Psychedelics: The pathway to implementation in the European healthcare systems

The paper presents a synthesis of regulatory and HTA landscapes relevant to psychedelic medicines rather than original empirical results. The authors describe HTA as a multidisciplinary evaluation distinct from regulatory approval that assesses clinical effectiveness, cost-effectiveness and broader social and ethical implications, and thus substantially influences reimbursement and patient access in Europe. They explain recent moves toward greater harmonisation under the European HTA Regulation (Regulation (EU) 2021/2282), with joint clinical assessments intended to reduce duplication from 2025 onwards, while member states retain final pricing and reimbursement decisions. Using recent pharmaceutical examples, the authors illustrate how HTA can impede market access even after EMA approval. They cite lurasidone and vortioxetine, which were approved by the EMA but later not recognised as offering additional benefit by Germany's G-BA and were withdrawn from the German market. The authors describe esketamine's trajectory in detail: initial EMA and FDA approvals were followed by negative or cautious HTA appraisals (G-BA, NICE, HAS) largely because the submitted evidence lacked comparisons against clinically relevant active comparators and had short follow-up periods. Subsequently, new data from the ESCAPE-TRD study — a head-to-head comparison of esketamine versus quetiapine as augmentation to an SSRI/SNRI with an eight-week acute phase and 26-week follow-up — showed higher remission rates (27.1% vs 17.6%) and lower relapse through week 32 among those who remitted at week 8 (21.7% vs 14.1%). These findings led the G-BA to recognise a "hint for a considerable additional benefit" for esketamine in TRD and to initiate price negotiations, while NICE had not yet incorporated the ESCAPE-TRD data at the time of the authors' writing, illustrating asynchronous HTA appraisal across jurisdictions. Focusing on psychedelic clinical development, the authors report that several compounds (notably psilocybin and LSD tartrate/MM-120) are in Phase 3 programmes, typically progressing with placebo-controlled trials. They state that none of the industry-led trials known to them include active comparator arms against standard pharmacological treatments, nor are such trials being planned. The authors argue this is problematic because many European HTA bodies require comparisons with accepted standard treatments to establish an "additional benefit." They note the EMA expects at least one longer-term study to assess maintenance of effect. The paper also highlights market incentives that favour US-focused development (the US accounted for 53.2% of global national pharmaceutical market share in 2024), meaning companies often prioritise FDA-oriented programmes that may not meet European HTA evidence expectations. On economic and implementation considerations, the authors summarise early model-based health-economic work suggesting that cost-effectiveness of psychedelic-assisted therapies is highly sensitive to the costs of therapy support (therapist time, preparation/integration) and to overall price. Models for MDMA-assisted therapy in PTSD indicate potential cost-savings or high cost-effectiveness from a payer perspective, but the authors emphasise the scarcity of HTA-grade analyses in Europe. They provide examples of national approaches: the Czech Republic's progressive stance, Germany's compassionate-use programme for psilocybin in TRD, Australia's 2023 TGA authorisation of psilocybin and MDMA under Schedule 8, and Health Canada's Special Access Programme enabling restricted access. Finally, they report that recent Phase 2 trials of psilocybin and LSD generally showed favourable safety profiles with no treatment-related serious adverse events; the most common transient effects were increases in anxiety or blood pressure.

Gründer and colleagues interpret their synthesis to mean that EMA approval alone will not guarantee patient access to psychedelic therapies across Europe: HTA evaluations that assess the full clinical intervention, including psychotherapy, are decisive for reimbursement and implementation. They argue that the prevailing design of industry trials — testing the investigational compound primarily as a stand-alone drug against placebo — is likely insufficient for European HTA agencies, which commonly require active-comparator studies and evidence of longer-term maintenance of benefit (often at least six months). The esketamine example is used to emphasise that a single well-designed comparator study with adequate duration can alter HTA conclusions and enable market access and price negotiations. The authors stress that psychedelic-assisted treatment will be appraised by HTA bodies as a combined pharmacological and psychotherapeutic intervention, not as separable elements. Consequently, the role, intensity and financing of psychotherapeutic support must be defined and incorporated into economic evaluations and reimbursement frameworks. They note that industry incentives to treat psychedelics as simple pharmacological products (which tends to maximise drug price) are at odds with HTA perspectives that evaluate whole-care pathways and personnel costs. The authors call for early planning of study programmes that include placebo-controlled efficacy trials, at least one head-to-head trial versus an accepted standard-of-care comparator, and longer-term follow-up to assess durability. Key uncertainties and limitations acknowledged by the authors include limited HTA-grade health-economic data in Europe and the current absence of active-comparator trials in industry Phase 3 programmes. They identify the need for new models of collaboration between public and private stakeholders, novel financing arrangements, therapist training, and close cooperation with regulators and HTA authorities to design trials and reimbursement pathways acceptable across jurisdictions. Their overall conclusion is cautious: under current development and evidence-generation strategies it is unlikely that psychedelic therapies will become widely available to patients in Europe in the next few years without deliberate efforts to meet HTA requirements and to harmonise methodological approaches across countries.