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MDMA-assisted psychotherapy is the use of prescribed doses of MDMA as an adjunct to psychotherapy sessions. Research suggests that MDMA-assisted psychotherapy for post-traumatic stress disorder (PTSD), including Complex PTSD, might improve treatment effectiveness. [1] [2] [3] In 2017, a Phase II clinical trial led to "breakthrough therapy" designation by the US Food and Drug Administration (FDA) for potential use as a treatment for PTSD. [4] [5]
MDMA-assisted psychotherapy is currently under investigation as a treatment for various other mental health disorders, including Major Depressive Disorder, social anxiety in autistic individuals, alcohol use disorder, and mood disturbances in individuals facing life-threatening illnesses. [6] [7] [8] The research is controversial [9] [10] in part because recreational MDMA use has been associated with harmful effects among some users. [11] [9] [12]
Post-traumatic stress disorder (PTSD) is most commonly treated by cognitive behavioral therapy (particularly prolonged exposure and cognitive processing therapy), eye movement desensitization and reprocessing, and psychodynamic psychotherapy. However, over half of these patients continue to have PTSD after completing therapy, with results from military PTSD being especially poor. [13]
PTSD is best treated when a patient is in the 'optimal arousal zone'. This is the zone in which emotions are engaged yet not overwhelming. In this zone, four symptom clusters of PTSD are sedated: [10] These are:
Subjects with PTSD exhibit extreme emotional numbing or anxiety and struggle to remain in the optimal arousal zone during conservative therapies. Threatening interpretations of memories are reinforced when patients are in low emotional states. [14] If traumatic memories are revisited in therapy when a patient is not within the optimal arousal state, therapy for PTSD can actually increase the patient's trauma. [14]
When used in therapy, MDMA has been reported to increase empathy, closeness between patient and therapist, relaxation, motivation to engage with therapy and introspective thought, and reduce depression and anxiety. MDMA makes it easier for a patient to stay in the optimal arousal zone by decreasing feelings of anxiety and defensiveness when revisiting traumatic memories. [10] By increasing feelings of closeness and empathy, it can improve the patient's trust in the therapist and encourage introspective thought to reassess memories and actions. Furthermore, research suggests that treatment may improve the quality of sleep of individuals affected by PTSD-related sleep disturbances. [15] It is believed that these factors may increase the success rate of psychotherapy.
Adverse effects, which can last from a few hours to several days, include diminished appetite, anxiety, headache, jaw tightness, tinnitus, nausea, asthenia, fatigue, acute sinusitis, nasopharyngitis, upper respiratory tract infection, disturbance in attention, tremor, tics, dysuria, erythema, and depression. [16]
With FDA approval granted in 2017, MDMA has been authorized for use in research related to psychotherapy. [4] MDMA-assisted psychotherapy is currently under investigation as a potential treatment for various mental health disorders, encompassing PTSD, Major Depressive Disorder, social anxiety in autistic individuals, [6] alcohol use disorder, [7] and mood disturbances in individuals facing life-threatening illnesses. [8] A large proportion of this research has been focused on PTSD and Major Depressive Disorder.
