The Psychedelic Future of Post-Traumatic Stress Disorder Treatment

Abstract

Post-traumatic stress disorder (PTSD) is a mental health condition that can occur following exposure to a traumatic experience. An estimated 12 million U.S. adults are presently affected by this disorder. Current treatments include psychological therapies (e.g., exposure-based interventions) and pharmacological treatments (e.g., selective serotonin reuptake inhibitors (SSRIs)). However, a significant proportion of patients receiving standard-of-care therapies for PTSD remain symptomatic, and new approaches for this and other trauma-related mental health conditions are greatly needed. Psychedelic compounds that alter cognition, perception, and mood are currently being examined for their efficacy in treating PTSD despite their current status as Drug Enforcement Administration (DEA)- scheduled substances. Initial clinical trials have demonstrated the potential value of psychedelicassisted therapy to treat PTSD and other psychiatric disorders. In this comprehensive review, we summarize the state of the science of PTSD clinical care, including current treatments and their shortcomings. We review clinical studies of psychedelic interventions to treat PTSD, trauma-related disorders, and common comorbidities. The classic psychedelics psilocybin, lysergic acid diethylamide (LSD), and N,N-dimethyltryptamine (DMT) and DMT-containing ayahuasca, as well as the entactogen 3,4-methylenedioxymethamphetamine (MDMA) and the dissociative anesthetic ketamine, are reviewed. For each drug, we present the history of use, psychological and somatic effects, pharmacology, and safety profile. The rationale and proposed mechanisms for use in treating PTSD and traumarelated disorders are discussed. This review concludes with an in-depth consideration of future directions for the psychiatric applications of psychedelics to maximize therapeutic benefit and minimize risk in individuals and communities impacted by trauma-related conditions.

Keywords: 3; 4-methylenedioxymethamphetamine (MDMA); Ayahuasca; Ketamine; Lysergic Acid Diethylamide (LSD); Post- Traumatic Stress Disorder (PTSD); psilocybin; psychedelics; trauma..

Fig. (1)

The human brain as affected by post-traumatic stress disorder (PTSD). The regions of the brain associated with changes in response to trauma and stress include the amygdala, hippocampus, and prefrontal cortex. The amygdala, an area of the brain known for emotional processing and fear conditioning, has shown increased activation as well as increased functional connectivity with other regions, including the insula and anterior cingulate cortex (ACC), in PTSD patients [144]. The hippocampus, a region known for the critical role it plays in memory consolidation, is also affected by PTSD, with patients showing decreased volume and functionality [59, 133, 134]. The prefrontal cortex, which is involved in cognitive control and emotional regulation, is also altered in PTSD, with reduced activity and resting state functional connectivity during cognitive tasks [143, 145]. Furthermore, recent PTSD fMRI imaging studies have found hyperactivation in the amygdala, decreased connectivity between amygdala and mPFC, increased connectivity between the amygdala and hypothalamus/brainstem, and decreased activity in the Default Mode Network (DMN) (ventromedial prefrontal cortex (vmPFC), inferior parietal lobe (IPL), posterior cingulate cortex (PCC)) and Central Executive Network (CEN) (dorsolateral prefrontal cortex (dlPFC), posterior parietal cortex (PPC)) [146]. These findings suggest that PTSD’s effects result in complex changes in brain structure and function involving multiple regions and networks, as represented in this figure.

Fig. (2)

Chemical structures of the five psychedelic and psychedelic-like compounds included in this review paper. Classic psychedelics include psilocybin, a tryptophan indole-based alkaloid with a base N,N-dimethyltryptamine structure and an added phosphoryloxy substituent at position 4; lysergic acid diethylamide-25 (LSD), a semisynthetic ergoline composed of an indole system and tetracyclic ring; and N,N-dimethyltryptamine (DMT), the psychoactive component of ayahuasca, a structural analog of tryptamine with two added N-methyl substituents. The entactogen 3,4-methylenedioxymethamphetamine (MDMA) is a ring-substituted phenethylamine that possesses chirality but is typically produced in its racemic form. MDMA has a 2-(methylamino)propyl group at position 5 that is an addition to the base form of 1,3-benzodioxole. The dissociative anesthetic, ketamine, is a racemic mixture composed of two enantiomers, (S)- and (R)-ketamine. Ketamine is a cyclohexanone molecule on which a 2-chlorophenyl group and a methylamino group substitute for the hydrogens typically found at position 2.

