Shroom & Magic MushroomMDMA-Assisted Psychotherapy for Treatment of Anxiety and Other Psychological Distress Related to Life-Threatening Illnesses

October 21, 2021by Dr.Jake Donaldson0



The success of modern medicine creates a growing population of those suffering from life-threatening illnesses (LTI) who often experience anxiety, depression, and existential distress. We present a novel approach, investigating MDMA-assisted psychotherapy for the treatment of anxiety in people with an LTI. Participants with anxiety from an LTI were randomized in a double-blind study to receive MDMA (125 mg, n = 13) or placebo (n = 5) in combination with two 8-h psychotherapy sessions. The primary outcome was change in State-Trait Anxiety Inventory (STAI) Trait scores from baseline to one month post the second experimental session. After unblinding, participants in the MDMA group had one open-label MDMA session and placebo participants crossed over to receive three open-label MDMA sessions. Additional follow-up assessments occurred six and twelve months after a participant’s last experimental session. Overall, MDMA was well-tolerated in this sample. These preliminary findings can inform development of larger clinical trials to further examine MDMA-assisted psychotherapy as a novel approach to treat individuals with LTI-related anxiety.




Individuals facing, or who have faced, a life-threatening illness (LTI), contend with more than just the physical symptoms of their condition. Anxiety, depression, anger, and despair often exacerbate the distress already caused by the illness itself, even after a remission or cure is achieved1. It is common for survivors to harbor fears of potential relapse, recurrence, and death2. The trauma of a devastating illness is often deep and difficult to integrate into moving on with one’s life. Additionally, the impact of LTIs on family, health care providers, and community can be profound and affect recovery. A significant increase in caregiver distress is also prevalent. There is a great need for new treatment options to address the psychological distress associated with LTIs. The social and personal burden of the immense numbers of people surviving LTIs necessitates our full attention and care.

Early investigations with psychedelic compounds such as lysergic acid diethylamide (LSD) suggested that psychoactive substances held promise in addressing distress, pain, and anxiety in people with LTI’s. Findings from studies reported from 2011 to 2016 provide evidence for the use of psychedelics, specifically psilocybin and lysergic acid diethylamide (LSD), as an efficacious modality for the treatment of depression, anxiety, and psycho-existential distress among those with LTIs, including the terminally ill. Randomized, placebo-controlled trials reported reduction in symptoms of anxiety and depression compared with controls, with some indication that symptom reduction might be linked to subjective drug effects, such as strength of a mystical experience. Manualized 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy shares a number of similarities with methods used in psychedelic-assisted psychotherapy.

MDMA is under investigation as an adjunct to psychotherapy for various anxiety-related conditions. Compelling results from six Phase 2 studies led the FDA to issue a Breakthrough Therapy designation for MDMA-assisted psychotherapy for treatment of posttraumatic stress disorder (PTSD) in 2017. In the Phase 2 trials, participants who were given active-dose MDMA (75–125 mg) and psychotherapy experienced significantly greater reductions in PTSD symptoms when compared with participants given inactive placebo or low-dose MDMA (0–40 mg). MDMA-assisted psychotherapy also reduced symptoms of depression and improved sleep quality. A study of MDMA-assisted psychotherapy in autistic adults with social anxiety also found significantly greater improvement in Leibowitz Social Anxiety Scale (LSAS) Total scores in the MDMA group compared to the placebo group.

MDMA stimulates release of monoamines (serotonin, dopamine, and norepinephrine), elevates levels of the neurohormone oxytocin, reduces amygdala and right insular activity in response to negative emotional stimuli, increases superior frontal cortex activity, and increases connectivity between the amygdala and hippocampus. In such studies, functional magnetic resonance imaging (fMRI) technique, blood oxygen level dependent imaging, or BOLD-contrast imaging, was used to assess neuronal activity in these regions. The effects of MDMA may reduce anxiety in the face of emotionally challenging thoughts or memories and can increase self-compassion and enhance fear-extinction learning. People with LTIs often experience anxiety and intrusive illness-related thoughts similar to symptoms of PTSD and may perceive or even develop PTSD from receiving an LTI diagnosis and/ or subsequent medical care. PTSD or PTSD-like symptoms are often reported after a cancer diagnosis, myocardial infarction, or stroke; and several participants in previous study of MDMA-assisted psychotherapy have reported an LTI or a medical treatment to be comparable to an index trauma. Considering the promising effects of MDMA-assisted psychotherapy in individuals with PTSD and social anxiety, a study was developed to assess MDMA-assisted psychotherapy in people with LTI-related anxiety.

