Rationale 3,4-methylenedioxymethamphetamine (MDMA) persistently improves symptoms of post-traumatic stress disorder (PTSD) when combined with psychotherapy. Studies in rodents suggest that these effects can be attributed to enhancement of fear memory extinction. Therefore, MDMA may improve the effects of exposure-based therapy for PTSD; particularly in treatment-resistant patients. However, given MDMA's broad pharmacological profile, further investigation is warranted before moving to a complex clinical population. Objectives We aimed to inform clinical research by providing a translational model of MDMA's effect, and elucidating monoaminergic mechanisms through which MDMA enhances fear extinction. Methods We explored the importance of monoamine transporters targeted by MDMA to fear memory extinction, as measured by reductions in conditioned freezing and fear-potentiated startle (FPS) in mice. Mice were treated with selective inhibitors of individual monoamine transporters prior to combined MDMA treatment and fear extinction training. Results MDMA enhanced the lasting extinction of FPS. Acute and chronic treatment with a 5-HT transporter (5-HTT) inhibitor blocked MDMA's effect on fear memory extinction. Acute inhibition of dopamine (DA) and norepinephrine (NE) transporters had no effect. 5-HT release alone did not enhance extinction. Blockade of MDMA's effect by 5-HTT inhibition also downregulated 5-HT2A-mediated behavior, and 5-HT2A antagonism disrupted MDMA's effect on extinction. Conclusions We validate enhancement of fear memory extinction by MDMA in a translational behavioral model, and reveal the importance of 5-HTT and 5-HT2A receptors to this effect. These observations support future clinical research of MDMA as an adjunct to exposure therapy, and provide important pharmacological considerations for clinical use in a population frequently treated with 5-HTT inhibitors.

6577 Background: Immune checkpoint inhibitors (ICI) can prolong survival for various cancers and are generally available as treatment options for most patients because of their favorable adverse effect profile. Although ICIs provide treatment for many patients who would otherwise be out of options, their variable and often delayed efficacy may postpone the de-escalation of care at the end of life. Palliative Care consultation (PCC) is well-established among patients receiving cytotoxic chemotherapy, but its effectiveness is less certain among patients receiving newer treatment modalities. We aimed to test the association of PCC with end-of-life (EOL) outcomes among patients treated with an ICI for any type of cancer. Methods: We created a retrospective registry of all patients who received at least one dose of ICI for any indication between 2/1/2011 and 4/7/2022 at a comprehensive cancer center and its outreach clinics. The investigators created a secure, cloud-based registry (REDCap), validated it with data quality rules, and resolved all discrepancies; clinical research specialists at Vasta Global captured most of the data. We used the chi-square test to compare categorical variables, defined statistical significance as p < 0.05, and used SAS version 9.4 for analyses. The study had institutional IRB approval. Results: The cohort consisted of 3,142 patients with lung cancer (45%) as the most common cancer type, followed by melanoma (14%) and head and neck squamous cell carcinoma (9%). ICI was most often given in the first line setting (46%) with good baseline performance status (ECOG 0-1, 50%). 915 (29%) patients had PCC, which was associated with a higher rate of code status de-escalation from “Full Code” at any point before death (92% vs. 87%, p 0.007). There was no association between PCC and either the initiation of ICI within 30 days of death (7% vs. 5%, p .0172) or any dose of ICI within 14 days of death (5% vs. 6%, p 0.33). Among patients with a confirmed location of death (1013, 32%), PCC was associated with a similar rate of death in the hospital at any level of care (30% vs. 28%, p 0.51). Conclusions: PCC was associated with code status de-escalation before death but similar risks of late ICI dosing or inpatient status at the time of death. Further studies are needed to risk-stratify patients starting ICI to identify the subgroups that would benefit the most from PCC.