-23913/ [3011]

According to the paper:

"BLA activity promotes eCB release at vHPC-BLA synapses

"Active stress coping recruits vHPC-BLA eCB signaling

"vHPC-BLA CB1 receptor deletion exacerbates stress-induced avoidance/anhedonia

"The endocannabinoid (eCB) system is a key modulator of glutamate release within limbic neurocircuitry and thus heavily modulates stress responsivity and adaptation. The ventral hippocampus (vHPC)-basolateral amygdala (BLA) circuit has been implicated in the expression of negative affective states following stress exposure and is modulated by retrograde eCB signaling. However, the mechanisms governing eCB release and the causal relationship between vHPC-BLA eCB signaling and stress-induced behavioral adaptations are not known. Here, we utilized in vivo optogenetic- and biosensor-based approaches to determine the temporal dynamics of activity-dependent and stress-induced eCB release at vHPC-BLA synapses. Furthermore, we demonstrate that genetic deletion of cannabinoid type-1 receptors selectively at vHPC-BLA synapses decreases active stress coping and exacerbates stress-induced avoidance and anhedonia phenotypes. These data establish the in vivo determinants of eCB release at limbic synapses and demonstrate that eCB signaling within vHPC-BLA circuitry serves to counteract adverse behavioral consequences of stress."

Vanderbilt University, Tennessee, authors Kondev et al (2023) say where this gets us to:

"A key question arises from our previous data demonstrating relatively enhanced DSE at vHPC-BLA synapses in stress-resilient mice and from our current data revealing 2-AG release at vHPC-BLA synapses in response to stress exposure: is 2-AG-CB1R signaling at vHPC-BLA synapses causally linked to stress-induced behavioral reactivity and adaptation? Our data address this question in two separate, but related, ways. First, we found that 2-AG release occurred during bouts of active stress coping that were preceded by increases in BLA neuron activity. Combined with previous data suggesting that BLA activity (or activity of a subset of BLA output neurons) is associated with active behavioral responses to stress, this suggests a possible scenario whereby increases in BLA activity drive 2-AG release to dampen vHPC afferent excitation via activation of presynaptic CB1R. That deletion of CB1R from vHPC-BLA terminals reduced active stress coping in a variety of assays (restraint stress, TST, FST) suggests that vHPC inputs to the BLA promote passive stress coping. This hypothesis is consistent with data demonstrating that vHPC-BLA circuits are critical for driving freezing responses to contextual threat. How vHPC inputs to the BLA selectively drive 'passive' output circuits or inhibit 'active' output circuits from the BLA is not known but represents an important open question. Second, we found that deletion of CB1R from vHPC-BLA synapses promotes anhedonia and avoidance selectively after stress exposure and, more robustly, after repeated stress exposure. These data suggest that 2-AG released within the synapse during stress exposure plays an important role in buffering against subsequent adverse behavioral consequences of stress, consistent with previous studies. Taken together, these data indicate that 2-AG-CB1 signaling at vHPC-BLA synapses plays an important role in regulating behavioral responses during and after stress exposure and provides further support for the contention that 2-AG signaling within defined limbic circuits is a critical mechanism buffering against the adverse effects of stress exposure. A key question arises from our previous data demonstrating relatively enhanced DSE at vHPC-BLA synapses in stress-resilient mice and from our current data revealing 2-AG release at vHPC-BLA synapses in response to stress exposure: is 2-AG-CB1R signaling at vHPC-BLA synapses causally linked to stress-induced behavioral reactivity and adaptation? Our data address this question in two separate, but related, ways. First, we found that 2-AG release occurred during bouts of active stress coping that were preceded by increases in BLA neuron activity. Combined with previous data suggesting that BLA activity (or activity of a subset of BLA output neurons) is associated with active behavioral responses to stress, this suggests a possible scenario whereby increases in BLA activity drive 2-AG release to dampen vHPC afferent excitation via activation of presynaptic CB1R. That deletion of CB1R from vHPC-BLA terminals reduced active stress coping in a variety of assays (restraint stress, TST, FST) suggests that vHPC inputs to the BLA promote passive stress coping. This hypothesis is consistent with data demonstrating that vHPC-BLA circuits are critical for driving freezing responses to contextual threat. How vHPC inputs to the BLA selectively drive 'passive' output circuits or inhibit 'active' output circuits from the BLA is not known but represents an important open question. Second, we found that deletion of CB1R from vHPC-BLA synapses promotes anhedonia and avoidance selectively after stress exposure and, more robustly, after repeated stress exposure. These data suggest that 2-AG released within the synapse during stress exposure plays an important role in buffering against subsequent adverse behavioral consequences of stress, consistent with previous studies.

