Rationale ±3,4-Methylenedioxymethamphetamine (MDMA) is a recreational drug that shows substantial promise as a psychotherapeutic agent. Still, there is some concern regarding its behavioral toxicity, and its dose-effect relationship is poorly understood. We previously explored the role of dose in the cognitive effects of MDMA in a systematic review of existing literature and found no evidence in animals that MDMA impairs memory at low doses (< 3 mg/kg) but mixed results at high doses (≥ 3 mg/kg). Since this review comprised mostly of single-dose studies and an assortment of methodologies, an empirical dose-ranging study on this topic is warranted. Objectives The current study aims to evaluate the conclusion from our systematic review that 3 mg/kg may be the threshold for MDMA-induced amnesia, and to further understand the dose-effect relationship of MDMA on behavioral assays of memory, addiction, and depression. Methods We systematically examined the effects of 0.01 to 10 mg/kg MDMA on Pavlovian fear conditioning; behavioral sensitization, conditioned place preference, and conditioned responding; and the Porsolt forced swim test in mice. Results High doses of MDMA (≥ 3 mg/kg) produced amnesia of fear conditioning memory, some evidence of an addictive potential, and antidepressant effects, while low doses of MDMA (≤ 1 mg/kg) had no effect on these behaviors. Conclusions The present dose-ranging study provides further evidence that 3 mg/kg is the threshold for MDMA-induced amnesia. These findings, in addition to our systematic review, demonstrate that careful selection of MDMA dose is critical. High doses (≥ 3 mg/kg) should likely be avoided due to evidence that they can produce amnesia and addiction. Conversely, there is little evidence to suggest that low doses, which are usually administered in clinical studies (approximately 1–2 mg/kg), will lead to these same adverse effects. Ultra-low doses (< 1 mg/kg) are likely even safer and should be investigated for therapeutic effects in future studies.

Current treatments for chronic pain have limited benefit. We describe a resilience intervention for individuals with chronic pain which is based on a model of viewing chronic pain as dysregulated homeostasis and which seeks to restore homeostatic self-regulation using strategies exemplified by survivors of extreme environments. The intervention is expected to have broad effects on well-being and positive emotional health, to improve cognitive functions, and to reduce pain symptoms thus helping to transform the suffering of pain into self-growth. A total of 88 Veterans completed the pre-assessment and were randomly assigned to either the treatment intervention (n = 38) or control (n = 37). Fifty-eight Veterans completed pre- and post-testing (intervention n = 31, control = 27). The intervention covered resilience strengths organized into four modules: (1) engagement, (2) social relatedness, (3) transformation of pain and (4) building a good life. A broad set of standardized, well validated measures were used to assess three domains of functioning: health and well-being, symptoms, and cognitive functions. Two-way Analysis of Variance was used to detect group and time differences. Broadly, results indicated significant intervention and time effects across multiple domains: (1) Pain decreased in present severity [F(1, 56) = 5.02, p < 0.05, η2p = 0.08], total pain over six domains [F(1, 56) = 14.52, p < 0.01, η2p = 0.21], and pain interference [F(1, 56) = 6.82, p < 0.05, η2p = 0.11]; (2) Affect improved in pain-related negative affect [F(1, 56) = 7.44, p < 0.01, η2p = 0.12], fear [F(1, 56) = 7.70, p < 0.01, η2p = 0.12], and distress [F(1, 56) = 10.87, p < 0.01, η2p = 0.16]; (3) Well-being increased in pain mobility [F(1, 56) = 5.45, p < 0.05, η2p = 0.09], vitality [F(1, 56) = 4.54, p < 0.05, η2p = 0.07], and emotional well-being [F(1, 56) = 5.53, p < 0.05, η2p = 0.09] Mental health symptoms and the cognitive functioning domain did not reveal significant effects. This resilience intervention based on homeostatic self-regulation and survival strategies of survivors of extreme external environments may provide additional sociopsychobiological tools for treating individuals with chronic pain that may extend beyond treating pain symptoms to improving emotional well-being and self-growth. Clinical Trial Registration: Registered with ClinicalTrials.gov (NCT04693728).