The aim of this pilot study was to examine the safety and efficacy of MDMA-assisted psychotherapy, among patients with cancer or non-dementing neurological diseases, to alleviate anxiety and other psychiatric symptoms, including depression and poor sleep quality, related to an LTI. There preliminary results will serve to inform development of larger clinical trials.

Summary of Findings


A total of 18 participants who met eligibility criteria were enrolled in the study between May 2015 to February 2017 and randomized to either receive MDMA (n = 13) or placebo (n = 5). Ninety-two of 110 participants who were initially screened failed to meet the inclusion criteria at telephone screening. The primary reasons for exclusion included not living in the study area and not being physically well enough, due to having a life-threatening illness, that prevented study participation. A few were lost to follow-up and three participants were excluded after enrollment and prior to randomization because they did not meet the study enrollment criteria. The overall sample had a mean (SD) age of 54.9 (7.9) years and was mostly female (77.8%) and White/Caucasian (83.3%).


All participants had a prior diagnosis of an LTI. For the primary diagnosis for study inclusion, 94.4% had a diagnosis of neoplasms and one participant had a diagnosis categorized as a musculoskeletal and connective tissue disorder. Medical histories indicated that many of the participants were previously diagnosed with anxiety (83.3%), major depression (77.8%), PTSD (72.2%), or insomnia (61.1%). All participants were found to have moderate to severe anxiety at baseline, with a mean (SD) STAI-Trait score of 61.1 (7.0) and STAI-State score of 57.4 (10.9). Assessment of the Structured Clinical Interview for DSM-IV Axis Disorders—Patient Edition (SCID-I/P Version 2.0) during intake indicated that the baseline anxiety experienced by participants mostly stemmed from symptoms related to their LTIs. Seven of 18 participants (39.0%) reported taking an opioid medication during the course of the study. Six discontinued opiate medications at least three days prior to and two days after a blinded or unblinded MDMA session. One full-dose group participant reported taking a medication containing tramadol, an opiate with some serotonergic activity, during the course of the study but did not take the medication before, during, or within 24 hours after an experimental session.




The present study examined MDMA-assisted psychotherapy for individuals with moderate to severe anxiety associated with life-threatening illnesses. The primary analysis indicated participants who received MDMA-assisted psychotherapy had greater reductions in anxiety (STAI-Trait), compared to those in the placebo group, although group differences did not reach statistical significance (p = 0.056). In this study sample, lack of statistical significance was likely influenced by one potential outlier in the control group who had a particularly large reduction in their STAI-Trait score (change score of − 35) compared to the placebo group’s median (IQR) reduction of − 3 (1.0). Exclusion of this outlier rendered the group difference statistically significant (p = 0.0066). Additionally, 2 of 5 placebo participants believed they were in the MDMA group which might have produced a placebo effect. Therefore, a larger sample would be needed to adequately identify/mitigate the impact of outliers and other biases. At the primary endpoint, among the MDMA group, after two MDMA sessions, there were significant improvements in FFMQ mindfulness and PTGI total scores, an indicator of greater perceived benefits or positive effects after a difficult experience. Other symptom improvements in the MDMA group included depression, sleep quality, STAI-State anxiety, and global functioning. Results from the blinded portion of the study warrant larger clinical trials to examine MDMA-assisted psychotherapy as a novel approach to treat individuals who suffer from LTI-related anxiety. Data from these trials can also elucidate the relationship between outcome measures including identification of potential covariates that may mediate or moderate the primary outcome results.


After MDMA and Placebo/ MDMA group participants received three MDMA sessions, from baseline to treatment exit, the overall sample had improvements in anxiety, depression, sleep, global functioning, wellbeing (i.e., physical, social and family, emotional, functional), self-compassion, mindfulness, and attitudes regarding death. There were limitations in the long-term follow-up results, specifically, lack of a control group to eliminate the role of other factors in long-term benefits. However, at the 6- and 12-month follow-up visits, these outcomes were stable and above baseline levels, which suggests the potential for MDMA-assisted psychotherapy to produce long-term benefits of up to one or more years. Death Attitude Profile subscale scores improved for fear or death, neutral acceptance, and approach acceptance to suggest that some relief regarding participants’ attitudes about death could have reduced their LTI-related anxiety. These results were consistent with findings from a study on psilocybin-assisted psychotherapy, which reported people with LTIs had changes in death-related attitudes. Participants’ attitudes towards death shifted after MDMA, as well as their daily coping mechanisms, as demonstrated by greater emotional and functional quality of life at the study endpoint. These preliminary findings suggest that MDMA-assisted psychotherapy might have the potential to provide long-term benefits for people who have or are overcoming a serious illness. Further research is also needed to examine possible mechanisms of MDMA-assisted psychotherapy including the role of potential mediators and moderators in reducing LTI-related anxiety.


