25-NB (psychedelics)

The 25-NB (25''x''-NB''x'') series, or NBOMe series, also known as the ''N''-benzylphenethylamines, is a family of serotonergic psychedelics. They are substituted phenethylamines and were derived from the 2C family. The most commonly encountered NBOMe drugs are 25I-NBOMe, 25B-NBOMe, and 25C-NBOMe.

The NBOMe drugs act as selective agonists of the serotonin 5-HT₂ receptors. The 25-NB family is unique relative to other classes of psychedelics in that they are, generally speaking, extremely potent and quite selective for the 5-HT₂ receptors.

Use of NBOMe series drugs has caused many deaths and hospitalisations since the drugs popularisation in the 2010s. This is primarily due to their high potency, unpredictable pharmacokinetics, and sellers passing off the compounds in the series as LSD.

Use

The 25-NB drugs are inactive orally and instead are typically used sublingually, buccally, by insufflation, or sometimes via inhalation. They are typically employed at doses in the range of 50 to 1,500μg, variable depending on the specific drug, and have durations in the range of 3 to 12hours. The table below provides an overview of the major 25-NB drugs and their properties.

Toxicity and harm potential

NBOMe compounds are often associated with life-threatening toxicity and death. Studies on NBOMe family of compounds demonstrated that the substance exhibit neurotoxic and cardiotoxic activity. Reports of autonomic dysfunction remains prevalent with NBOMe compounds, with most individuals experiencing sympathomimetic toxicity such as vasoconstriction, hypertension and tachycardia in addition to hallucinations. Other symptoms of toxidrome include agitation or aggression, seizure, hyperthermia, diaphoresis, hypertonia, rhabdomyolysis, and death. Researchers report that NBOMe intoxication frequently display signs of serotonin syndrome. The likelihood of seizure is higher in NBOMes compared to other psychedelics.

NBOMe and NBOHs are regularly sold as LSD in blotter papers, which have a bitter taste and different safety profiles. Despite high potency, recreational doses of LSD have only produced low incidents of acute toxicity. Fatalities involved in NBOMe intoxication suggest that a significant number of individuals ingested the substance which they believed was LSD, and researchers report that "users familiar with LSD may have a false sense of security when ingesting NBOMe inadvertently". While most fatalities are due to the physical effects of the drug, there have also been reports of death due to self-harm and suicide under the influence of the substance.

Given limited documentation of NBOMe consumption, the long-term effects of the substance remain unknown. NBOMe compounds are not active orally, and are usually taken sublingually. When NBOMes are administered sublingually, numbness of the tongue and mouth followed by a metallic chemical taste was observed, and researchers describe this physical side effect as one of the main discriminants between NBOMe compounds and LSD.

Neurotoxic and cardiotoxic actions

Many of the NBOMe compounds have high potency agonist activity at additional 5-HT receptors and prolonged activation of 5-HT_2B can cause cardiac valvulopathy in high doses and chronic use. 5-HT_2B receptors have been strongly implicated in causing drug-induced valvular heart disease. The high affinity of NBOMe compounds for adrenergic α₁ receptor has been reported to contribute to the stimulant-type cardiovascular effects.

''In vitro'' studies, 25C-NBOMe has been shown to exhibit cytotoxicity on neuronal cell lines SH-SY5Y, PC12, and SN471, and the compound was more potent than methamphetamine at reducing the visibility of the respective cells; the neurotoxicity of the compound involves activation of MAPK/ERK cascade and inhibition of Akt/PKB signaling pathway. 25C-NBOMe, including the other derivative 25D-NBOMe, reduced the visibility of cardiomyocytes H9c2 cells, and both substances downregulated expression level of p21 (CDC24/RAC)-activated kinase 1 (PAK1), an enzyme with documented cardiac protective effects.

Preliminary studies on 25C-NBOMe have shown that the substance is toxic to development, heart health, and brain health in zebrafish, rats, and ''Artemia salina'', a common organism for studying potential drug effects on humans, but more research is needed on the topic, the dosages, and if the toxicology results apply to humans. Researchers of the study also recommended further investigation of the drug's potential in damaging pregnant women and their fetus due to the substance's damaging effects to development.

Emergency treatment

At present, there are no specific antidotes for NBOMes, and all acute intoxication is managed by symptomatic treatments, such as administration of benzodiazepines, antipsychotic drugs, and antiarrhythmic agents, such as beta blockers; some emergency interventions are intended to specifically treat rhabdomyolysis, which may lead to critical complications such as metabolic acidosis and acute kidney injury.

