Treatment of Anxiety and Other Psychological Distress Associated With Terminal Illnesses with MDMA-Assisted Psychotherapy

The triumph of modern medicine has led to an increase in the number of people with life-threatening illnesses (LTI), many of whom also suffer from existential anguish, sadness, and anxiety. We explore a unique strategy for treating anxiety in LTI patients by using MDMA-assisted psychotherapy.

• In a double-blind trial, participants with anxiety after an LTI were randomized to receive MDMA (125 mg, n = 13) or a placebo (n = 5) along with two 8-hour psychotherapy sessions. The State-Trait Anxiety Inventory (STAI) Trait score change from baseline to one month after the second experimental session was the main result.

After unblinding, those in the MDMA group underwent one open-label MDMA session, whereas those in the placebo group switched over and underwent three open-label MDMA sessions. 

Introduction

People who are dealing with or have dealt with a life-threatening illness (LTI) struggle with more than simply their physical symptoms. Even after a remission or recovery is attained, feelings of anxiety, melancholy, wrath, and despair frequently make the distress the sickness itself had previously caused worse1. Survivors frequently worry about relapse, recurrence, and passing away.

The trauma of a fatal illness is frequently severe and challenging to integrate into one’s ability to move on with one’s life. LTIs can also have a significant negative effect on family, medical professionals, and the community, which can hinder recovery. There has also been a notable rise in caregiver distress. New therapeutic approaches are desperately needed to deal with the psychological anguish brought on by LTIs.

Early research using psychedelic substances like lysergic acid diethylamide (LSD) revealed that psychoactive drugs might be effective in treating patients with LTIs’ discomfort, suffering, and anxiety. According to research results published between 2011 and 2016, psilocybin and lysergic acid diethylamide (LSD) are particularly effective at treating depression, anxiety, and psycho-existential distress in people with LTIs, including those who are terminally ill. Randomized, placebo-controlled studies found that, compared to controls, there was a reduction in anxiety and depressive symptoms.

• There is some evidence that this symptom reduction may be related to the subjective drug effects, such as the intensity of a mystical experience. There are several similarities between the techniques employed in psychedelic-assisted psychotherapy and manualized 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy.

The use of MDMA as a psychotherapy add-on for a variety of anxiety-related illnesses is now being studied. The FDA designated MDMA-assisted psychotherapy as a Breakthrough Therapy for the treatment of posttraumatic stress disorder (PTSD) in 2017 as a result of compelling findings from six Phase 2 studies.

• When compared to those who received an inactive placebo or low-dose MDMA, those who received active-dose MDMA (75-125 mg) with psychotherapy showed considerably higher reductions in PTSD symptoms (0-40 mg). Additionally, MDMA-assisted psychotherapy decreased depressive symptoms and enhanced sleep.

Leibowitz Social Anxiety Scale (LSAS) Total score improvements were also shown to be considerably greater in the MDMA group compared to the placebo group in a trial of MDMA-assisted psychotherapy in autistic people with social anxiety.

• Serotonin, dopamine, and norepinephrine release are stimulated, oxytocin levels are raised, amygdala and right insular activity in response to negative emotional stimuli are decreased, superior frontal cortex activity is increased, and amygdala-hippocampus connection is increased. These investigations evaluated neural activity in these regions using the functional magnetic resonance imaging (fMRI), blood oxygen level dependent imaging, or BOLD-contrast imaging techniques. The effects of MDMA can boost self-compassion, improve learning to overcome fears, and lessen anxiety when confronted with emotionally taxing ideas or memories.

People with LTIs frequently suffer worry and intrusive thoughts about their illnesses, which are hallmarks of PTSD, and they may believe that receiving an LTI diagnosis and/or subsequent medical therapy would cause them to acquire PTSD. Following a cancer diagnosis, myocardial infarction, or stroke, PTSD or symptoms similar to it are frequently reported.

• Several individuals in a prior trial of MDMA-assisted psychotherapy also described an LTI or medical treatment as being analogous to an index trauma. A study was designed to evaluate the effectiveness of MDMA-assisted psychotherapy in people with LTI-related anxiety in light of the positive results of this treatment in people with PTSD and social anxiety.