"Taken together, these data indicate that 2-AG-CB1 signaling at vHPC-BLA synapses plays an important role in regulating behavioral responses during and after stress exposure and provides further support for the contention that 2-AG signaling within defined limbic circuits is a critical mechanism buffering against the adverse effects of stress exposure."
https://www.cell.com/cell-reports/fulltext/S2211-1247(23)01038-0 [3012]

In their 2022 paper "Neuroinflammation in Post-Traumatic Stress Disorder" Dong-Hun Lee and colleagues at the Department of Neurosurgery, College of Medicine, Soonchunhyang University, Cheonan Hospital, Korea, pointed to pro-inflammatory cytokines as biomarkers of PTSD:

"The Marine Resiliency Study reported that preexisting concentrations of C-reactive protein (CRP) were directly correlated with the occurrence and severity of PTSD, three months after a seven-month military deployment, and elevated levels of interleukin (IL)-6, IL-8, and transforming growth factor β (TGF-β) during hospitalization predicted the development of PTSD one month later. These data suggest that immune dysregulation predisposes individuals to PTSD. The elevation of inflammatory cytokines in PTSD has clinical significance, as chronic inflammation can adversely affect cardiovascular and physical health. In addition, individuals with PTSD are significantly more likely to suffer autoimmune disorders compared with those with other psychiatric conditions. Inflammation-related mediators, such as IL-1, IL-6, and tumor necrosis factor alpha (TNF-α), may pass through the blood–brain barrier, and the overproduction of pro-inflammatory cytokines can activate brain microglia. A few small studies have examined the cerebrospinal fluid levels of cytokines in PTSD but have yielded conflicting results."

We like the large studies.

"One of the largest studies exclusively of men exposed to combat trauma reported a significantly elevated pro-inflammatory composite, comprising IL-1β, IL-6, TNF-α, IFN-γ, and CRP levels in those with PTSD compared to those without PTSD. The predominant cytokines were different for each group, and differences were observed in TNF-α, IFN-γ, and IL-6 values. The pro-inflammatory cytokine levels remained significantly higher in individuals with PTSD after controlling for early-life trauma, major depressive disorder and its severity, body mass index, ethnicity, education, asthma and/or allergies, time since combat, potentially confounding inflammatory illnesses, and medications. Immune activation of PTSD was also found to be significantly high in male groups who experienced combat trauma.

"Conversely, several other studies have reported no significant difference in inflammatory marker levels between patients with PTSD and healthy controls."

Lee et al discuss the role of DAMP, HPA axis, serotonin and tryptophan–kynurenine pathways:

"Damage-associated molecular patterns (DAMPs) are host-derived non-bacterial immune response molecules released due to PTSD-related stress. These molecules act as danger signals when cells are damaged. When DAMPs are released from cells, pattern recognition receptors (PRRs) are expressed in astrocytes and microglia to promote neuroinflammatory reactions. The PRR is a protein expressed by innate immune system cells such as dendritic cells, macrophages, monocytes, and neutrophils, and is a receptor that recognizes DAMPs and plays an important role in innate immunity. One of the PRRs, the Toll-like receptor (TLR), is expressed in various cells of the CNS, including neurons, microglia, and astrocytes. These PRRs are activated by detecting endogenous molecules such as DAMPs, and the persistent neuroinflammatory action of glial cells can lead to neurodegeneration."