Interactions

2C drugs like 2C-I are metabolized by the monoamine oxidase (MAO) enzymes, including both MAO-A and MAO-B. As a result, 2C drugs may be potentiated by monoamine oxidase inhibitors (MAOIs), such as phenelzine, tranylcypromine, moclobemide, and selegiline. This has the potential to lead to overdose and serious toxicity. In contrast to 2C drugs, 25I-NBOMe has been found not to be metabolized by MAO-A or MAO-B and instead only by cytochrome P450 enzymes. Other 25-NB drugs besides 25I-NBOMe were not assessed.

Pharmacology

Pharmacodynamics

Actions

The NBOMe drugs are highly potent and selective agonists of the serotonin 5-HT₂ receptors, including of the 5-HT_2A, 5-HT_2B, and 5-HT_2C receptors. However, they are much less potent and efficacious at the serotonin 5-HT_2B receptor compared to the serotonin 5-HT_2A and 5-HT_2C receptors. The drugs are highly selective for the serotonin 5-HT₂ receptors over other serotonin receptors and over a variety of other biological targets. They are likewise inactive as monoamine reuptake inhibitors and releasing agents. Many of the NBOMe drugs are partial agonists of the rat and mouse trace amine-associated receptor 1 (TAAR1), but they are inactive as agonists of the human TAAR1.

Effects

In accordance with their psychedelic effects, NBOMe drugs induce the head-twitch response, a behavioral proxy of psychedelic effects, in rodents. They have also been found to produce hyperlocomotion at low doses and hypolocomotion at high doses in rodents.

Unlike most other serotonergic psychedelics, the NBOMe drugs 25B-NBOMe and 25N-NBOMe have been found to produce reinforcing effects in rodents, and hence may have misuse potential. Relatedly, 25B-NBOMe robustly increased dopamine levels in the nucleus accumbens similarly to methamphetamine. The reinforcing effects of 25B-NBOMe were not blocked by serotonin 5-HT_2A receptor antagonism, and it is unclear how they are produced. However, some NBOMe drugs, such as 25N-NBOMe, have been found to increase phosphorylation of the dopamine transporter (DAT) in the striatum similarly to methamphetamine in rodents. DAT phosphorylation is associated with dopamine reverse transport and efflux, which in turn increases extracellular dopamine levels.

Similarly to other psychedelics like DOI and 2C-T-7, tolerance has been found to gradually develop to the head-twitch response induced by 25I-NBOMe with chronic administration in rodents.

Chemistry

The 25-NB compounds are mostly ''N''-benzylphenethylamines, though in some cases the phenyl ring of the N-benzyl group is replaced by other heterocycles such as thiophene, pyridine, furan, tetrahydrofuran, benzodioxole or naphthalene, among others.

Generally speaking, they have methoxy groups at the 2 and 5 positions of the phenyl ring, a substitution such as a halogen or alkyl group at the 4 position of the phenyl ring, and a methoxy or other substitution (e.g., hydroxyl, fluoro) at the 2 position of the ''N''- benzyl ring. More rarely, other substitution patterns may be present (see e.g. NBOMe-mescaline, 25G-NBOMe, 2CBFly-NBOMe, 25C-NB3OMe). They differ from the 2C series by the presence of the ''N''-benzyl moiety.

Rarely an alpha-methyl group is present making them N-benzyl amphetamines rather than N-benzyl phenethylamines, but this greatly reduces potency and activity. However in some cases where a side chain methyl group is cyclised back to the ring (e.g. in 2CBCB-NBOMe) or links the two alpha positions (e.g. in DMBMPP), this can improve selectivity for the 5-HT_2A receptor subtype.

History

2C-B, the first major 2C drug and an analogue of mescaline, was first described by Alexander Shulgin in the 1970s. Richard Glennon and colleagues synthesized and described 25B-NB (''N''-benzyl-2C-B) along with a variety of other 25-NB derivatives in 1994. It was observed at the time that 25B-NB had slightly higher affinity for the serotonin 5-HT_2A receptor than 2C-B and that other 25-NB derivatives with substituents on the benzyl ring showed very high affinity for the receptor, though functional data were not reported.

