A retrospective analysis of the “Neverending Trip” after administration of a potent full agonist of 5-HT2A receptor - 25I-NBOMe

25I-NBOMe is a highly potent phenethylamine acting as a full agonist at the serotonin 5-HT2A receptor that emerged as a designer drug in the 2010s and has been misused as a substitute for LSD. Earlier literature has concentrated on acute toxicity of NBOMe compounds and on classic hallucinogens such as LSD, but chronic or long-term adverse effects of potent 5-HT2A agonists are poorly characterised. In particular, hallucinogen persisting perception disorder (HPPD) and related phenomena (derealization, depersonalization, persistent pseudohallucinations) have been described after classic psychedelics but less is known about their incidence and risk factors following NBOMe exposures. Schetz and colleagues set out to evaluate the risk of persistent, HPPD-like symptoms after single or repeated 25I-NBOMe use by analysing all medically confirmed adverse-reaction reports submitted to the Pomeranian Pharmacovigilance Centre (PPC) between 2013 and 2020. The investigators aimed to identify which exposures and acute symptom patterns predict later HPPD-like outcomes, to establish the typical timing of symptom onset, and to describe clinical course, triggers and responses to treatments in affected patients. This study represents a retrospective, case-series comparison between patients with only acute effects and those with prolonged HPPD-like symptoms drawn from the PPC database.

The researchers performed a retrospective review of PPC records, which collect clinician- and patient-reported adverse and toxic reactions to drugs and novel psychoactive substances. From 2013 to 2020 the PPC received reports related to 25I-NBOMe; only medically confirmed reports were included and for patient-submitted reports accompanying medical documentation was required. When the initial report lacked relevant detail, the PPC contacted the reporter to obtain additional information. Inclusion required absence of pre-existing psychiatric disorders and no prior HPPD-like symptoms; reports in which similar symptoms predated 25I-NBOMe use, reports with concurrent mental disorders known to cause similar symptoms (except mild, well-controlled depression), and reports where other psychoactive substances had been used prior to first HPPD symptoms were excluded. HPPD-like symptoms were identified according to DSM-5 criteria. The investigators divided cases into two groups: a control group with acute, time-limited symptoms occurring during intoxication, and a study group with persistent or relapsing HPPD-like symptoms. The analysis compared these groups to identify risk factors such as frequency of drug use, exposure to stress or excitement, history of depression, family psychiatric history, severity of acute symptoms, tolerance development, and time from last use to symptom onset. The study did not attempt dose–response analyses because NBOMe products lack reliable dosing information.

From 96 medically confirmed PPC reports related to 25I-NBOMe, 38 were excluded per the prespecified criteria, leaving 58 reports meeting inclusion criteria. These 58 reports derived from patients (36), doctors (18) and nurses (4). The control group comprised 43 cases (patients aged 16–32 years) with acute symptoms that resolved as the pharmacological effects waned; 68% of these acute reactions were classified as moderate and 37% (16 cases) were associated with overdose. Typical acute features included hallucinations and bizarre delusions, hypertension, tachycardia, agitation and mydriasis. The study group comprised 15 reports in patients aged 19–26 years whose symptoms persisted for months after stopping 25I-NBOMe and were characterised by recurrent, lower-severity, relapsing perceptual disturbances. Visual pseudohallucinations were reported in 11 cases and included visual snow, afterimages, flashes of colour, geometric shapes and halos. Bizarre delusions and derealization/depersonalization each occurred in 9 cases. Other problems included development or worsening of depression measured by HAM-D in 8 cases, panic reactions in 6, and suicidal thoughts in 5. Onset of HPPD-like symptoms typically occurred within 1–7 days after the last 25I-NBOMe exposure (53% within 4–7 days, 40% within 1–3 days); one case had onset at 8–14 days. Triggers or intensifiers reported were incidental alcohol use (10 cases), excitement (9), stress (7), incidental cannabinoid use (4), darkness (3), fatigue (3), viral infection with fever (1), and opiate use (1); symptoms could also recur without an identifiable trigger. Pharmacological treatment was required in four patients for severe HPPD-like symptoms and/or coexisting depression; treatments included benzodiazepines and selective serotonin reuptake inhibitors (SSRIs). Three patients received clonazepam (two prescribed, one self‑medicated); clonazepam produced only partial relief of anxiety and panic but visual symptoms generally persisted, and clonazepam dependence and withdrawal exacerbation occurred in one patient. One patient treated with citalopram did not improve, and one patient on escitalopram prior to NBOMe use had to discontinue it because symptoms were potentiated. Rapid development of tolerance to 25I-NBOMe effects was commonly reported in both groups, beginning around the third day of consecutive use (16 cases); among those who developed HPPD-like symptoms, drug-cessation intervals to regain effect often spanned 2 to several weeks. HPPD-like symptoms were most common among patients who used the drug several times a month (67%), although three affected patients reported only a single NBOMe exposure. Patients with higher-risk exposure to stress (47%) and strong emotions (60%) more often developed HPPD-like symptoms. The investigators observed that severe acute visual pseudohallucinations, severe bizarre delusions and derealization/depersonalization immediately after intake were more frequent in those who later developed HPPD-like symptoms (reported proportions include 67% for severe acute visual pseudohallucinations, 80% for severe bizarre delusions and 73% for derealization/depersonalization within the higher-risk subgroup).