and

"IL-1 receptors (IL-1Rs) are produced by microglia, astrocytes, and brain oligodendrocytes, and have been shown to be highly concentrated in the pituitary and meninges. IL-1R mRNA is expressed in the capillaries and glial cells throughout the hippocampus, choroid plexus, cerebellum, and brain, and the IL-1 type 1 receptor is expressed in humans’ hypothalamus. The secreted inflammatory cytokines are received in these glial cells and contribute to neuroinflammation. Therefore, the impairment of the HPA axis due to PTSD can lead to neuroinflammation."

and

"Tryptophan is an essential amino acid used in protein biosynthesis and is mainly metabolized with kynurenine. Kynurenine is a metabolite of tryptophan that performs a variety of biological functions, including vasodilation and immune response during inflammation. This kynurenine pathway is modified in several diseases, including mental disorders such as schizophrenia and depressive disorders. Pro-inflammatory cytokines can enhance the activity of indolamine 2,3-dioxigenase (IDO), the first and rate-limiting enzyme in the tryptophan degradation pathway. Elevated levels of pro-inflammatory cytokines increase IDO enzyme activity. IDO is involved in tryptophan metabolism, which upregulates the production of kynurenine. Kynurenine is converted into several metabolites, including quinolinic and kynurenic acids, and it is involved in the activity and inhibition of NMDA (N-methyl-d-aspartate), with elevated pro-inflammatory cytokines producing relatively larger amounts of quinolinic acid (Figure 4). This increase in quinoline acid has a potent neurotoxic effect, which can activate microglia and macrophages, increase reactive oxygen and reactive nitrogen species due to lipid peroxidation, and interfere with nerve function or cause apoptosis. Some studies have also shown that quinoline acid may also be linked to mental disorders, although the mechanism is still unclear. However, quinoline acid has been found in the postmortem brain of depressed patients."

The authors briefly mention cannabis, and claim rather ignorantly

"...very few studies have reported the potential usefulness of cannabis in the treatment of PTSD."

In Korea, perhaps. There are only 13.9 million Google results for "cannabis ptsd korea". However these authors suggest a variety of drug treatments including NSAIDs, steroids, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, and invasive treatments like deep brain stimulation (DBS).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9138406/ [4076]

In 2007 Miller and Wrosch found that carrying on with unattainable goals appears to affect C-reactive protein.

"The notion that persistence is essential for success and happiness is deeply embedded in popular and scientific writings. However, when people are faced with situations in which they cannot realize a key life goal, the most adaptive response for mental and physical health may be to disengage from that goal. This project followed 90 adolescents over the course of 1 year. Capacities for managing unattainable goals were assessed at baseline, and concentrations of the inflammatory molecule C-reactive protein (CRP) were quantified at that time, as well as 6 and 12 months later. To the extent that subjects had difficulties disengaging from unattainable goals, they displayed increasing concentrations of CRP over the follow-up. This association was independent of potential confounds, including adiposity, smoking, and depression. Because excessive inflammation contributes to a variety of adverse medical outcomes, these findings suggest that in some contexts, persistence may actually undermine well-being and good health."
https://pubmed.ncbi.nlm.nih.gov/17760771/ [4698]

We underestimate the effect of trauma on third parties, as shown by Song et al in "Firearm Injuries In Children And Adolescents: Health And Economic Consequences Among Survivors And Family Members" (2023):

