Posttraumatic Stress Disorder (PTSD) is a serious mental health condition affecting millions worldwide. It can develop in individuals who have experienced or witnessed a traumatic event, such as military combat, sexual assault, natural disasters, or serious accidents. PTSD can have long-lasting effects on an individual's daily life, relationships, and overall well-being, and it's a complex disorder that researchers are still working to understand. In recent years, researchers have made considerable progress in uncovering the underlying mechanisms of PTSD and developing more effective treatments. Two recent articles on the topic - “Posttraumatic Stress Disorder Is Associated with α Dysrhythmia across the Visual Cortex and the Default Mode Network” by Kevin Clancy et al. and "MDMA-assisted psychotherapy for PTSD: Are memory reconsolidation and fear extinction underlying mechanisms?" by A.A. Feduccia and M.C. Mithoefer - shed new light on the potential mechanisms involved in PTSD.
Clancy et al.’s research investigated the relationship between PTSD and α dysrhythmia, a dysfunctional brain wave pattern associated with the visual cortex and the default mode network. The default mode network (DMN) is a set of brain regions active when a person is not focused on the outside environment. Electroencephalogram analysis of healthy brains reveals that α brain waves are correlated to DMN activity and the resting brain, as they participate in the suppression of visual cortex excitation and other sensory information routed to the DMN. People with PTSD are deficient in these α oscillations, and the experiment was designed to demonstrate how the DMN responds to sensory input in people with PTSD. The results showed that individuals with PTSD exhibited disrupted α dysrhythmia in the visual cortex and DMN. These findings suggest that the visual cortex and DMN may be involved in developing and maintaining PTSD. While Clancy et al. provided insight into the neurological mechanisms of PTSD, Feduccia and Mithoefer's research explored a promising new treatment approach using MDMA-assisted psychotherapy.
While exposure therapy is currently the standard treatment for PTSD, its success rate is limited with 40-60% of patients not responding, and many patients are unable to tolerate the intense emotions associated with exposure to trauma-related cues. This is where the study on MDMA-assisted psychotherapy for PTSD comes in. In the article by Feduccia and Mithoefer, the authors report that MDMA administration during exposure-style therapy reduces PTSD symptoms in the majority of patients after just 2-3 sessions. MDMA is a Schedule 1 psychoactive drug that mediates the release of serotonin (5-HT), dopamine (DA), norepinephrine (NE), and many other molecules that the authors hypothesize contribute to the therapeutic effects of MDMA on PTSD patients. The authors propose three potential mechanisms through which MDMA-assisted psychotherapy reduces PTSD symptoms: the drug's pro-social effects, its impacts on fear memory reconsolidation, and its enhancement of fear extinction learning.
MDMA's pro-social effects are believed to promote feelings of safety and improve the therapeutic relationship between the patient and therapist. This is attributed to the release of serotonin and oxytocin, and studies demonstrate that feelings of security to be necessary for traumatic memories to be reconsolidated with less fear. Research has also demonstrated that MDMA's effects on dopamine and serotonin contribute to the modification and reconsolidation of fear memories. Memory reconsolidation is a protein-synthesis-dependent process by which a recalled and reactivated memory is modified or updated with additional information. It is hypothesized that when traumatic memories are recalled under the influence of MDMA, there is a significant mismatch between the MDMA-induced feelings of love and euphoria and the feelings of fear and anxiety associated with the memory. MDMA-mediated dopamine release plays a significant role in this modification by destabilizing the memory through dopamine release into the amygdala via the ventral tegmental area (VTA), and DA release into the midbrain which is associated with prediction error.
Researchers have also noted that MDMA can affect emotional processing. Under the influence of MDMA, healthy subjects have shown reduced activation of the left amygdala in response to angry faces and have reported feeling less distress associated with traumatic memories. This effect was associated with increased activation of the superior frontal gyrus and dorsomedial prefrontal cortex (dmPFC) and diminished activation of the left anterior temporal lobe.
In addition to its effects on memory reconsolidation, research suggests that MDMA may also play a role in extinguishing learned fear responses. According to the authors of "MDMA-assisted psychotherapy for PTSD: Are memory reconsolidation and fear extinction underlying mechanisms?" rodent studies have shown that MDMA enhances extinction learning. In one study, fear-conditioned mice were given a dose of 7.8 mg/kg of MDMA 30 minutes before extinction training, resulting in improved and long-lasting extinction of a conditioned freezing response. During the extinction test, the mice were given an identical dose of MDMA and exhibited a reduced startle response to the conditioned stimuli. The authors hypothesize that MDMA may reduce fear in individuals with PTSD, allowing for full access and reprocessing of traumatic memories by inhibiting top-down overstimulation from the prefrontal cortex to limbic regions. This mechanism may contribute to the effectiveness of MDMA-assisted psychotherapy in treating PTSD.
In addition to its role in enhancing emotional memory reconsolidation and fear extinction learning, MDMA has also been linked to synaptogenesis, the formation of new synaptic connections in the brain. The authors propose that this is a BDNF-dependent mechanism. Brain-derived neurotrophic factor (BDNF) is a growth factor crucial for synaptic plasticity, and low levels of BDNF have been associated with depression and acute stress. The release of BDNF triggered by MDMA may promote the formation of new synaptic connections through the activation of signaling cascades that induce long-term potentiation (LTP), a process that enhances the strength of synaptic connections between neurons. Therefore, MDMA-assisted psychotherapy may not only promote the modification and reconsolidation of traumatic memories but also potentially promote the growth of new neural connections in the brain, providing another possible mechanism for its long-lasting therapeutic effects.
References:
Feduccia, Allison A., and Michael C. Mithoefer. “MDMA-Assisted Psychotherapy for PTSD: Are Memory Reconsolidation and Fear Extinction Underlying Mechanisms?” Progress in Neuro-Psychopharmacology and Biological Psychiatry, vol. 84, 7 Mar. 2018, pp. 221–228, https://doi.org/10.1016/j.pnpbp.2018.03.003.
Clancy, Kevin J., et al. “Posttraumatic Stress Disorder Is Associated with α Dysrhythmia across the Visual Cortex and the Default Mode Network.” Eneuro, vol. 7, no. 4, July 2020, https://doi.org/10.1523/eneuro.0053-20.2020.
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