A phase 3 study indicated that MDMA-assisted therapy represents a potential breakthrough treatment for severe PTSD that merits expedited clinical evaluation. [17] Based on this study, MDMA-assisted psychotherapy was granted breakthrough therapy designation by the FDA, a designation that indicates that there is preliminary evidence that an intervention might offer a substantial improvement over other options for a serious health condition. [5] However, given the lack of blinding, several researchers have postulated that the results of the phase 3 trial might be heavily influenced by expectancy effects. [18] [19] There are no trials comparing MDMA-assisted psychotherapy to already existing first-line psychological treatments for PTSD which seems to attain similar or elevated symptom reduction compared with that due to MDMA-assisted psychotherapy based on indirect evidence. [20]
There have been several studies that investigated MDMA-assisted psychotherapy as a potential treatment for Major Depressive Disorder (MDD). An analysis of six phase 2 trials showed a trend toward significance, while a phase 3 trial reported that MDMA-assisted psychotherapy had antidepressant effects. Given that unprocessed trauma is considered a causative factor in some individuals with depression, it has been proposed that the benefit observed in PTSD trials might be applicable to MDD as well. [21]
PTSD inhibits a subject's ability to respond appropriately to trauma-related stimuli. [10] The current model of PTSD proposes that it results from amplified and uncontrolled responses from the amygdala to trauma-specific cues. [14] Oxytocin, which is increased by MDMA, has been found to increase trust and emotional awareness and reduce amygdala responses as well as reduce coupling of the amygdala to brainstem regions associated with autonomic and behavioral characteristics of fear. [22] [23] [24] It has been proposed that these effects foster memory reconsolidation by allowing the patient to access the traumatic memory while feeling detached from the sense of imminent threat. [14] MDMA is believed to create neuroplasticity, which can help break habits associated with OCD and addiction.
MDMA was first synthesized by the German pharmaceutical company Merck KGaA in 1912 as an intermediate in the synthesis of a potential blood clotting medication. Its psychoactive effects were not noted until the early 1960s. In the 1970s and early 1980s, MDMA emerged as a novel psychotherapeutic tool. The medicine demonstrated a unique ability to create feelings of empathy, openness, and reduced fear. These early explorations laid the groundwork for its later use in treating conditions such as Post-Traumatic Stress Disorder (PTSD). [25] Alexander Shulgin, an American chemist, synthesized MDMA in order to investigate its properties and was responsible for introducing the compound to a small number of American psychiatrists in the early 1970s. Shuglin and another chemist, David E. Nichols, are credited with publishing the first report regarding the effects and pharmacology of MDMA in humans. [26]
Psychotherapists using MDMA for therapeutic purposes initially desired to keep its use within the clinical research community; however, the medication gained popularity in the club scene in the early 1980s. This eventually led to the drug being classified as a Schedule One substance by the US Drug Enforcement Administration (DEA) in 1986. The scheduling of MDMA made it illegal to manufacture, possess, or distribute, essentially ending the practice of MDMA-assisted psychotherapy in the US. Despite this, MDMA continued to be used recreationally in the club and rave scene. [26]
Switzerland continued to study the drug for use in individual, couple, and group therapies until 1993, when the Swiss Ministry of Health withdrew permission to use MDMA and LSD by psychiatrists due to concerns about a lack of research methodology. Over 100 patients in Switzerland with a variety of mental illnesses were treated with MDMA-assisted psychotherapy during this time frame. [26]
In 1986, MDMA was classed as a Schedule One drug by the United Nations according to its Convention on Psychotropic Substances of 1971 due to increasing rates of non-clinical use and police seizures, along with its high potential for abuse. [10] [26] MDMA has remained a Schedule One substance since 1986, and most research was stopped at that time. In response to this, researchers interested in MDMA for use in psychotherapy founded and funded the US-based non-profit research organization, Multidisciplinary Association for Psychedelic Studies (MAPS). [26] MAPS is now one of the leading organizations funding research on psychedelic and controlled substances.