"More US children and adolescents today die from firearms than any other cause, and many more sustain firearm injuries and survive. The clinical and economic impact of these firearm injuries on survivors and family members remains poorly understood. Using 2007–21 commercial health insurance claims data, we studied 2,052 child and adolescent survivors compared to 9,983 matched controls who did not incur firearm injuries, along with 6,209 family members of survivors compared to 29,877 matched controls, and 265 family members of decedents compared to 1,263 matched controls. Through one year after firearm injury, child and adolescent survivors experienced a 117 percent increase in pain disorders, a 68 percent increase in psychiatric disorders, and a 144 percent increase in substance use disorders relative to the controls. Survivors’ health care spending increased by an average of $34,884—a 17.1-fold increase—with 95 percent paid by insurers or employers. Parents of survivors experienced a 30–31 percent increase in psychiatric disorders, with 75 percent more mental health visits by mothers, and 5–14 percent reductions in mothers’ and siblings’ routine medical care. Family members of decedents experienced substantially larger 2.3- to 5.3-fold increases in psychiatric disorders, with at least 15.3-fold more mental health visits among parents. Firearm injuries in youth have notable health implications for the whole family, along with large effects on societal spending."
https://www.healthaffairs.org/doi/abs/10.1377/hlthaff.2023.00587 [4085]

Clearly, individuals vary in their susceptibility to PTSD for a variety of reasons. Unusual long-term background stressors and acute trauma have conspired against the Defendant's well-being fully justifying continued use of both cannabis and psychedelics with no need for therapy. Indeed in one unpopular paper it was shown that therapists add no value to psychedelics: "no significant association was found between the number of therapy hours and outcome in either the short-term (b = −0.05, p = .327) or long-term."
https://www.sciencedirect.com/science/article/pii/S0163834325001562 [5294]

In the view of the Defendant and most illicit users, therapy is a two-edged sword, as likely to undermine the confidence of the subject as rebuild it.

Exploitation is a real probability, best averted not by having no unsupervised psychedelicism, but by having no therapist.

Psychiatrists reinforce the sick role.

150 years ago the concept did not really exist.

Psychedelic therapy could make someone else legally and morally liable for a person's mistakes.

Therapists are more expensive than real friends.

Therapists may try to do too many things at once, not all of them for the "patient".

As in the wider field of psychiatry, psychedelic therapy is an attempt at labelling all users as mentally ill in one way or another.

And with those endless categories and theories, and mental confusion about "drugs", even with mushrooms welcomed back into the pharmaceutical fold, psychiatrists can start out meaning well...but they face difficulties being part of the set and setting of a therapeutic journey, with psychedelics or without.

9 to 40 million years after the first biosynthesis of psilocybin [3252] individual vulnerability to PTSD was addressed by Suprani et al [2025]:

"While the symptom burden can be substantial-particularly in high-risk populations exposed to cumulative or prolonged trauma-the lifetime prevalence of full-syndrome PTSD in the general population remains lower; for instance, it is estimated at 6.1% in the United States. Epidemiological evidence has consistently shown that only a minority of trauma exposed individuals go on to develop PTSD. The neurobiological mechanisms underpinning the individual variation in vulnerability to PTSD development following trauma are still unclear. Different biological systems have been investigated, such as those involved in neuroplasticity and immunoregulation. More recently, the endocannabinoid (eCB) system has received attention in the PTSD research field, given its modulatory effect on memory consolidation, retrieval and extinction. There is a large amount of data in animal models supporting the eCB system role in regulating fear and stress responses. The fatty acid-derived signaling molecule Anandamide (AEA), the first discovered endocannabinoid, was shown to facilitate fear extinction in mice by activating the Cannabinoid receptor 1 [CB1]. When research on the eCB system in fear responses was extended to humans, consistent results were found, mostly on healthy subjects. Three different human studies replicated the association between enhanced fear extinction and a hypofunctional genetic variation in the fatty acid amide hydrolase (FAAH), an enzyme that catabolizes AEA. Positive results in genetics research were also published by Heitland et al., who found that A/A carriers of rs2180619 (a polymorphism located in the promoter region of CB1), exhibited impaired fear extinction. In line with preclinical and healthy volunteers’ literature, individuals with PTSD were shown to have a reduction in circulating endocannabinoids levels.

