2. What Is PTSD, and How Can We Treat this Disorder?
There are different forms of potentially traumatic experiences that a person undergoes in the course of a lifetime
[8][9][10,11]. First, there are “minor traumas” or “t’s,” subjectively disturbing experiences characterized by a perceived danger that is not particularly intense. Events such as humiliation suffered or abrupt interactions with significant persons during childhood can be included in this category
[10][12]. Next to these minor traumas are “T-traumas,” i.e., all those events that lead to death or threaten one’s physical integrity or that of loved ones. Finally, significant events, such as natural disasters, abuse, accidents, etc., belong to this category.
The only diagnosis in the DSM-5
[11][13] that includes trauma as an etiological factor among the diagnostic criteria is “Disorders due to traumatic and stressful situations.” Some examples of these diseases are reactive attachment disorder, uninhibited social engagement disorder, post-traumatic stress disorder (PTSD), acute stress disorder, adaptation disorders, and other disorders with or without additional criteria.
The following conditions must be met for PTSD to develop in an individual
[12][14].
The individual has been exposed to trauma, such as actual or threatened death, serious injury, or sexual assault (criterion A), either directly or indirectly by experiencing the traumatic event themselves or through hearing about a violent or unintentional traumatic event that occurred to a member of their family or a close friend. Additionally, frequent or excessive exposure to the fundamental components of the traumatic event qualifies as traumatizing, as in the case of first responders gathering human remains or police officers being repeatedly exposed to aspects of child abuse.
After the traumatic occurrence, intrusive symptoms, such as recollections, dreams, and flashbacks that cause a complete loss of awareness of the surroundings, develop (criterion B). In addition, when triggers that represent or resemble the trauma occur, there are significant or protracted psychological discomfort and physical responses.
The next criterion consists of persistent avoidance of the traumatic event’s associated stimuli after the catastrophic event (criterion C). This involves internal and external factors that trigger unpleasant memories, thoughts, or feelings connected to or closely associated with the traumatic event. Examples of internal factors include unpleasant memories, beliefs, or feelings related to or closely associated with the traumatic event. External factors include people, places, conversations, activities, objects, and situations.
After the traumatic occurrence, negative changes in feelings and thoughts connected to the traumatic event take place (criterion D). The individual loses track of specific essential details of the traumatic incident and forms ingrained, exaggerated negative views or expectations about the world, other people, or themselves. It is possible to have distorted and persistent opinions regarding the origins or effects of the traumatic incident, which can lead to blaming oneself or others. The inability to feel pleasant emotions, like happiness, contentment, or love, can also indicate a negative emotional state, as can persistent feelings of fear, terror, rage, guilt, or humiliation. Other symptoms include a sharp decline in interest or participation in worthwhile activities.
After the traumatic experience, significant changes in arousal and reactivity linked to it lead to irritable behavior (criterion E). Anger outbursts are typically expressed through verbal or physical aggression toward people or objects; reckless, self-destructive behavior; hypervigilance; exaggerated alarm responses; concentration issues; and sleep-related symptoms, like trouble falling or staying asleep or restless sleep (with little to no provocation).
The reported alterations last for more than a month (criterion F).
The illness results in clinically substantial distress or reduced functioning in essential domains such as social, occupational, or other (criterion G).
The problem is not caused by another medical illness or the physiological effects of a substance like alcohol or drugs (criterion H).
If the symptomatology has been present for less than three months, the disorder is classified as acute; if it lasts longer than three months, it is chronic; and if, on the other hand, it occurs at least six months after the trauma, it is classified as late onset
[13][15].
Concerning the lifetime prevalence of the disorder among the general population, epidemiological studies have estimated it to be between 1% and 10% for women and 5% for men, with variability attributable to the methods of ascertaining and sampling the population used
[14][16]. People with PTSD often fulfill the criteria for at least one other diagnosis in comorbidity
[15][17]. The most common appears to be major depression, with frequency rates of around 46%, followed by other anxiety disorders, particularly panic disorder and social phobia, which affect between 20 and 30% of subjects
[16][18]. A diagnosis of substance abuse or dependence is also prevalent for 52% of men and 28% of women with chronic PTSD
[17][19]. Somatic symptoms that meet the criteria for a diagnosis of somatization disorder may also be present
[16][18]. Another widespread condition, although not an actual diagnosis, is the frequent feeling of guilt experienced by individuals with PTSD concerning their behaviors to ensure their survival, including the fact that they survived when others died, and their reactions after the traumatic event
[18][19][20,21].