The US Food and Drug Administration (FDA) and Drug Enforcement Administration (DEA) granted approval for researching MDMA's efficacy as an adjunct to psychotherapy in 2004, and the first trial was carried out in 2011. [10] [27] In 2023, MAPS announced that it is compiling data from 18 different phase 2 and phase 3 studies with plans to file a New Drug Application with the FDA. MAPS hopes to receive FDA approval by the end of 2024. [27]
In July 2023, Australia became the first country to approve the legal use of MDMA-assisted psychotherapy for the treatment of depression and PTSD. [28]
MDMA's effects vary across people and settings and include adverse outcomes. [9] [12] The drug causes neurotransmitter activation across the main neural pathways (including serotonin and dopamine, noradrenaline) that can result in large mood swings. The memories that emerge under the influence of MDMA can evoke unwanted emotions. [9] Side effects of MDMA use by recreational users include appetite fluctuations, food cravings, and disordered eating. [9]
Once the effects of MDMA wear off, there is a "period of neurochemical depletion" that invokes anhedonia, lethargy, anger, depression, irritability, brooding, greater everyday stress, altered pain thresholds, changes in sleep, and bad dreams, especially in female participants. [9] The symptoms are thought to be due to the depletion of serotonin, as a result of the large release of serotonin triggered by MDMA and have been called "neurotoxic in terms of causing serotonergic dysfunction." [9]
There are also concerns surrounding "drug-dependent learning" — the theory that patients will return to the drug to access the state they were in when on the drug in therapy. [9]
There were 92 MDMA-related deaths in England and Wales in 2018, up from 56 the year before, [29] and 10,000 hospitalizations for MDMA-related illness/injury in 2011 in the US. [11] However, as of 2021, there have been no such cases reported for clinical settings.
Media reports and statements of academic authors have often transmitted the view of MDMA as a possible medicine or treatment rather than as an adjunct to psychotherapy. [10] This has been considered dangerous because it could lead people to believe that MDMA is an effective treatment alone, without concomitant psychotherapy. [10]
3,4-Methyl
Post-traumatic stress disorder (PTSD) is a mental and behavioral disorder that develops from experiencing a traumatic event, such as sexual assault, warfare, traffic collisions, child abuse, domestic violence, or other threats on a person's life or well-being. Symptoms may include disturbing thoughts, feelings, or dreams related to the events, mental or physical distress to trauma-related cues, attempts to avoid trauma-related cues, alterations in the way a person thinks and feels, and an increase in the fight-or-flight response. These symptoms last for more than a month after the event. Young children are less likely to show distress, but instead may express their memories through play. A person with PTSD is at a higher risk of suicide and intentional self-harm.
Dialectical behavior therapy (DBT) is an evidence-based psychotherapy that began with efforts to treat personality disorders and interpersonal conflicts. Evidence suggests that DBT can be useful in treating mood disorders and suicidal ideation as well as for changing behavioral patterns such as self-harm and substance use. DBT evolved into a process in which the therapist and client work with acceptance and change-oriented strategies and ultimately balance and synthesize them—comparable to the philosophical dialectical process of thesis and antithesis, followed by synthesis.
Empathogens or entactogens are a class of psychoactive drugs that induce the production of experiences of emotional communion, oneness, relatedness, emotional openness—that is, empathy or sympathy—as particularly observed and reported for experiences with 3,4-methylenedioxymethamphetamine (MDMA). This class of drug is distinguished from the classes of hallucinogen or psychedelic, and amphetamine or stimulants. Major members of this class include MDMA, MDA, MDEA, MDOH, MBDB, 5-APB, 5-MAPB, 6-APB, 6-MAPB, methylone, mephedrone, GHB, αMT, and αET, MDAI among others. Most entactogens are phenethylamines and amphetamines, although several, such as αMT and αET, are tryptamines. When referring to MDMA and its counterparts, the term MDxx is often used. Entactogens are sometimes incorrectly referred to as hallucinogens or stimulants, although many entactogens such as ecstasy exhibit psychedelic or stimulant properties as well.
Psychedelic therapy refers to the proposed use of psychedelic drugs, such as psilocybin, MDMA, LSD, and ayahuasca, to treat mental disorders. As of 2021, psychedelic drugs are controlled substances in most countries and psychedelic therapy is not legally available outside clinical trials, with some exceptions.
Nightmare disorder is a sleep disorder characterized by repeated intense nightmares that most often center on threats to physical safety and security. The nightmares usually occur during the REM stage of sleep, and the person who experiences the nightmares typically remembers them well upon waking. More specifically, nightmare disorder is a type of parasomnia, a subset of sleep disorders categorized by abnormal movement or behavior or verbal actions during sleep or shortly before or after. Other parasomnias include sleepwalking, sleep terrors, bedwetting, and sleep paralysis.