"A recent study identified the amygdala-projecting medial prefrontal cortex (mPFC) neurons as a potential neural basis for the effect of the eCB system on fear extinction. The amygdala is a primary hub in the brain that regulates the processing of aversive memories, by integrating information from different cortical brain regions. Among these regions, the mPFC was shown to exert top-down control of negative emotions over the amygdala in mice. Findings in patients with PTSD suggest that the interaction between the mPFC and the amygdala becomes dysfunctional, resulting in the heightened responsivity of the latter. Several recent studies with different designs support this hypothesis. For instance, neurosurgical patients with ventral mPFC lesions exhibited potentiated amygdala responses to aversive images compared to neurologically healthy controls. Consistently, Feng et al., showed that the resting-state functional connectivity between the ventral mPFC and the amygdala is positively correlated with fear extinction after fear reminder in healthy subjects. Overall, numerous lines of evidence point toward a potential role of the eCB system in PTSD vulnerability following trauma, possibly via altered top-down control on the amygdala."

https://www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2025.1584583/full [5295]

In "The Effectiveness and Adverse Events of Cannabidiol and Tetrahydrocannabinol Used in the Treatment of Anxiety Disorders in a PTSD Subpopulation" (2023) from Stack et al of the University of Sydney's School of Pharmacology and Applied Cannabis Research in Sydney, NSW, Australia:

"The median doses taken were 50.0 mg/day for CBD and 4.4 mg/day for THC. The total participant sample reported significantly improved anxiety, depression, fatigue, and ability to take part in social roles and activities. Those who were diagnosed with PTSD (n = 57) reported significantly improved anxiety, depression, fatigue, and social abilities. The most common AEs reported across the whole participant cohort were dry mouth (32.6%), somnolence (31.3%), and fatigue (18.5%), but incidence varied with different cannabis formulations. The inclusion of THC in a formulation was significantly associated with experiencing gastrointestinal AEs; specifically dry mouth and nausea. Conclusions: Formulations of cannabis significantly improved anxiety, depression, fatigue, and the ability to participate in social activities in participants with anxiety disorders. The AEs experienced by participants are consistent with those in other studies."

And of special note:

"Participants who took a THC-dominant formulation reported a significant decrease in their anxiety levels. Those same participants also represented the highest proportion of participants that were classified as having clinical improvement (61.1%, n = 11), compared with participants who were prescribed other formulation types. This was unexpected as the median THC dose for this participant group was 33.8 mg/day, and it has been suggested that doses higher than 30 mg/day could be anxiogenic.14 A study reported that doses of CBD ranging from 15 to 60 mg/day could offset the anxiogenic properties of THC, which is reflected in our data; however, with lower doses of CBD (median = 6.0 mg/day CBD)."
https://journals.sagepub.com/doi/pdf/10.1177/87551225231180796 [4557]

epidemic declared March 12 then again October 19 2020
102 C/C polymorphism and suicide
Several lines of evidence indicate that abnormalities in the functioning of the central serotonergic system are involved in the pathogenesis of depressive illness and suicidal behavior.

https://pubmed.ncbi.nlm.nih.gov/19224112/ [298]
https://pubmed.ncbi.nlm.nih.gov/29526601/ [299]
https://pubmed.ncbi.nlm.nih.gov/11727894/ [300]

Research does not seek to eliminate environmental influences in favour of genetic disposition in depression, suicidal ideation and completed suicide. But there are only two hypotheses for the high incidence in Slovenia, both of which may be right, namely that some are genetically predisposed to snap when stress is prolonged or reaches a certain level, or that living conditions for some, according to the rules constructed by their own society, are relentlessly sub-optimal.

