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

This retrospective analysis (2022) analysed 58 reports of adverse reactions caused by 25I-NBOMe (an uncommonly used psychedelic) to identify factors that may increase the risk of hallucinogen persisting perception disorder (HPPD) following its use. In 15 reports, symptoms persisted months after HPPD use the most common of which were: pseudohallucinations, bizarre delusions and derealization. Additionally, 25I-NBOMe induced HPPD can last from 2 months up to 2 years in some cases.

Abstract

Background: 5-HT2A receptor (e.g. 25I-NBOMe) agonists not only pose risks of acute intoxication but also long-term effects and significant adverse reactions, e.g. hallucinogen persisting perception disorder (HPPD), derealization, and depersonalization.

Aims: We evaluated the risk associated with single and repeated use of 25I-NBOMe. We aimed to identify factors that may increase the risk of HPPD, increase its severity and determine the time when the first symptoms appear. Herein, we report the first extensive evaluation of 25I-NBOMe-induced HPPD.

Method: We assessed all reports (58) collected by The Pomeranian Pharmacovigilance Centre (PPC) from 2013 to 2020.

Results: The study included a total of 58 reports of adverse reactions caused by 25I-NBOMe. In the case of 15 reports (in patients aged 19–26 years), symptoms persisted many months after the discontinuation of 25I-NBOMe. The most common were: pseudohallucinations, bizarre delusions, derealizations and in some cases development or worsening of depression has been diagnosed. HPPD-like symptoms were most common in patients who took the drug regularly (i.e., several times a month). The risk of HPPD-like symptoms is higher in patients who have severe visual pseudohallucinations, severe bizarre delusions, derealization and/or depersonalization onset immediately after taking the drug. Recurrence of HPPD symptoms may be provoked by many factors, however, there is some cases there is no apparent reason. HPPD after 25I-NBOMe use can last from 2 months up to 2 years. In some patients, pharmacological treatment was necessary due to 25I-NBOMe-induced HPPD and depression.

Conclusions: The study showed long-lasting effects after 25I-NBOMe administration and allowed for the determination of HPPD risk factors.

Authors: Daria Schetz, Adriana Schetz & Ivan Kocić

Summary

5-HT2A receptor agonists pose risks of acute intoxication and long-term effects.

We evaluated the risk associated with 25I-NBOMe.

We report the first extensive evaluation of 25I-NBOMe-induced HPPD.

25I-NBOMe, a phenethylamine derivative, was discovered in 2003 and sold as a “designer drug” in 2010. It has become very popular over the past few years due to its availability on the Internet, ease of synthesis, low cost, high potency, and lack of information on its toxicities. 25I-NBOMe can be administered by oral ingestion, intravenous injection, buccal administration, vapour inhalation and nasal insufflation. A threshold dosage of 50 – 250 g is needed to induce psychoactive effects.

We evaluated all reports received from doctors and patients collected by The Pomeranian Pharmacovigilance Centre (PPC) from 2013 to 2020 and found that 25I-NBOMe may cause hallucinogen persisting perception disorder (HPPD). This is the first extensive survey evaluating 25I-NBOMe-induced HPPD.

  1. Method

The Pomeranian Pharmacovigilance Centre collects information about adverse and toxic reactions to drugs, paramedics, nurses, pharmacists, and patients.

PPC received numerous reports from teenagers and young adults who had taken 25I-NBOMe and had experienced moderate to severe adverse reactions.

In our study, we collected all medically confirmed reports of adverse and toxic reactions to 25I-NBOMe in patients without psychological disorders.

This study evaluated the risk of chronic adverse reactions symptoms in 25I-NBOMe users. It did not determine the risk of specific symptoms depending on the dose of the agent, but did assess whether the phenomenon we studied was more common in the drug abusing population.

In the study, factors such as frequency of taking the drug, frequent exposure to stress or excitement, history of depression, and a first-degree family relative with a psychiatric disorder were assessed for the risk of HPPD-like symptoms.

Any cases where symptoms resembling HPPD had occurred in the past before the patient took 25I-NBOMe were excluded, as were cases where the patient was using other psychoactive substances before the first symptoms of HPPD-like symptoms appeared.

All procedures contributing to this work complied with the ethical standards of the relevant national and institutional committees on human experimentation.

  1. Results

96 reports of medically confirmed adverse reactions were obtained from the PPC data between 2013 and 2020. Of these, 58 reports were from patients, doctors, and nurses.

3.1. Control group

43 patients aged 16 – 32 years reported acute symptoms that appeared immediately after 25I-NBOMe administration and disappeared at the end of the pharmacological action of the agent. The most common symptoms were hallucinations and bizarre delusions.

3.2. Study group (patients suffering from HPPD-like symptoms)

In 15 reports, patients aged 19 – 26 years reported chronic adverse drug reactions that persisted even many months after the discontinuation of 25I-NBOMe. The most common symptoms were visual pseudohallucinations, bizarre delusions, derealization and/or depersonalization, and panic reactions.

