2026 ECNP Congress

PS04-4206

Acute effects of the synthetic cannabinoid JWH-018 in humans: subjective experience, cognition, and brain activity

Katharina Lege — P. Mallaroni, N. Mason, D. Tse, A. Zschiesche, E. Theunissen, J. Ramaekers · Maastricht University- Faculty of Psychology and Neuroscience, Department of Neuropsychology and Psychopharmacology, Maastricht, Netherlands

2026 ECNP Congress

Introduction: Synthetic cannabinoids (SCs) constitute the largest class of novel psychoactive substances and represent a major public-health risk, with recurrent reports of severe poisoning including agitation, neurocognitive dysfunction, psychosis or even seizures (1,2). SCs such as JWH-018 are full agonists at central cannabinoid receptors, producing prolonged and often unpredictable effects that exceed those of natural cannabis (3). However, their potency is often unknown to users, a concern amplified by their resurgence as adulterants in other recreational drugs (4). Despite the known threat of SCs, few controlled human trials have assessed their acute effects, and to date none have investigated their neural underpinnings. The present study therefore aimed to characterize the subjective and cognitive profile of acute JWH-018 intoxication, alongside potential changes in brain function, in healthy participants.

Methods: Twenty-five occasional cannabis users received a single dose of vaporized JWH-018 (7.5 mg, 6 mg, or 75 µg/kg) and placebo on two separate testing days in a randomized, double-blind, within-subject design. To assess functional connectivity and indirect changes in dopaminergic neurotransmission, resting-state fMRI data were acquired at 7T during acute intoxication. Vital signs, pharmacokinetics and Visual Analogue Scale (VAS) ratings of subjective drug effects were assessed at regular intervals within 3.5 hours after administration, complemented by single-timepoint measures of subjective experience and cognition. All measures were tested for drug, dose (and time) effects using linear mixed models.

Results: Across all doses, JWH-018 produced significant subjective intoxication compared to placebo, with peak subjective high (mean 80%) and plasma concentrations (mean 11.65 ± 7.84 ng/ml) reached 30 minutes after administration. Significant cardiovascular activation was also observed, with increased heart rate and rate pressure product. JWH-018 induced psychedelic-like changes in consciousness and perception (5D-ASC, Bowdle-VAS), as well as dissociative (CADSS) and psychotomimetic effects (CAPE-P15). Although JWH-018 was less tolerable than placebo, participants preferred it over cannabis more than they did placebo (RDRV) and rated it as more pleasant (SCRQ), suggesting reinforcing properties. Cognitive performance was impaired during intoxication, with increased reaction times and attentional lapses on a psychomotor vigilance task. Exploratory dose analyses confirmed dose-dependent Cmax and revealed reduced drug liking and good drug effect ratings alongside increased anxiety at higher doses, while general drug effects such as subjective high were unaffected. Resting-state fMRI analyses examining functional connectivity within the mesocorticolimbic circuit, a key substrate of dopaminergic reward signalling, and at the whole-brain level are ongoing and will be presented at the conference.

Conclusion: The current findings extend earlier reports of acute JWH-018 effects, demonstrating a complex profile of physiological and subjective changes accompanied by cognitive impairment. Together with forthcoming neuroimaging results, which will provide the first neural characterization of acute JWH-018 intoxication in humans, this work informs our understanding of current public-health concerns surrounding synthetic cannabinoids.

References

  1. United Nations Office on Drugs and Crime. (2025). World Drug Report 2025. United Nations.
  2. European Union Drugs Agency. (2025). European Drug Report 2025: Trends and developments. Publications Office of the European Union.
  3. Alves, V. L., Gonçalves, J. L., Aguiar, J., Teixeira, H. M., & Câmara, J. S. (2020). The synthetic cannabinoids phenomenon: from structure to toxicological properties. A review. Critical Reviews in Toxicology, 50(5), 359–382. https://doi.org/10.1080/10408444.2020.1762539
  4. Jones, A. T., Abu Taha, A. M., & Miller, G. P. (2025). The resurgence of synthetic cannabinoid receptor agonists as adulterants in the era of cannabis legalization: Lessons from prior epidemics and clinical implications. Neuroscience & Biobehavioral Reviews, 170, 106043. https://doi.org/10.1016/j.neubiorev.2025.106043