Slovenia is an ideal candidate for psychedelic therapy. Slovenia ruminates endlessly about the past. Millions of tonnes of CO2 are expended generating hot air about long-dead regimes and ideologies, because they have affected people in this area. But arguing about what Tito wrote about Stalin in 1940 won't bring your dead relatives back or make you happy and strong today. To ignore the past and bury the hatchet seems like a cop-out. But the past is getting in the way of the present, and the future.

"In 1976, a man known as Ka-Tzetnik 135633 (original name: Yehiel De-Nur) underwent LSD-assisted psychotherapy. At the time, he was under the supervision of Prof. Jan Bastiaans at the State University of Leiden in the Netherlands. Bastiaans was the psychiatrist who had first identified concentration camp syndrome, also known as survivor syndrome. This syndrome is a form of what we would now call post-traumatic stress disorder (PTSD). Its characteristics include social withdrawal, sleep disturbance, anxiety, and depression. Bastiaans had also successfully treated this syndrome with LSD-assisted psychotherapy. Ka-Tzetnik 135633 was a survivor of Auschwitz, where he was a prisoner for two years. This trauma was followed by three decades of torment, in which he relived the horror of those two years at night. Through LSD-assisted psychotherapy, however, Ka-Tzetnik 135633 found healing.

"Almost a half century after Bastiaans' successful trials, the regulation of psychedelics for treating PTSD is finally underway. Think of the Holocaust survivors who might have found healing through these medicines, but couldn't because of a politically-motivated ban on psychedelics. This realization brings home the horrific impact of the failed war on drugs.'"
https://realitysandwich.com/psychedelics-and-judaism/ [1092]

Psychedelics break the rumination cycle by disrupting - in a good way - brain activities which perpetuate habitual thinking and behaviour.

The most abundant 5-HT receptors expressed in the medial prefrontal cortex (mPFC) are 5-HT1AR and 5-HT2AR. The 5-HT2AR pathway is enhanced by 5-HT2AR-agonist psychedelics.
https://pubmed.ncbi.nlm.nih.gov/28858536/ [301]

In mice, given a single dose of psilocybin or LSD, and using the social reward conditioned place preference (sCPP) assay Nardou et al have made an important step forward in understanding the mechanism by which psychedelics can override cultural log-jams retarding progress and societal happiness, such as we see in Slovenia. "Psychedelics reopen the social reward learning critical period" (2023) finds:

"Psychedelics are a broad class of drugs defined by their ability to induce an altered state of consciousness. These drugs have been used for millennia in both spiritual and medicinal contexts, and a number of recent clinical successes have spurred a renewed interest in developing psychedelic therapies. Nevertheless, a unifying mechanism that can account for these shared phenomenological and therapeutic properties remains unknown. Here we demonstrate in mice that the ability to reopen the social reward learning critical period is a shared property across psychedelic drugs. Notably, the time course of critical period reopening is proportional to the duration of acute subjective effects reported in humans. Furthermore, the ability to reinstate social reward learning in adulthood is paralleled by metaplastic restoration of oxytocin-mediated long-term depression in the nucleus accumbens. Finally, identification of differentially expressed genes in the ‘open state’ versus the ‘closed state’ provides evidence that reorganization of the extracellular matrix is a common downstream mechanism underlying psychedelic drug-mediated critical period reopening. Together these results have important implications for the implementation of psychedelics in clinical practice, as well as the design of novel compounds for the treatment of neuropsychiatric disease."
https://www.nature.com/articles/s41586-023-06204-3 [2825]

But we do not need to rely on mice when there are real-life mass traumas going on. A special opportunity came along on 7 October 2023 in the Hamas attack on Supernova. "Trauma Under Psychedelics: MDMA Shows Protective Effects During the Peritraumatic Period" say Netzer et al (2024):