The purpose of this pilot study was to investigate the efficacy and safety of MDMA-assisted psychotherapy for treating anxiety and other psychological symptoms associated with an LTI in patients with cancer or non-dementing neurological disorders. The creation of more extensive clinical trials will be guided by the preliminary findings there.

Findings

Between May 2015 and February 2017, a total of 18 participants who satisfied the study’s eligibility requirements were enrolled. They were then randomly assigned to receive either MDMA (n = 13) or a placebo (n = 5). Ninety-two of the initial 110 participants that were assessed did not match the criterion for inclusion during telephone screening. Not living in the study area and not being physically healthy enough to participate in the study due to a life-threatening illness were the main grounds for exclusion. Three participants were eliminated after enrolment and before randomization because they did not match the study enrollment criteria, while a few others were lost to follow-up. The whole sample was primarily female (77.8%) and White/Caucasian (83.3%), with a mean (SD) age of 54.9 (7.9) years.

• Each subject had previously received an LTI diagnosis. One participant had a main diagnostic of musculoskeletal and connective tissue condition, while 94.4% of participants had a diagnosis of neoplasms. Many of the individuals had prior diagnoses of anxiety (83.3%), major depression (77.8%), PTSD (72.2%), or insomnia (61.1%), according to medical histories. At the outset, it was determined that all participants had moderate to severe anxiety, with a mean (SD) STAI-Trait score of 61.1 (7.0) and a STAI-State score of 57.4. (10.9).

• The Structured Clinical Interview for DSM-IV Axis Disorders – Patient Edition (SCID-I/P Version 2.0) assessment conducted during intake revealed that the participants’ baseline anxiety was mostly caused by symptoms connected to their LTIs. 39.0% of the study’s 18 participants, seven out of them, reported using an opioid prescription at some point. At least three days before and two days after a blinded or unblinded MDMA session, six opiate drugs were discontinued. One member in the full-dose group admitted to taking a drug during the trial that contained tramadol, an opioid with some serotonergic activity, but not taking the drug prior to, during, or within 24 hours following an experimental session.

Discussion

In the current study, MDMA-assisted psychotherapy for people with moderate to severe anxiety related to life-threatening conditions was investigated. Although group differences did not achieve statistical significance (p = 0.056), the primary analysis showed that participants who underwent MDMA-assisted psychotherapy saw higher decreases in anxiety (STAI-Trait) than those in the placebo group.

• One apparent outlier in the control group, who experienced a notably large reduction in their STAI-Trait score (change score of 35) compared to the placebo group’s median (IQR) reduction of 3 in this study sample, probably contributed to the lack of statistical significance (1.0). When this outlier was taken into account, the group difference became statistically significant (p = 0.0066).

• Furthermore, 2 of 5 people who took a placebo thought they were in the MDMA group, which may have had a placebo effect. The impact of outliers and other biases would therefore need to be properly identified and mitigated, which would require a bigger sample. The FFMQ mindfulness and PTGI total scores, a measure of increased felt advantages or positive impacts after a challenging encounter, significantly improved at the primary endpoint among the MDMA group after two MDMA sessions. Additionally, depression, sleep quality, STAI-State anxiety, and general functioning all improved in the MDMA group.

Results from the study’s blinded section call for larger clinical studies to investigate MDMA-assisted psychotherapy as a unique strategy for treating people who experience anxiety due to LTI. The relationship between outcome measures, as well as the identification of relevant factors that may mediate or moderate the primary end outcomes, can be clarified by the data from these trials.

The overall sample showed improvements in anxiety, depression, sleep, overall functioning, wellbeing (i.e., physical, social and family, emotional, functional), self-compassion, mindfulness, and attitudes toward death after MDMA and Placebo/MDMA group participants underwent three MDMA sessions from baseline to treatment exit. The lack of a control group to rule out the influence of other factors in the long-term advantages was one of the drawbacks of the long-term follow-up data. However, these results remained steady and above baseline levels at the 6- and 12-month follow-up visits, suggesting that MDMA-assisted psychotherapy may be able to provide long-term advantages of up to one or more years.

• The participants’ ratings on the subscales of the Death Attitude Profile that measure fear of death, neutral acceptance, and approach acceptance improved, which may have helped them feel less anxious about their LTI. These results were in line with research on psilocybin-assisted psychotherapy, which found that persons with LTIs experienced changes in attitudes toward death. Greater emotional and functional quality of life at the study’s endpoint served as evidence that participants’ attitudes toward mortality as well as their everyday coping techniques changed after taking MDMA.