PTSD is a rather pervasive disorder; the sufferer is absorbed in painful memories of the traumatic event or avoids reliving it
[20][22]. He/she has difficulty expressing and experiencing emotions, decreased sexual desire, and a loss of interest in previously pleasurable activities, so much so that he/she gives the impression of thinking only of him/herself
[21][23]. He/she often feels tired and constantly threatened, has sudden outbursts of anger, and is continuously nervous. In addition, he/she has feelings of shame, despair, and guilt. This often impacts interpersonal and work relationships, hindering or making it impossible to lead an everyday life
[10][12]. Social withdrawal and frequent marital conflicts are often observed, leading to relationship breakdown and divorce, as significant others and the partner in this condition can feel neglected, rejected, or unloved
[22][24]. Similarly, the overall symptom picture at work often leads to frequent arguments with colleagues and superiors and a decline in performance, leading to dismissal
[22][24].
Medications must be considered more as an opportunity to nurture patient compliance and not as a treatment in itself; only very rarely do drugs bring about a complete remission of symptoms, so it is essential to combine psychotherapy
[23][35]. Some medications, such as fluoxetine, paroxetine, or venlafaxine, seem to have a positive effect on the symptoms of PTSD. Still, most others do not seem to have significant efficacy, highlighting the need for more research
[24][36]. It has been shown that the remission of symptoms achieved with psychotherapy (particularly Eye Movement Desensitization and Reprocessing, EMDR) remains over the long term
[25][37]. In contrast, using medication alone and its subsequent discontinuation can lead to rapid relapses. However, other studies have pointed out that there is no robust evidence to prove a better efficacy of the combination of psychotherapy and pharmacotherapy than either treatment modality taken alone
[26].
A new frontier in treating PTSD is using substances that can enhance the psychotherapy experience and enactment. Among these, exciting data have emerged on the use of MDMA
[27][38].
3. Current Psychotherapies in the Treatment of PTSD: Benefits and Limitations
One of the most widely recognized and evidence-based therapies for PTSD is cognitive–behavioral therapy (CBT)
[28][39], and several studies have proven the effectiveness of CBT in reducing PTSD symptoms and improving overall functioning
[29][30][40,41].
EMDR therapy is another highly effective approach for treating PTSD
[31][42]. EMDR integrates elements of CBT with bilateral stimulation, typically achieved by asking patients to focus on a therapist’s moving hand or using alternating sounds
[32][43]. This bilateral stimulation is theorized to help reprocess traumatic memories, thereby reducing the distress associated with them
[33][44]. EMDR also incorporates cognitive restructuring techniques, fostering a more positive belief system surrounding the traumatic event
[34][45]. Research has shown that EMDR significantly reduces PTSD symptoms and helps individuals experience significant improvement in their overall well-being
[31][35][42,46].
Narrative exposure therapy (NET) is a psychotherapeutic approach that is designed specifically for individuals who have experienced complex and multiple traumas
[36][47]. It emphasizes the importance of reconstructing a coherent narrative around the traumatic events and integrating it into the individual’s life story
[37][48]. NET combines exposure therapy, cognitive restructuring, and cognitive processing therapy
[38][49]. By creating a detailed and organized account of the traumatic experiences, NET allows individuals to gain a renewed sense of control and mastery over their memories and emotions
[39][50]. Multiple studies have demonstrated the efficacy of NET in reducing PTSD symptoms and improving overall psychological functioning
[40][41][51,52].
Alongside these therapies, acceptance and commitment therapy (ACT) has shown promising results in treating PTSD
[42][53]. ACT focuses on helping individuals accept their traumatic experiences and associated emotional responses without trying to suppress or change them. Through mindfulness techniques and identifying personal values, ACT helps individuals develop greater dynamic flexibility and engage in behaviors that align with their core values. This approach enables individuals to focus on living a meaningful life despite their traumatic past. Recent studies have indicated that ACT can help reduce PTSD symptoms, improve well-being, and enhance overall psychological flexibility
[42][43][53,54].
An “alternative” approach using MDMA during psychotherapy, if available, is an excellent option to treat resistant cases and overcome barriers
[44][67].
4. History of MDMA, Chemistry, and Pharmacokinetics
MDMA was synthesized in 1912 by the German company Merck when researchers were trying to develop a vasoconstrictor to stop bleeding
[45][46][68,69]. However, they accidentally discovered MDMA instead, called methylsafrylaminc
[47][70]. Between 1970 and 1980, MDMA was used by some psychiatrists, as they believed that it resulted in effective communication with patients, even though it was not approved by the FDA for human use or formal clinical trials
[48][49][71,72].
In 1985, the Drug Enforcement Agency (DEA) observed MDMA abuse as a nationwide problem and announced an emergency ban on MDMA, which was classified as a “Schedule I drug”
[48][71]. Then, in the mid-1990s, the US FDA approved the phase I trial of MDMA in healthy volunteers for the first time
[4].
Currently, the use of MDMA is restricted because of its high risk of abuse potential and side effects, and clinicians should weigh the risks vs. benefits of such a treatment. Although MDMA-assisted psychotherapy can be considered in reactive disorders such as PTSD, it can exacerbate some other mental health disorders, so it should be used cautiously
[50][73].