Fig. (3)

Mechanisms of MDMA. Left: Typical neurotransmission. Right: MDMA acts by increasing synaptic monoamine concentrations through three mechanisms: (1) inhibition of presynaptic membranal monoamine transporters with relative selectivity for NET > SERT > DAT [326, 328]; (2) reversal of monoamine transporters by MDMA entering presynaptic nerve terminals during ion exchange in place of extracellular K⁺ and directly stimulating efflux of cytoplasmic monoamines; (3) binding as a substrate for vesicular monoamine transporter VMAT2 causing efflux of monoamines from vesicles into the cytoplasm and inhibiting uptake of monoamines into the vesicles. In addition to the above, MDMA demonstrates affinity as an agonist at various receptors, including 5HT1A, 5HT2A, 5HT2B, 5HT2C, 5HT4, adrenergic, dopamine D1 and D2, among others [326, 329, 330]. Bottom Right: Within the hypothalamus, the supraoptic nucleus (SON) and paraventricular nucleus (PVN) contain cell bodies of oxytocinergic neurons [330, 331]. These neurons contain presynaptic 5-HT₄ and postsynaptic 5-HT_1A receptors that, when stimulated by serotonin, trigger the release of oxytocin [329, 330]. Oxytocin (OT) has several downstream targets that are thought to contribute to a wide range of behavioral and physiological effects [332] associated with MDMA and potentially underlie some of the therapeutic efficacy of MDMA-AT for PTSD [333, 334].

Fig. (4)

Effects of MDMA on the brain. MDMA reduces cerebral blood flow in the right amygdala and hippocampus [376]. fMRI findings show that MDMA attenuates amygdala reactivity in response to participant exposure to angry faces while amplifying ventral striatum response to happy faces [365]. The left anterior temporal cortex, a region proximal to and densely connected with the amygdala, demonstrates reduced activation in healthy participants following MDMA intake. This reduced activity occurred while participants were reflecting upon their worst autobiographical memories and was correlated with a reportedly less negative subjective experience of these memories. In contrast, participants reported their favorite autobiographical memories as more emotionally intense and positive after MDMA, which correlated with increased activations of the ventral visual and somatosensory cortices [377]. Resting-state functional connectivity (RSFC) between the ventromedial prefrontal cortex and posterior cingulate cortex is attenuated following MDMA consumption, an observation that has also been found following psilocybin administration [376, 378, 379]. Patients with PTSD demonstrate increased RSFC between the medial prefrontal cortex and hippocampus [375], whereas MDMA decreases RSFC between these two regions [376]. Additionally, increases in amygdala-hippocampal RSFC were observed after MDMA administration [376]; a notable finding as decreased amygdala-hippocampal RSFC has been seen in patients with PTSD [142]. Lastly, MDMA has been shown to decrease Salience Network FC, specifically between the right insula and superior frontal gyrus [380].

Fig. (5)

Molecular mechanisms of classic psychedelics. Serotonergic psychedelics activate 5-hydroxytryptamine 2A (5-HT_2A) receptors, causing glutamate release and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) potentiation. The resulting release of brain-derived neurotrophic factor (BDNF) activates tropomyosin-related kinase B (TrkB) receptors, ultimately resulting in activation of the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway and increasing expression of synaptic proteins [530]. Classic psychedelics also bind to the G protein-coupled receptors (GPCR) 5-HT_2A receptors on the post-synaptic cell, activating downstream cascades. One of these cascades is the Gq-mediated response pathway, leading to production of phospholipase C (PLCβ) that catalyzes the production of second messengers inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG), in turn activating protein kinase C (PKC) and then extracellular signal-regulated kinase 1/2 (ERK1/2) to mobilize intracellular calcium and, eventually, changes in gene expression. This and other intracellular pathways are part of the pro-neuroplastic effects of classic psychedelics [531].