HPPD-like symptoms appeared within 1 – 7 days after the last 25I-NBOMe administration, and varied in intensity depending on a variety of triggering factors, including alcohol, excitement, stress, cannabinoid use, darkness, fatigue, viral infection with a fever, and opiate use.

In 4 patients, benzodiazepines or SSRIs were necessary due to the severity of 25I-NBOMe-induced HPPD-like symptoms and/or coexisting depression. Clonazepam was partially ineffective, and rapid clonazepam withdrawal caused significant intensification of depersonalizations and derealizations (i.e., worsening of symptoms).

3.3. The comparison of study group with control group

In both populations, tolerance to 25I-NBOMe was common and occurred from the third day of administration. However, in study group, drug cessation need was longer.

HPPD-like symptoms were more common in patients who took the drug several times a month on a regular basis, and in those with a higher-risk exposure to stress and strong emotions.

  1. Discussion

Psychedelic NPS pose risks of acute intoxication and long-lasting effects, which are described by many patients as very unpleasant and incapacitating.

Following cessation of use of a hallucinogen, impairment in occupational, social areas of functioning or clinically significant distress may occur.

A study revealed that LSD use increases the risk of developing HPPD, which is characterized by disinhibition of visual processes and dysfunction of the central nervous system.

Patients taking 25I-NBOMe only once may experience long-lasting HPPD, which has been reported in the literature. However, it has also been pointed out that the condition is not necessarily accompanied by any evident additional psychiatric disorder.

25I-NBOMe acts as a potent full agonist of the serotonin 5-HT2A receptor, which is located in brain areas involved in social interactions and cognitive functions. This receptor is also involved in many diseases, including schizophrenia, obesity, and drug addiction.

We believe that 25I-NBOMe can provide valuable new data to help understand the HPPD phenomenon, but the underlying mechanism is still unknown.

The timing of onset of HPPD-like symptoms was generally within 1 – 7 days after the last 25I-NBOMe administration. The symptoms were described by patients as “resembling drug use symptoms with lower severity” and “persistently relapsing”.

In our study, 25I-NBOMe users complained about rapid development of tolerance to the psychoactive effect of the agent. This study provides accurate estimation of the onset of tolerance in both patient populations.

Patients who reported HPPD-like symptoms after 25I-NBOMe use stated that they had recurrent visual pseudohallucinations. In 67% of patients with HPPD-like symptoms, severe visual pseudohallucinations occurred immediately after taking the drug (acute severe symptoms), thus suggesting that the risk of HPPD-like symptoms is higher in these patients.

Our study has shown that severe bizarre delusions and derealization and/or depersonalization occurred much more often in patients with HPPD-like symptoms after 25I-NBOMe administration, than in the control group.

In HPPD patients, depression was common, and in some cases worsened after 25I-NBOMe use. This may indicate that the effectiveness of SSRIs is reduced in patients with preexisting depression, and this phenomenon is exaggerated by 25I-NBOMe use. A patient with HPPD has frequent unpleasant effects, which can cause frustration and anxiety. This can trigger depressive disorders and relapse.

Although 25I-NBOMe administration increased severity of HPPD-like symptoms, no drug – condition interaction was observed. This suggests that SSRIs do not generally produce the hallucinogenic effects of psychedelics because they elevate serotonin, thus indirectly acting at all subtypes of serotonin receptors.

Nevertheless, there are some case reports of patients who experienced LSD-induced HPPD-like symptoms with concurrent SSRI treatment, and it is probable that SSRIs may interact with 25I-NBOMe. Therefore, pharmacological treatment of 25I-NBOMe-induced depression may be problematic, and may require the use of an antidepressant drug than SSRIs.

According to the literature, environmental stimuli related to the original experience can trigger HPPD, and many former 25I-NBOMe and other new substance users seek medical advice because of recurring pseudohallucinations and coexisting problems.

Researchers suggest that high-potency benzodiazepines with serotonergic properties, such as clonazepam, may be more effective in the treatment of some symptoms of LSD-induced HPPD, and that clonazepam may be particularly beneficial in patients with high levels of background anxiety who suffer from depersonalizations.

In 4 cases, pharmacological treatment of HPPD was necessary, and clonazepam 2 mg/day was used. However, there was no significant improvement in the resolution of HPPD symptoms, and the patient developed addiction to clonazepam.

Patients with the history of 25I-NBOMe induced HPPD should avoid trigger factors such as psychoactive agents, overstimulation, and fatigue. Cognitive-behavioral psychotherapy can be helpful.

  1. Conclusion

25I-NBOMe can cause HPPD-like symptoms, derealizations, depersonalizations and panic reactions, which are described by patients as very unpleasant. HPPD-like symptoms are more common in patients who take the drug several times a month and regularly, and are higher in patients with severe visual pseudohallucinations immediately after taking the drug.

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