"Traumatic events (TEs) play a causal role in the etiology of psychopathologies such as depression and posttraumatic stress disorder (PTSD). Recent research has highlighted the therapeutic potential of psychoactive substances and especially 3,4-methylenedioxymethamphetamine (MDMA), in alleviating trauma symptoms in chronic patients. However, little is known regarding the consequences of trauma that is acutely experienced under the influence of psychoactive substances. Here we investigated the acute experiences and peritraumatic processing of 657 survivors from the high-casualty terror attack at the Supernova music festival in Israel on October 7th, 2023. Data were collected four to twelve weeks following the TE. Approximately two-thirds of survivors were under the influence of psychoactive substances at the time of the TE, offering a tragic and unique natural experiment on the impact of psychoactive compounds on TE processing. Our findings reveal that individuals who experienced the trauma while under the influence of MDMA demonstrated significantly improved intermediate outcomes compared to those who were under the influence of other substances or no substances at all. Specifically, the MDMA group reported increased feelings of social support, more social interactions and enhanced quality of sleep during the peritraumatic period, yielding reduced levels of mental distress and reduced PTSD symptom severity. These novel findings suggest that the influence of MDMA during the TE may carry protective effects into the peritraumatic period, possibly mediated through the known effects of MDMA in reducing negative emotions and elevating prosociality. These protective effects in turn may mitigate the development of early psychopathology-related symptoms. Current preliminary results underscore the need for further understanding of the cognitive and physiological processes by which psychedelic substances intersect with trauma recovery processes."
https://www.biorxiv.org/content/10.1101/2024.03.28.587237v1 [3174]

Another alternative to mice is "Human pluripotent stem cells as a translational toolkit in psychedelic research in vitro". As Salerno and Rehan explain:

"PSCs can differentiate into various brain cell types, mirroring endogenous expression patterns and cell identities to recreate disease phenotypes. Brain organoids derived from PSCs resemble cell diversity and patterning, while region-specific organoids simulate circuit-level phenotypes. PSC-based models hold significant promise to illuminate the cellular and molecular substrates of psychedelic-induced phenotypic recovery in neuropsychiatric disorders."

and

"The identities of the signaling pathways responsible for psychedelics’ hallucinogenic and therapeutic properties and whether these are distinct or overlapping pathways are some of the questions still under debate.

"The Gq or β-arrestin-2 recruitment paradigm represents a glimpse into the extensive network of pathways regulated by 5-HT2AR activation via psychedelics. For example, distinct psychedelics activate phospholipase A2 and phospholipase D via ADP-ribosylation factor 1. The activation of 5-HT2AR, triggered by various agonists including DOI and LSD, can lead to the heterodimerization of the receptor with metabotropic glutamate receptor 2 and dopamine D2 receptor, both of which are Gi-coupled receptors. This transactivation blocks the cAMP’s synthesis by adenylate cyclase and prompts heterotrimeric Gi/o proteins to trigger Src-mediated downstream events.

"A burst of glutamate also follows psychedelic administration, mainly in the cortical layer V of the neocortex, which is a 5-HT2AR-enriched area.8,23 High glutamate levels activate the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), boosting the secretion of brain-derived neurotrophic factor (BDNF), which in turn signals through the tyrosine receptor kinase B (TrkB) and mammalian target of rapamycin (mTOR) pathways, sustaining both the AMPAR activation and BDNF secretion in a positive feedback loop of neural plasticity.

"Furthermore, the hallucinogenic properties of different psychedelics are also proposed to be influenced by other 5-HTRs, and not all 5-HT2AR agonists have hallucinogenic properties. For instance, human studies also provide evidence supporting the involvement of the 5-HT1AR in the effects of psilocybin. Competition binding studies on rodent brains and primary cells revealed a lack of pronounced selectivity of psilocin for 5-HT2AR over 5-HT1AR. Nevertheless, the role of the 5-HT2AR remains the subject of more extensive study and investigation. Ketanserin, a selective antagonist of the 5-HT2Rs, effectively eliminates head-twitch behavioral responses in mice; however, it does not attenuate psilocybin-induced structural modifications in the prefrontal cortex. As a result, uncertainties remain about whether and how the neuroplastic effects on rescuing disease phenotypes relate to behavioral responses, especially in humans. Moreover, human studies investigating the molecular mechanisms of psychedelic-induced plasticity rely on global parameters such as peripheral BDNF levels, which may not correlate with the molecular mechanisms occurring in brain cells. For in-depth cellular and molecular insights into the role of 5-HT2AR, in vitro investigations are required."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11019282/ [3173]