The Multidisciplinary Association for Psychedelic Studies (MAPS) is an American nonprofit organization working to raise awareness and understanding of psychedelic substances. MAPS was founded in 1986 by Rick Doblin and is now based in San Jose, California.
Treatment-resistant depression (TRD) is major depressive disorder in which an affected person does not respond adequately to at least two different antidepressant medications at an adequate dose and for an adequate duration. Inadequate response has most commonly been defined as less than 25% reduction in depressive symptoms following treatment with an antidepressant. Many clinicians and researchers question the construct validity and clinical utility of treatment-resistant depression as currently conceptualized.
In applied psychology, interventions are actions performed to bring about change in people. A wide range of intervention strategies exist and they are directed towards various types of issues. Most generally, it means any activities used to modify behavior, emotional state, or feelings. Psychological interventions have many different applications and the most common use is for the treatment of mental disorders, most commonly using psychotherapy. The ultimate goal behind these interventions is not only to alleviate symptoms but also to target the root cause of mental disorders.
Prolonged exposure therapy (PE) is a form of behavior therapy and cognitive behavioral therapy designed to treat post-traumatic stress disorder. It is characterized by two main treatment procedures – imaginal and in vivo exposures. Imaginal exposure is repeated 'on-purpose' retelling of the trauma memory. In vivo exposure is gradually confronting situations, places, and things that are reminders of the trauma or feel dangerous. Additional procedures include processing of the trauma memory and breathing retraining.
Substituted amphetamines are a class of compounds based upon the amphetamine structure; it includes all derivative compounds which are formed by replacing, or substituting, one or more hydrogen atoms in the amphetamine core structure with substituents. The compounds in this class span a variety of pharmacological subclasses, including stimulants, empathogens, and hallucinogens, among others. Examples of substituted amphetamines are amphetamine (itself), methamphetamine, ephedrine, cathinone, phentermine, mephentermine, tranylcypromine, bupropion, methoxyphenamine, selegiline, amfepramone (diethylpropion), pyrovalerone, MDMA (ecstasy), and DOM (STP).
PTSD or post-traumatic stress disorder, is a psychiatric disorder characterised by intrusive thoughts and memories, dreams or flashbacks of the event; avoidance of people, places and activities that remind the individual of the event; ongoing negative beliefs about oneself or the world, mood changes and persistent feelings of anger, guilt or fear; alterations in arousal such as increased irritability, angry outbursts, being hypervigilant, or having difficulty with concentration and sleep.
The Spring Grove Experiment is a series of lysergic acid diethylamide (LSD) studies performed from 1963 to 1976 on patients with psychotic illnesses at the Spring Grove Clinic in Catonsville, Maryland. These patients were sponsored by the National Institute of Mental Health to be part of the first study conducted on the effects of psychedelic drugs on people with schizophrenia. The Spring Grove Experiments were adapted to study the effect of LSD and psychotherapy on patients including alcoholics, heroin addicts, neurotics, and terminally-ill cancer patients. The research done was largely conducted by the members of the Research Unit of Spring Grove State Hospital. Significant contributors to the experiments included Walter Pahnke, Albert Kurland, Sanford Unger, Richard Yensen, Stanislav Grof, William Richards, Francesco Di Leo, and Oliver Lee McCabe. Later, Spring Grove was rebuilt into the Maryland Psychiatric Research Center where studies continued to be performed for the advancement of psychiatric research. This study on LSD is the largest study on psychedelic drugs to date.
Psilocybin therapy is the use of psilocybin in treating a range of mental health conditions, such as depression, anxiety, addictions, obsessive compulsive disorder, and psychosis. It is one of several forms of psychedelic therapy under study. Psilocybin was popularized as a psychedelic recreational drug in the 1970s and was classified as a Schedule I drug by the DEA. Research on psilocybin as a medical treatment was restricted until the 1990s because of the sociocultural fear of dependence on this drug. As of 2022, psilocybin is the most commonly researched psychedelic due to its safety and low potential for abuse and dependence. Clinical trials are being conducted at universities and there is evidence confirming the use of psilocybin in the treatment of depression, PTSD and end of life anxiety.