MDMA is a ring-substituted amphetamine that is structurally similar to methamphetamine and mescaline. It is usually present in two optical isomers, with the dextrorotatory form, S (+) MDMA, being more potent in the central nervous system (CNS)
[51][74]. The psychostimulant and empathic effects of MDMA are caused by the S (+) isomer, whereas the R isomer is responsible for its hallucinogenic properties
[52][75]. It is commonly given via the oral route, but it is also inhaled for a faster effect. MDMA is rapidly absorbed in the bloodstream, and two metabolic pathways metabolize it. The central metabolism pathway starts with demethylation by cytochrome P450 (CYP) 2D6 to intermediate 3,4-dihydroxy methamphetamine (HHMA). Then, after conversion to 4-hydroxy-3-methoxyamphetamine (HMA) following many steps in a minor pathway, it is N-demethylated to 3,4-methylenedioxyamphetamine MDA (which is sometimes used recreationally) before ending up in HMA
[53][76]. The combination of MDMA and HHMA is accountable for 58% of the total drug in the urine
[53][54][76,77].
When taken orally, its effects begin in 30 to 60 min and last up to 8 h, and its peak plasma concentrations occur 2 to 4 h after an oral dose. The half-life of MDMA is between 7.7 and 8.6 h. The 11 S (+) isomer has a 30% shorter half-life than the levorotatory form because its metabolism is faster and more extensive
[55][56][78,79].
Despite this, however, not all evil leads to harm. Paracelsus is considered the father of modern medicinal chemistry and toxicology. It was Paracelsus who said, “It is the dose that makes the poison” (in Latin, “Sola dosis facit venenum”). Even today, Paracelsus’s quote is true, especially for several specific substances, such as ketamine, psilocybin, Lysergic Acid Diethylamide (LSD), and MDMA. These substances, under strict control, at the proper doses, and in medical settings are an essential breakthrough in treating complex disorders such as major depression, substance abuse, and, obviously, PTSD. Therefore, MDMA, when used as a medication and not as a drug of abuse, can be helpful in treating several psychiatric disorders.
5. MDMA-Assisted Psychotherapy in PTSD: An Overview
Trauma-focused cognitive–behavioral therapy (CBT) and eye movement desensitization and reprocessing (EMDR) are the most common treatments for PTSD. A meta-analysis of published clinical trials from 1980 to 2003 on the clinical efficacy of psychotherapy for PTSD treatment by Bradley et al. showed that around 67% of patients completed treatment, and the recovery rate for PTSD averaged 50–60% who received therapy
[57][87]. PTSD is a complicated disorder that needs psychological and pharmacological intervention. Currently, only two similar-acting medication therapies—Sertraline and Fluoxetine—have been approved by the FDA
[58][59][27,88].
All current MDMA-based psychotherapies are randomized controlled trials that are monitored by the FDA and overseen by the Institutional Review Board (IRB)
[50][60][73,89]. Due to the schedule of MDMA, a level-controlled substance review committee is required. MDMA-assisted psychotherapy utilizes single-dose MDMA administration once a month, on two or three occasions, followed by preparatory and psychotherapy sessions
[50][61][73,90]. MDMA is a psychoactive compound that is commonly misused under the name of the street drug “Ecstasy,” which reduces the uptake of amines such as serotonin, dopamine, and norepinephrine from presynaptic terminals, thus contributing to overcoming anxiety and increased bonding
[62][63][91,92].
Investigations were conducted on MDMA-assisted psychotherapy for PTSD patients who had failed previous treatments. Marseille et al.
[49][72] conducted a cross-sectional study with 29 participants who received forgiveness treatment and 29 who received an inactive placebo as part of the control group. The results from the pre- and post-tests suggested that MDMA-assisted psychotherapy is helpful for those who have gone through psychological trauma but cannot find relief from their difficulties by using conventional treatments.
Interestingly, a study employed an Interpretative Phenomenological Analysis (IPA) for seven participants who met the criteria for severe PTSD to develop a better understanding of MDMA-assisted therapy and its efficacy
[64][108]. The subjects reported significantly improved conflict tolerance, connectedness, and positive emotions. In addition, they showed increased acceptance, self-forgiveness, and self-empathy, which are vital in addressing moral injury and the feelings of guilt and shame common in severe PTSD.
The abovementioned study also investigated how the use of psychedelics eased the effects of racial PTSD among black, indigenous, and other people of color (BIPOC) after experiencing racism
[65][109]. Questions on encounters with racism, mental health symptoms, and immediate and long-lasting psychedelic effects were included in the cross-sectional online study survey. In addition, retrospective reports of symptoms from the 30 days before and 30 days after an experience with psilocybin, lysergic acid diethylamide, or MDMA were used to measure changes in mental health. Three hundred thirteen volunteers from various BIPOC populations in the US and Canada were recruited for the study. Compared to before and after the psychedelic experience, the findings showed a substantial and modest reduction in PTSD symptoms.
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