''N''-Benzyl derivatives of the ketanserin-related quinazolinedione EZS-8, such as RH-34, were first described by Heinz Pertz, Sigurd Elz, and Ralf Heim by 1996 or 1998. NBOMe-mescaline and NBOMe-escaline were first described by Pertz and colleagues by 1999,Pertz, H. H., Rheineck, A., & Elz, S. (1999). N-Benzylated derivatives of the hallucinogenic drugs mescaline and escaline as partial agonists at rat vascular 5-HT2A receptors. Naunyn-Schmiedeberg’s Arch Pharmacol, 359(Suppl 3), R29. https://scholar.google.com/scholar?cluster=8208583485236470656Ratzeburg, K., Heim, R., Mahboobi, S., Henatsch, J., Pertz, H. H., & Elz, S. (2003, March). Potent partial 5-HT2A-receptor agonism of phenylethan-amines related to mescaline in the rat tail artery model. ''Naunyn-Schmiedebergs Archives of Pharmacology'', ''167'', R31–R31. https://scholar.google.com/scholar?cluster=411158176506751110 while 25B-NBOMe was first described by Heim and colleagues in 1999.Heim, R., Pertz, H. H., & Elz, S. (1999). Preparation and in vitro pharmacology of novel secondary amine-type 5-HT2A receptor agonists: from submillimolar to subnanomolar activity. Arch. Pharm. Pharm. Med. Chem, 332, 34. https://bitnest.netfirms.com/external/Arch.Pharm.Pharm.Med.Chem/331.S1.34 25I-NBOMe and other 25-NB compounds such as 25TFM-NBOMe and 2CBFly-NBOMe were described by Heim and colleagues by 2000.Heim, R., Pertz, H. H., & Elz, S. (2000). Partial 5-HT2A-receptor agonists of the phenylethanamine series: effect of a trifluoromethyl substituent. Arch. Pharm. Pharm. Med. Chem, 333, 45. https://bitnest.netfirms.com/external/Arch.Pharm.Pharm.Med.Chem/333.S2.45 25I-NBOMe and other 25-NB drugs were subsequently further described by Heim in his dissertation in 2003. 25C-NBOMe was not described in the literature until 2010.Ettrup, A. (2010). Serotonin receptor studies in the pig brain: pharmacological intervention and positron emission tomography tracer development (Doctoral dissertation, Faculty of Health Sciences, University of Copenhagen). https://research.regionh.dk/en/publications/serotonin-receptor-studies-in-the-pig-brain-pharmacological-inter The discovery of the 25-NB compounds by Heim and colleagues has been described by David E. Nichols as structurally remarkable, since ''N''-alkylation of psychedelic phenethylamines, for instance Beatrice (''N''-methyl-DOM), has otherwise invariably abolished the hallucinogenic effects of this class of compounds.

The NBOMe drugs, primarily 25I-NBOMe, were encountered as novel recreational drugs by 2010, and by 2012 had eclipsed other psychedelics like LSD and psilocybin-containing mushrooms in popularity, at least for a time. Various NBOMes, such as 25I-NBOMe, became Schedule I controlled substances in the United States in 2013.

Society and culture

Legal status

United Kingdom

A large number of substances in the 25-NB class are Class A drugs in the United Kingdom as a result of the N-benzylphenethylamine catch-all clause in the Misuse of Drugs Act 1971 or are otherwise covered by the Psychoactive Substances Act 2016.

List of 25-NB compounds

By chemical class

By individual compound

This list includes notable compounds representative of most of the structural variations that have been explored in this series, but is by no means exhaustive. Many derivatives invented for scientific study into the structure-activity relationships of 5-HT₂ receptor agonists have never appeared as designer drugs, while conversely some derivatives that have appeared as designer drugs are structurally novel and of unknown pharmacological activity (e.g. C30-NBOMe, 5-APB-NBOMe).

Related compounds

Similar compounds with related structures are also known including:

See also

* Substituted methoxyphenethylamine
* 4-Substituted 2,5-dimethoxyphenethylamines (2Cs)
* 4-Substituted 2,5-dimethoxyamphetamines (DOx)
* 4-Substituted 2,5-dimethoxy-α-ethylphenethylamines (4Cs)
* List of miscellaneous 5-HT_2A receptor agonists

Notes

References

External links

VICE In-house Chemist Hamilton Morris on the Dangers of the NBOMe Hallucinogen - VICE - YouTube

What Are N-Bombs? (25-I-NBOMe) — Avoid This Psychedelic - Tripsitter

Unmasking Fake Acid: The Dangers of 25I-NBOMe Disguised as LSD - Psychedelic Spotlight

{{Chemical classes of psychoactive drugs

5-HT2A agonists
5-HT2B agonists
5-HT2C agonists
Chemical classes of psychoactive drugs
Secondary amines
TAAR1 agonists