Schetz and colleagues interpret their findings as evidence that 25I-NBOMe can produce not only acute toxicity but also persistent, distressing perceptual disturbances consistent with HPPD. The investigators note that while HPPD has been most often associated with LSD in prior literature, their data show that a single exposure to a potent 5-HT2A full agonist such as 25I-NBOMe can occasionally precipitate long-lasting, relapsing pseudohallucinations and associated symptoms. They highlight that HPPD-like symptoms in this series predominantly affected visual perception and were frequently accompanied by derealization, depersonalization and mood disturbance. Mechanistically, the authors discuss 5-HT2A receptor agonism as the likely initiating event, with possible downstream alterations in receptor signalling or cellular physiology that might underlie prolonged effects; they also cite receptor downregulation and desensitisation as an explanation for the rapid tolerance reported. Regarding comorbid depression and interactions with antidepressants, the investigators describe some patients whose depressive symptoms worsened after NBOMe exposure and cases in which SSRIs were ineffective or appeared to worsen HPPD-like symptoms, but they emphasise that causal relationships remain uncertain. Treatment responses were limited in this series: clonazepam provided partial anxiolytic benefit in some patients but visual symptoms largely persisted, and benzodiazepine dependence posed an additional risk. The authors acknowledge that HPPD risk factors and pathogenesis remain incompletely understood and call for further research. They recommend, based on their observations, that patients with NBOMe-induced HPPD avoid known triggers (psychoactive substances, overstimulation, fatigue) and consider non-pharmacological approaches such as cognitive-behavioural therapy to manage stress and coping skills. The discussion also notes methodological constraints inherent to the data set: uncertainty about product dose and composition, the retrospective design, and exclusion of many reports because of confounding substance use; these limitations reduce the capacity to infer causality or quantify incidence precisely and point to the need for further study.

1) 25I-NBOMe can cause long-lasting effects including HPPD-like symptoms, derealization, depersonalization and panic reactions that patients describe as distressing and incapacitating. 2) HPPD-like symptoms were most commonly observed in people who used the drug several times a month, although some cases followed a single administration. 3) Severe visual pseudohallucinations occurring immediately after intake appear to predict a higher risk of later HPPD-like symptoms; severe bizarre delusions, derealization/depersonalization and a history of moderate depression were also identified as important risk indicators. 4) Recurrences are provoked by diverse triggers such as alcohol, other drugs, stress, excitement, fatigue, darkness and infections, but episodes may also occur without an obvious precipitant. 5) HPPD after 25I-NBOMe may persist from approximately 2 months up to 2 years in this series. 6) Rapid tolerance to psychoactive effects commonly developed by the third day of repeated use, often prompting weeks of cessation to regain effects. 7) Recognition and effective treatment of NBOMe-induced HPPD and HPPD-associated depression remain challenging; some evidence suggests certain SSRIs may increase HPPD frequency or intensity, and benzodiazepines such as clonazepam have limited efficacy and carry dependence risk. The investigators conclude that more effective treatments and further research are urgently needed.