Using PSCs Schmidt et al (2024) of the University of Heidelberg showed that psilocin causes 5-HT2A receptor internalization and redistribution in human cortical neurons, induces BDNF expression and downstream signaling in human neurons in a dose-dependent manner, induces gene expression changes associated with axonal and synaptic plasticity, increases dendritic complexity, and increases synaptic strength and synaptogenesis.
https://www.researchgate.net/publication/381253376_Psilocin_fosters_neuroplasticity_in_iPSC-derived_human_cortical_neurons [3175]

Administration of psychedelics to a relatively small number of people could bring the paralysing stand-off over Slovenia's past to a quick and elegant halt. The participants would see the damage they are doing - to themselves and the country - by perpetuating hostilities against groups and against individuals long dead. They would be able to more accurately gauge the importance of the historical against the challenges of the present and future. They would be less susceptible to fearmongering and superstition. Their nightmares would be put into perspective.

The Slovenians who stand to gain the most from ranting on about the past for political purposes are the least likely to have taken them. Among them you will find the most enthusiastic opponents of the benefits of psychedelics, about which their ignorance resembles what the average villager in Radenci knows of Tito in the 1940s, i.e. what they have been told, not what they have experienced.

Unnecessary and counterproductive rigidity are legal and mental constructs that can be ameliorated by mind-expanding drugs. They offer a sideways view, and offer users the opportunity to invite unnecessary and counterproductive rigidity to get lost. And this is why the anti-drug religion, prohibition, doesn't like them.

Oblivion from alcohol, often associated with violence, is a legally approved coping mechanism, but is solipsistic and does nothing to solve the underlying malaises. Drugs other than alcohol, which can give rise to creative solutions to life stresses or at least relief by way of euphoria are legally disapproved, and the users accused of escapism. A drug user is not concerned with his or her genetic predisposition. They can't change that.

What Slovenia's warring factions need is not more press stories about what the communists did, but consolation now. Now does not contain the grudges of the past, nor the anxieties of the future. Now is not a popular concept for political manipulators. "Now" suggests something should be done, rather than talked about. "Now" cannot play on people's resentments and fears. Dealing with "Now" may be financially expensive compared to promises and grumbling.

Although it is not necessary to understand the mechanisms of the human brain by which consolation takes place, and psychedelic people have managed without this so far, it's good to know the scientists are finally being allowed to fill in the details, and the activation of 5-HT1A receptors in the anterior cingulate cortex was sufficient to reverse consolation and sociability deficits in Chinese mandarin voles.
https://elifesciences.org/articles/67638 [302]

The Defence thinks it might work in Slovenians too.

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The Englishman stands for the rights of everyone disadvantaged, discriminated against, persecuted, and prosecuted on the false or absent bases of prohibition, and also believes the victims of these officially-sanctioned prejudices have been appallingly treated and should be pardoned and compensated.

The Englishman requests the return of his CaPs and other rightful property, for whose distraint Slovenia has proffered no credible excuse or cause.

The Benedictions represent both empirical entities as well as beliefs. Beliefs which the Defence evidence shows may be reasonably and earnestly held about the positive benefits of CaPs at the population level, in which the good overwhelmingly outweighs the bad. Below, the latest version of this dynamic list.


THE BENEDICTIONS                            REFERENCES                        TIMELINE OF DRUG LAW v. SCIENCE