Doc's Telling Me To Pop Pills?

You may have heard that popping pills can solve problems, and this might be the case in helping relieve patients with severe PTSD. Ecstasy, also known as MDMA and 3,4-Methylenedioxymethamphetamine, as of October 21, 2021, was on a clinical trial of assisted psychotherapy for post traumatic stress disorder in the USA, Canada, and Israel.  These trials, led by the Multidisciplinary Association for Psychedelic Studies (MAPS) are figuring out if this treatment is effective and safe enough so that MDMA can be prescribed as a regular treatment for PTSD. Imagine your doctor prescribing you hard core drugs! However, the results from the trial have been promising. 

A photo of ecstasy pills. (The friendliest looking pills i've ever seen; very misleading lol) 

Lets understand some background information first and how certain things work here:

What is PTSD?

In American history, PTSD arises from various wars such as the Civil War, shell shock from WW1, combat fatigue from WW2, and delayed stress from the Vietnam War. Sadly, between these wars, PTSD was forgotten about until Vietnam veterans advocated for PTSD to make its way into the American psychiatric nomenclature as a formal diagnostic in 1980. Post traumatic stress disorder (PTSD) is the only major mental disorder for which a cause is considered to be known whether its an event or threat that then triggers a response of fear, horror, or helplessness. It must be understood at the organic, molecular, and biological levels. Brain scans show that PTSD symptoms and behaviors are caused by biological changes in the brain and not by some personal "failure." 

The many reactions PTSD can cause. 

Researchers now know that PTSD syndrome is a blend of intrusive memories of the traumatic event, emotional numbing, and hyperarousal, and that people with PTSD have an imbalance between two neurochemical systems in the brain: serotonin and substance P. The greater the imbalance, the more serious symptoms patients have. With PTSD, the nerve circuits connecting the amygdala, hippocampus and prefrontal cortex aren't working correctly. The hippocampus can't store the memory and the prefrontal cortex can't override the hippocampus to tell the amygdala to calm down when there is no danger. The amygdala is an almond-shaped structure that helps us process emotions and it also helps regulate how we respond to fear and create emotional memories. Hence, traumatic stress over-activates the amygdala. When this happens, our fear responses become more intense. This means that memories of traumatic events can become nightmares and flashbacks.

A brain scan showing the difference in activity in a healthy brain vs an abused brain.  

This PET image above shows a higher mGluR5 receptor availability in an individual with PTSD. The mGluR5 receptors are G‐protein coupled receptors abundantly expressed on cortical, hippocampal and striatal regions in the human brain and are highly implicated in the pathophysiology of schizophrenia too. Interestingly, in animals, overstimulation of mGluR5 is associated with fear and stress-related behaviors so drugs that reduce mGluR5 function may reduce these symptoms in humans. 

GluR5 is an excitatory Gq-coupled G protein-coupled receptor mainly expressed on the postsynaptic sites of neurons. The glutamate receptors are ligand-gated ion channels that act as postsynaptic receptors to mediate the vast majority of excitatory neurotransmission in the brain. Calcium entry through certain glutamate receptor channels plays important roles in development and in forms of synaptic plasticity that may determine higher order processes such as learning and memory. 

Glutamate is the most widespread excitatory neurotransmitter in the mammalian brain.  It is an amino acid and a neurotransmitter. Glutamates major roll in the brain is that of a precursor of the neurotransmitter amino acids: the excitatory amino acids, glutamate (Glu), aspartate, and butyric acid. Glutamate pathways are linked to many other neurotransmitter pathways, and glutamate receptors are found throughout the brain and spinal cord in neurons and glia.

What is ecstasy? 

Ecstasy, ( 3,4-Methylenedioxymethamphetamine), also known as molly or MDMA is a synthetic drug known for its hallucinogenic and stimulant effects. It affects the brain's chemistry by releasing a high level of serotonin which in our body's, regulates mood, energy level and appetite. It can also be incredibly dangerous and addictive and lead to death. In these trials however, the clinical MDMA that is used is not the same as ecstasy. MDMA for clinical use is produced to a pharmaceutical standard. A regulated dose is given in a controlled setting by trained health professionals for specific conditions only. In contrast, the dose and purity of ecstasy is unknown and it can be mixed with other dangerous ingredients. 

How does this trial show that ecstasy can benefit PTSD patients? 

MDMA can assist psychotherapy by reducing defensiveness and anxiety, increasing relaxation and improving mood. It can also improve the bond between the therapist and patient. Patients with PTSD have low serotonin levels, therefore MDMA benefits their brains by increasing the activity of three neurotransmitters: serotonin, dopamine, and norepinephrine. Also, because MDMA appears to reduce anxiety associated with recalling traumatic experiences, it can help increase insight and memory. Combined with psychotherapy MDMA can help a traumatized patient remain in a state of emotional security so they can live with their traumatic memories without being overwhelmed by the powerful negative affect that usually is brought up with these intrusive thoughts. 

Signal Transduction Pathway of serotonin from MDMA

The image above shows the pathway of MDMA entering via the serotonin transporters that then accumulate in the VMAT storing serotonin vesicles. The serotonin is released within the cytosol and the MDMA changes the direction of SERT to be transported out of the neuron to then make sure there is constant activity on serotonin receptors. 

Conclusion: 

Follow-up research from the Phase 2 trials led by MAPS showed MDMA-assisted treatment was effective in improving PTSD symptoms. At least one year later, 67% of Phase 2 trial participants surveyed no longer met the criteria for a PTSD diagnosis. With the progress of MAPS-driven trials into Phase 3 overseas, it’s worth taking a look at MDMA-assisted psychotherapy, and why it seems to help people with PTSD. If there is a positive result from this trial, MDMA could be legally prescribed to PTSD patients in the USA as soon as 2022!