2026 ECNP Congress

PS03-3017

In vivo occupancy of psilocybin and LSD at serotonergic receptors and the serotonin transporter in pigs using PET imaging

Elisabeth Kolesnik — C.A. Madsen, V. Richin, V. Drejfeldt, V. Camporesi, A. Nasser, V. Shalgunov, G.M. Knudsen · Copenhagen University Hospital, Neurobiology Research Unit, Copenhagen, Denmark

2026 ECNP Congress

Background

Psychedelics have demonstrated therapeutic potential across a range of psychiatric disorders [1], [2]. Serotonergic psychedelics, including psilocybin and LSD, exert their psychedelic effects primarily through activation of the serotonin 2A receptor (5-HT2AR). In humans, a profound psychedelic experience is observed with >60 % 5-HT2AR occupancy [3]. Similarly, in pigs, psilocybin administration resulting in approximately 67 % 5-HT2AR occupancy induces robust head-shaking and scratching behaviors, considered translational proxies of psychedelic effects [4]. However, it remains unclear whether the therapeutic effects of psychedelics are mediated exclusively via 5-HT2AR activation or involvement of additional serotonergic receptors. Given the limited in vivo data on target engagement of serotonergic receptors beyond the 5-HT2AR, we aimed to quantify receptor occupancy of psilocybin and LSD at the serotonin 1B receptor (5-HT1BR), serotonin 4 receptor (5-HT4R), and the serotonin transporter (SERT) in pigs, at doses achieving >60 % 5-HT2AR occupancy.

Methods

Five female pigs each underwent 2-3 positron emission tomography (PET) scans using [11C]AZ10419369, [11C]SB207145 or [11C]DASB targeting 5-HT1BR, 5-HT4R, and SERT, respectively. [11C]AZ10419369 scans were conducted with within-scan intravenous administration of psilocybin (38µg/kg) or LSD (0.84µg/kg) at 50 min post tracer injection. For [11C]SB207145 and [11C]DASB, baseline scans were followed by blocking scans in which drug was administered intravenously prior to tracer injection. Positive control scans were performed for each target using intravenous injections of GR127935 (0.2 mg/kg), GR113808 (0.44 mg/kg) and escitalopram (0.35 mg/kg) for 5-HT1BR, 5-HT4R, and SERT, respectively. Kinetic modelling of [11C]AZ10419369 data employed a displacement model based on a one-tissue compartment model to estimate receptor occupancies [5]. For [11C]SB207145, invasive Logan graphical analysis was used to derive volume of distribution (VT), and Lassen plot to estimate occupancies. Metabolite corrected arterial input function was applied for modelling of both tracers. The simplified reference tissue model (SRTM) was also used for [11C]SB207145 as well as for [11C]DASB, with the cerebellum as the reference region, to estimate non-displaceable binding potential (BPND), in which occupancies were calculated as ((BPNDbaseline-BPNDdrug)/BPNDbaseline) x 100.

Results

Psilocybin and LSD at the chosen doses produced negligible occupancy at all three receptors. In contrast, the positive control for 5-HT1BR achieved 80 % occupancy. The 5-HT4R positive control generated 85 % occupancy using the Lassen approach (VT’s determined by Logan plot); a similar striatal occupancy was found based on SRTM. For SERT, the positive control yielded a striatal occupancy of 53 %.

Conclusions

At doses associated with substantial 5-HT2AR occupancy, psilocybin and LSD do not produce measurable in vivo occupancy at 5-HT1BR, 5-HT4R, or SERT in the pig brain. These findings suggest that both compounds do not show any relevant target engagement of these receptors at clinically relevant doses. How these psychedelic drugs interact with other receptors in vivo, and at what doses, remains to be determined.

References

  1. R. von Rotz et al., 2023. Single-dose psilocybin-assisted therapy in major depressive disorder: A placebo-controlled, double-blind, randomised clinical trial (eClinicalMedicine).
  2. F. Holze et al., 2013. Lysergic Acid Diethylamide–Assisted Therapy in Patients With Anxiety With and Without a Life-Threatening Illness: A Randomized, Double-Blind, Placebo-Controlled Phase II Study (Biological Psychiatry).
  3. M. K. Madsen et al., 2019. Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels (Neuropsychopharmacology).
  4. L. L. Donovan et al., 2021. Effects of a single dose of psilocybin on behaviour, brain 5-HT2A receptor occupancy and gene expression in the pig (European Neuropsyhopharmacology).
  5. G. L. Laurell et al., 2023. Kinetic models for estimating occupancy from single-scan PET displacement studies (JCBFM).