• These preliminary results imply that MDMA-assisted psychotherapy may have the ability to offer serious sickness patients and those recovering from serious illnesses long-term advantages. Additional investigation is required to study potential mechanisms of MDMA-assisted psychotherapy, particularly the function of conceivable mediators and moderators in lowering anxiety caused by LTI.

The benefits of MDMA-assisted psychotherapy on anxiety and other symptoms have a number of plausible explanations. According to earlier research, PTSD can develop in persons with chronic illnesses who are receiving treatment, and its symptoms can even last years after the patient’s condition has improved.

• The effect of MDMA on decreasing amygdala activity and enhancing frontal lobe activity during the presentation of negative stimuli may be one method by which it lessens the symptoms of PTSD. Seventy-two percent of participants in the current sample with an LTI also had a PTSD diagnosis in their medical records. It is possible that traumas and complicated emotions were dealt with through similar neural mechanisms and therapeutic processing, even though the index trauma for the PTSD diagnoses was not gathered.

MDMA has been referred to as a “heart-opening” therapeutic drug that promotes self-awareness, introspection, and empathy for others and oneself. MDMA’s effects enable empathetic executive function intervention toward oneself and others. Reduced right insular activity may lessen anxiety by reducing attention to and worry about the physical symptoms of anxiety.

• The salience network appears to be mostly unaffected by MDMA-induced changes in connection, and only certain parts of the network appear to be affected. Improved oxytocin, higher serotonergic activity, increased self-compassion, and prosocial interactions with others are additional neurochemical and behavioral effects of MDMA that can improve rapport and trust with therapists.

When used in conjunction with psychotherapy, MDMA has been shown to consistently reduce the symptoms of post-traumatic stress disorder (PTSD) in people who have not responded well to previous psychotherapeutic or pharmacological therapies. In the blinded portion of the trial, the MDMA group showed a tendency toward fewer psychiatric symptoms linked with LTIs, such as anxiety, depression, and self-reported poor sleep quality, compared to the placebo group. Acute changes in memory and emotional processing-related brain circuits could have allowed participants to approach emotionally upsetting memories or ideas with empathy and compassion rather than feeling overwhelmed by anxiety when under the influence of MDMA.

• Prior research in healthy adults found that taking MDMA decreased the intensity and vividness of people’s “worst” memories while increasing the vividness and intensity of their emotionally favorable memories. By embracing compassion for oneself, others, and one’s circumstance, this technique may aid those with LTIs by lowering worries of disease recurrence or death in the setting of psychotherapy.
• Three MDMA-assisted psychotherapy sessions for people with LTIs resulted in long-term reductions in anxiety as measured by the MADRS at the 6- and 12-month follow-ups, as well as significantly improved posttraumatic growth or perceived benefits from an LTI, mindfulness (FFMQ), social and family wellbeing (FACIT-S).

Safety tests showed that MDMA was well tolerated by people with an LTI, in line with earlier studies from PTSD samples, and no participants quit therapy as a result of MDMA-related side effects. With the exception of the body temperature, vital indicators in the MDMA group increased to predicted levels after dosing. During the experimental sessions, the MDMA group also reported more negative side effects, such as tightening of the jaw, thirst, dry mouth, and perspiration.

The majority of the time, reactions disappeared by the end of an experimental session or the following week. Reactions were brief in nature. Adverse psychiatric events were rare, and MDMA was not linked to significant suicidal conduct or ideation. In this very small sample, the benefits of MDMA-assisted psychotherapy surpassed the costs of moderate and transient side effects, according to the overall safety profile for MDMA in this controlled clinical context. Future research should keep assessing the risks of unfavorable outcomes in a wider sample of patients with life-threatening conditions.

Summation

These results offer early support for the possibility that LTI patients with anxiety reduction and remission of other mental symptoms of their condition may benefit from MDMA-assisted psychotherapy, which is safe and practicable. According to study findings, MDMA-assisted psychotherapy is a viable option for the long-term management of anxiety caused by LTI. Future clinical trials with greater sample sizes and more diverse demographics will be developed using the information from these findings.