Post-traumatic stress disorder (PTSD) can affect about 3.6% of the U.S. population each year, and 6.8% of the U.S. population over a lifetime. 8.4% of people in the U.S. are diagnosed with substance use disorders (SUD). Of those with a diagnosis of PTSD, a co-occurring, or comorbid diagnosis of a SUD is present in 20–35% of that clinical population.
Una D. McCann is a board certified psychiatrist and researcher at Johns Hopkins School of Medicine in the Department of Psychiatry. She is also the Director of the Anxiety Disorders Program, and Co-Director of the Center for Interdisciplinary Sleep Medicine and Research, and Associate Program Director at the Johns Hopkins Bayview Medical Center. McCann is considered to be an expert in anxiety and stress disorders and her primary areas research revolves around amphetamine-induced monoamine neurotoxicity and neurobiology of anxiety disorders.
Psychoplastogens are a group of small molecule drugs that produce rapid and sustained effects on neuronal structure and function, intended to manifest therapeutic benefit after a single administration. Several existing psychoplastogens have been identified and their therapeutic effects demonstrated; several are presently at various stages of development as medications including ketamine, MDMA, scopolamine, and the serotonergic psychedelics, including LSD, psilocin, DMT, and 5-MeO-DMT. Compounds of this sort are being explored as therapeutics for a variety of brain disorders including depression, addiction, and PTSD. The ability to rapidly promote neuronal changes via mechanisms of neuroplasticity was recently discovered as the common therapeutic activity and mechanism of action.
Psychedelic treatments for trauma-related disorders are the use of psychedelic substances, either alone or used in conjunction with psychotherapy, to treat trauma-related disorders. Trauma-related disorders, such as post-traumatic stress disorder (PTSD), have a lifetime prevalence of around 8% in the US population. However, even though trauma-related disorders can hinder the everyday life of individuals with them, less than 50% of patients who meet criteria for PTSD diagnosis receive proper treatment. Psychotherapy is an effective treatment for trauma-related disorders. A meta-analysis of treatment outcomes has shown that 67% of patients who completed treatment for PTSD no longer met diagnostic criteria for PTSD. For those seeking evidence-based psychotherapy treatment, it is estimated that 22-24% will drop out of their treatment. In addition to psychotherapy, pharmacotherapy (medication) is an option for treating PTSD; however, research has found that pharmacotherapy is only effective for about 59% of patients. Although both forms of treatment are effective for many patients, high dropout rates of psychotherapy and treatment-resistant forms of PTSD have led to increased research in other possible forms of treatment. One such form is the use of psychedelics.
Ketamine-assisted psychotherapy(KAP) is the use of prescribed doses of ketamine, the drug, as an adjunct to psychotherapy sessions. KAP shows significant potential in treating mental disorders such as treatment-resistant depression (TRD), anxiety, obsessive–compulsive disorders (OCD), post-traumatic stress disorders (PTSD), and other conditions. It can also be used for those experiencing substance abuse and physical pain. While it is primarily used as a veterinary anaesthetic, ketamine has also been found to have rapid analgesic and hallucinogenic effects, which has sparked interest in its use as an antidepressant. Despite initial trials of its use in the treatment of mental disorders focussing primarily on its antidepressant effects, newer studies are attempting to harness its psychedelic effects to bring about altered states of consciousness, which will augment the adjunct psychotherapy. Ketamine's neuroplasticity-promoting effects strengthen the cognitive restructuring that takes place through traditional psychotherapy, thereby leading to long-lasting behavioural change. KAP offers promising directions for research on new antidepressant alternatives, but is still not sufficiently defined or evaluated as a treatment combination.