New Treatment Options for Life Threatening Illness

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^3,4. 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^1,5. 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 LTIs^6,7. Findings from studies reported from 2011 to 2016^8–12 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^13,14. 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 experience¹⁵. 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 2017¹⁶. 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)^17–21. 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 group²².

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^23–26. 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^27–30. 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^31–33; and several participants in previous study of MDMA-assisted psychotherapy have reported an LTI or a medical treatment to be comparable to an index trauma²⁰. 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.

Results

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 (Fig. 1). Table ​Table11 compares baseline characteristics between treatment groups. 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)³⁴ 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 h after an experimental session.