ERPPAD: Efficacy in Relapse Prevention: Psilocybin in Alcohol use disorder with Depressive symptoms. A new phase 3 study in France

The resurgence of psychedelic research in France

After several decades of limited scientific activity, interest in psychedelic-assisted therapies has re-emerged internationally, driven by encouraging results in depression, addiction, and other disorders. In France, the use of psychedelics remains restricted to clinical research, but recent years have seen the launch of modern clinical trials evaluating psilocybin in carefully controlled hospital settings. This renewed scientific interest reflects the need for innovative treatment approaches for complex disorders, while maintaining the highest standards of safety and regulatory oversight. Medical administration of psilocybin in France, which had been discontinued in the late 1960s, resumed with the PAD study, paving the way for larger confirmatory trials such as ERPPAD.

Alcohol Use Disorder (AUD) and depression: a common and burdensome dual disorder 

Up to 40% of individuals with alcohol use disorder (AUD) experience depression, which increases the risk of early relapse. Depression can cause relapse to occur 3 times faster in individuals with AUD who experience depressive symptoms at discharge. Despite the high need, no treatments have been approved for individuals with both AUD and depression. Psilocybin shows promising results in treating both depression and addiction. It may be particularly effective for preventing relapse in people with AUD who also have depressive symptoms after detoxification, offering quicker action than traditional antidepressants. 

Psilocybin Alcohol Depression (PAD): the pilot study

We recently conducted a pilot study, Psilocybin Alcohol Depression (PAD), to evaluate the feasibility, acceptability, and preliminary efficacy outcomes of psilocybin treatment for post-detoxification AUD with depression. Our pilot study recruited 30 participants at a single center in less than nine months, and demonstrated the feasibility of and high demand for alternative and more effective therapeutic strategies for this dual disorder, particularly psychedelic-assisted psychotherapy. While efficacy was not the primary outcome, we observed significant between-group differences favoring the 25 mg group in both AUD (drinking days, abstinence rate, craving frequency) and depression. The results are very encouraging at 12 weeks, with abstinence rates of 55% in the 25 mg group compared to 11% in the 1 mg group. Anxiety levels remained low, supporting the quality of preparation in our recruited population despite a reduced preparation protocol consisting of only one session before each dosing session. This finding aligns with the therapeutic manual’s components, which emphasize exposure to a modified state of consciousness through mindfulness practice during the preparation session, psychoeducation, and the development of a horizontal, patient-centered therapeutic relationship. 

Our results support their acceptability and feasibility of  psilocybin-assisted psychotherapy for individuals with AUD and depressive symptoms as an add-on to an intensive relapse prevention program (treatment-as-usual). The very low anxiety levels observed in the study population may also be partly explained by the high proportion of patients taking antidepressants, which could have attenuated the intensity of the psychedelic experience. However, our findings support recent studies suggesting that antidepressants (SSRIs or SNRIs) do not reduce the therapeutic response to psychedelics or impact side effects.

ERPPAD: the ongoing phase 3 study

Now, we have just started the ERPPAD trial: a large-scale, double-blind, multicenter randomized controlled trial funded by the French Ministry of Health. This  double-blind randomized controlled trial (RCT) compares 2 administrations of high-dose psilocybin (25 mg) and low-dose psilocybin (3 mg) 3 weeks apart, alongside usual care, for individuals with alcohol use disorder and persistent depressive symptoms. At 6 months, participants can opt for a third 25 mg dose. This study revises our pilot design by increasing the low-dose from 1 mg to 3 mg and introducing the optional third dose to reduce unblinding, participant disappointment in the low-dose group, and the risk of self-administration during the follow-up period. Participants will be followed for 12 months from baseline, with hospital stays around each psilocybin cycle and regular assessments throughout. We propose psilocybin-assisted psychotherapy following the 3-step cycle: preparation - dosing session - integration. Cycles include a preparation session with psychoeducation and mindfulness, a dosing session with psychological support and an integration session with a debriefing. The intervention is an add-on to treatment-as-usual including an intensive relapse prevention program with at least 2 individual or group sessions per week between the first and second dosing sessions. The trial design is aligned with FDA recommendations and addresses challenges observed in the PAD pilot study, such as participant disappointment in the low-dose group and risk of arm contamination due to underground administration of psychedelics. 

In summary

This research aims to provide critical insights into the efficacy of psilocybin in preventing relapse in AUD patients, potentially influencing future therapeutic approaches. Relapse prevention is a major public health issue due to the heavy health and social burden of AUD. AUD is an increasing challenge to health care providers due to high prevalence, poor treatment seeking and very high relapse rate. Comorbid depression precipitates relapse. Several meta-analyses have reported moderate effect sizes of approved drugs in alcohol use  disorder and in depression. There is a serious need to enhance standard care in this comorbid population. Psilocybin, administered as an add-on to treatment-as-usual, could enhance successful outcomes and help prevent relapses, and in particular early relapses in relation to depressive symptoms.

Julien Chupin

 Amandine Luquiens