Fig. (6)

Effects of classic psychedelics on the brain. Psilocybin decouples functional connectivity between the ventral medial prefrontal cortex (vmPFC) and posterior cingulate cortex (PCC) in the Default Mode Network (DMN). Acute decreases in cerebral blood flow and bold signaling are observed in the thalamus and in the anterior and posterior cingulate cortices following psilocybin ingestion [378]. The intensity of the subjective effects of psilocybin is predicted by the magnitude of decreased activity within the anterior cingulate cortex (ACC) and medial prefrontal cortex (mPFC) [378]. Psilocybin also decreases amygdala reactivity to negative and neutral stimuli [592]. LSD reduces associative connectivity (i.e., medial and lateral prefrontal cortex, cingulum, insula, and temporoparietal junction) and simultaneously increases sensory-somatomotor (i.e., occipital cortex, superior temporal gyrus, postcentral gyrus, and precuneus) brain-wide and thalamic connectivity [578]. LSD, similar to psilocybin, acutely decouples functional connectivity between the ventral medial prefrontal cortex and posterior cingulate cortex in the DMN. Moreover, LSD decreases connectivity between the parahippocampus and retrosplenial cortex, which has been correlated with clinically measured ratings of “ego-dissolution” and “altered meaning” [580]. Ayahuasca ingestion significantly decreases activity through most parts of the DMN, including the posterior cingulate cortex (PCC)/precuneus and the medial prefrontal cortex (mPFC). Additionally, functional connectivity within the PCC/precuneus is significantly decreased [577, 582].

Fig. (7)

Molecular mechanisms of ketamine, highlighting the glutamatergic system where the cellular mechanisms of ketamine and classic psychedelics may converge: Ketamine antagonizes NMDA receptors on gamma-aminobutyric acid (GABA)ergic interneurons, leading to disinhibition (releasing the breaks on hyperpolarization) of the target glutamatergic cortical neuron and in turn causes a glutamate surge. Glutamate then acts on α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors in the post-synaptic cell, leading to increased BDNF release, activation of the tropomyosin-related kinase receptor type B (TrkB), and activation of mTORC1, essentially increasing rapid BDNF translation and leading to an upregulation of plasticity genes [661]. A particular ketamine metabolite, (2R,6R)-hydroxynorketamine [(2R,6R)-HNK], may additionally promote synaptic potentiation [530]. Ketamine may also block spontaneous neurotransmission mediated by NMDAR, preventing the phosphorylation of eEF2 and resulting in increased translation of BDNF [661]. Ketamine selectively inhibits extra-synaptic NMDARs, which is believed to de-suppress mTORC1 activity, leading to increased protein synthesis [661, 667].

Fig. (8)

Effects of ketamine on the brain. Ketamine administration produces rapid, focal decreases in activity within the ventromedial frontal cortex, including the orbitofrontal cortex and the subgenual cingulate. This decrease was strongly predictive of ketamine’s dissociative effects [670]. Ketamine increases neural activation in the midcingulate cortex, the dorsal part of the anterior cingulate cortex (ACC), the insula bilaterally, and the thalamus. Ketamine also decreases neural activity in a cluster within the subgenual/subcallosal part of the anterior cingulate cortex, the orbitofrontal cortex, and the gyrus rectus [671]. In the Executive Control Network (ECN), ketamine significantly increases the functional connectivity with parts of the anterior cingulum and superior frontal gyrus. Ketamine decreases connectivity between the Salience Network (SN) and the calcarine fissure, which is significantly correlated with negative symptoms (PANSS) [672]. Finally, ketamine decreases functional connectivity in the medial prefrontal cortex (mPFC) and increases connectivity in the intraparietal cortices [673].