There are several possible explanations for the effects of MDMA-assisted psychotherapy on anxiety and other symptoms. Previous studies have reported that PTSD can occur among people with chronic illnesses undergoing treatment, and that PTSD symptoms even persist long after remission. A possible mechanism for MDMA reducing PTSD symptomology could be MDMA’s effect of decreasing amygdala activity, during presentation of negative stimuli, and increasing frontal lobe activity. In the current sample with an LTI, a large number of participants (72.2%) also had a PTSD diagnosis in their medical history. Although the index trauma for the PTSD diagnoses was not collected, it is likely that traumas and complex emotions were addressed through similar neural mechanisms and therapeutic processing. MDMA has previously been described as a “heart-opening” therapeutic substance, which stimulates mindfulness, introspection, and empathy toward oneself and others. The effects of MDMA allow for empathic intervention of executive functions toward oneself and others. Reduction in right insular activity may reduce anxiety through reducing attention and concern over the bodily experience of anxiety. MDMA-induced changes in connectivity appear to be restricted to specific regions in the salience network, and not affecting connectivity globally. Other neurochemical and behavioral effects of MDMA include increased oxytocin, elevated serotonergic activity, increased self-compassion, and prosocial interactions with others, which can enhance trust and rapport with therapists.


MDMA-assisted psychotherapy has demonstrated sustained reductions in PTSD symptoms in individuals who had failed to respond adequately to existing pharmacologic or psychotherapeutic treatments. Compared to the placebo group in the blinded segment of the present study, the MDMA group trended toward reduced psychiatric symptoms, such as anxiety, depression and self-reported impaired sleep quality, associated with LTIs. While under the effects of MDMA, acute alterations in brain circuits important for in memory and emotional processing could have allowed participants to approach emotionally painful memories or thoughts with empathy and compassion rather than feeling overwhelmed by anxiety. Prior studies in healthy adults have reported reduced negative ratings of person’s “worst” memories and increased vividness and intensity of emotionally positive memories after MDMA. In the context of psychotherapy, this process may help people with LTIs by reducing fears of disease recurrence or death, and embracing compassion for self, others, and one’s situation. Individuals with LTIs who received three MDMA-assisted psychotherapy sessions showed long-term reduction in anxiety, assessed by MADRS at the 6- and 12-month follow-ups, and significant positive gains in posttraumatic growth or perceived benefits arising from an LTI, mindfulness (FFMQ), and social and family wellbeing (FACIT-S). The durability of improvement several months after MDMA-assisted psychotherapy sessions demonstrates benefits might extend beyond the acute treatment effects.


Consistent with previous reports from PTSD samples, safety measures demonstrated that MDMA was well-tolerated by individuals with an LTI and no participants discontinued treatment due to adverse effects related to MDMA. After MDMA administration, MDMA group vital signs increased to expected levels, with only body temperature rising higher than the placebo group. The MDMA group also reported more adverse reactions during the experimental sessions, including jaw clenching/tight jaw, thirst, dry mouth, and perspiration. Reactions were short in duration and mostly subsided by the end of an experimental session, or during the week following. Psychiatric adverse events were infrequent, and MDMA was not associated with serious suicidal ideation or behavior. Overall, the safety profile for MDMA in this controlled clinical setting indicated that MDMA-assisted psychotherapy was a safe treatment in this relatively small sample where the benefits outweighed the cost of mild and short-term reactions. Future studies should continue to evaluate risks of adverse events in a larger sample of individuals with life-threatening illnesses.


Study limitations included the study design and small sample. This pilot study was exploratory and not powered to detect statistical significance. Additionally, the degree of group differences was impacted by an outlier in the placebo group who responded exceptionally well to psychotherapy alone compared to other participants in the placebo group during the blinded segment. This could have been influenced by a potential placebo effect, since 2 of 3 placebo participants believed they were assigned MDMA during the blinded sessions. In this relatively small study sample, this outlier might explain the lack of statistical significance in the between-group differences in primary outcome change scores, although a larger study would be needed to elucidate these findings. The study sample was mostly female and White/Caucasian, although males and persons of other ethnicities were also represented. After all participants received three MDMA sessions, results indicated significant improvements in outcomes at treatment exit, 6-month and 12-month endpoints. However, the interpretation of these results was limited due to lack of a control group after crossover.




These findings provide preliminary evidence to support that MDMA-assisted psychotherapy may be a safe and feasible treatment for those with LTIs for anxiety reduction and relief of other psychiatric symptoms associated with their illness. Study results support the feasibility of MDMA-assisted psychotherapy as a novel approach for potential long-term treatment of LTI-related anxiety. These findings will inform development of future clinical trials with larger sample size and among more diverse populations.



Dr.Jake Donaldson

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