ToxCard – Novel Phenethylamines: 2-C and N-BOME

Authors: Aaron Sherwood, MD (Emergency Medicine Resident, Atrium Health’s Carolinas Medical Center); Ann-Jeannette Geib, MD (Emergency Medicine Attending, Medical Toxicologist, Atrium Health’s Carolinas Medical Center) // Reviewed by: Anthony Spadaro, MD (@TSpadaro91, Medical Toxicology Fellow, Rutgers New Jersey Medical School, Newark, NJ); James Dazhe Cao, MD (@JamesCaoMD, Associate Professor of EM, Medical Toxicology, UT Southwestern Medical Center, Dallas, TX); Alex Koyfman, MD (@EMHighAK); Brit Long, MD (@long_brit)

Case:

A 22-year-old man who reports no significant past medical history is brought to the emergency department by a friend with complaints of palpitations, nausea, diaphoresis, and auditory hallucinations that sound like whispering voices after taking a “research chemical” that his friend ordered on the dark web.He admits to an extensive history of psychedelic drug use, including LSD, psilocybin mushrooms, ketamine, and “2C” drugs, including 2C-I and 2C-B, but this was the first time he has tried “N-Bomb”. He takes no medications on a daily basis and denies ingestion of any other substances today.Initial vital signs include a temp of 100°F, HR 101, BP 133/90, RR 18, O2 99%

The patient is awake, alert, and oriented, but appears anxious and is fidgeting in bed. His pupils are 5mm and reactive bilaterally. He is mildly diaphoretic. Physical examination is otherwise normal. The patient has no clonus, rigidity, or hyperreflexia. An EKG shows sinus rhythm with normal intervals.

Questions:

1. What are substituted phenethylamines?
2. What are “2C” drugs?
3. What are “NBOMe” drugs?

Background:

• In 1974, 2,5-dimethoxy-4-bromophenethylamine (2C-B) was first synthesized by American chemist Alexander Shulgin. 2C-B was the first in a series of phenethylamine substituted compounds, now known as “2C” drugs. 
• Phenethlyamine drugs have been used for hallucinogenic and euphoric effects. 
• The number of phenethylamines has increased as new chemicals get synthesized. By the end of 2021 the European Monitoring Centre for Drugs and Addiction (EMCDDA) was monitoring around 930 novel psychoactive substances, 41 of which were first reported in 2022. Categories of novel psychoactive substances include synthetic cannabinoids, benzodiazepines, opioids, arylcyclohexylamines, arylalkylamines, tryptamines, and phenethylamines.[1]

Substituted Phenethylamines  

A phenethylamine is a naturally occurring compound with a chemical structure containing a primary amino group attached to phenyl ring by a two-carbon side chain.[2] An almost innumerable number of compounds can be formed by altering substituents on the aromatic ring of the phenethylamine. Many of these substances have psychopharmacological effects, including, hallucinogenic and stimulant effects.[3]

Substituted phenylethylamines include:

• Endogenous neurotransmitters such as dopamine, norepinephrine, and epinephrine.
• Sympathomimetic pharmaceuticals, including ephedrine and phenylephrine (used as vasopressors), bupropion, and amphetamine.
• Synthetic recreational substances such as methamphetamine, 3,4-methyl​enedioxy​methamphetamine (MDMA/ecstasy), cathinones, and “2C” drugs.
• Mescaline, a naturally occurring substituted phenethylamine, is known for its hallucinogenic effects.

“2C” Drugs

2C series drugs are phenethylamine compounds with methoxy groups at positions 2 and 5 of the phenyl ring, as well as a hydrophobic substituent at position 4 of the ring.[4]

Like many hallucinogens, modulation of serotonin 2A (5-HT2A) receptors is a primary mechanism by which 2C drugs produce their effects.[5]  Interactions with 5-HT2B and 5-HT2C serotonergic receptors have also been observed.[6] They also inhibit norepinephrine transporters (NET) and serotonin transporters (SERT) and interact with adrenergic alpha-1 receptors, similar to amphetamines.[6,7]

“NBOMe” Drugs

N-benzylphenethylamines (“NBOMes”) drugs were developed after it was discovered that N-benzyl substitution of 2C drugs increased their affinity for the 5-HT2A receptor.[6]

• Studies show NBOMe drugs have a high-affinity binding and potent activation of serotonin receptors.[6]  One animal study suggested that N-(2-methoxybenzyl)-2,5-dimethoxy-4-iodophenethylamine (25I-NBOMe) was 14-fold more potent than its 2C counterpart, 2C-I.[8] 
• Another study saw 6 to 100-fold increases in 5-HT2A receptor affinity in N-2-methoxybenzyl derivatives, although this did not always translate to increases in receptor activation potency.[6]

Epidemiology:

Individuals who seek out 2C and NBOMe drug experiences may identify with a culture of people that seek to expand their experience with hallucinogens and sometimes refer to themselves as “psychonauts”.  The substances are often procured on the internet, but are also obtained from friends, parties, and music festivals.[9] 

Some individuals ingest the compounds unknowingly, while seeking out other drug experiences. One study found that 66.7% of blotter paper seized from the streets, which has historically been used to distribute LSD, contained one or more NBOME compounds.[10]

Clinical Presentation:

• Patient’s with 2C and NBOMe intoxication may present with sympathomimetic and serotonergic toxidromes. Signs and symptoms include nausea, vomiting, tachycardia, hypertension, and hyperthermia. In severe cases rhabdomyolysis, seizures, and death can occur. Patients may also present with hallucinations, acute psychosis, or agitation.[11,12] 
• Individuals often present having co-ingested other recreational substances.
• One series identified violent agitation and hallucinations as especially prominent with NBOMe intoxication.[16]
• There are no readily available laboratory tests to confirm a 2C or NBOMe ingestion and should be suspected based on patient presentation and history.
• Laboratory tests such as a complete blood count (CBC), basic metabolic panel (BMP), and Creatinine Phosphokinase (CPK) should be obtained.

Management:

• There is no antidote for 2C and NBOMe intoxication and management focuses on supportive care and symptomatic treatment.[11]
• Like most sympathomimetic and serotonergic toxidromes, cardiopulmonary monitoring and benzodiazepines are the mainstay of treatment. IV hydration and rapid cooling measures are indicated if there is concern for hyperthermia or rhabdomyolysis. Intubation and paralysis may be required in severe cases.[13]
• Very high doses of benzodiazepines may be required in severe NBOMe intoxications. There is one case report that describes administering 34 milligrams of lorazepam over a 4.5 hour time frame in escalating doses with the patient ultimately walking out of the hospital 48 hours after their presentation to the Emergency Department.[11] 
• The management of serotonin syndrome and toxicological causes of hyperthermia are discussed elsewhere. 
• Consider 2C and NBOMe ingestion in patients who report taking LSD or blotter acid that present with sympathomimetic toxidromes.
• Consider co-intoxication. Other hallucinogens, other stimulants, alcohol, cannabis, and benzodiazepines are just a few of the drugs that were co-ingested in 2C and NBOMe drug user “trip reports”.[14,15]

Case Follow-up:

The patient was given benzodiazepines for their anxiety and were monitored in the ED for seven hours. Their tachycardia improved and on re-evaluation they were no longer diaphoretic or anxious. Their mental status returned to baseline and were no longer complaining of hallucinations. They were ultimately discharged from the ED.

Clinical Pearls:

• A phenethylamine is a naturally occurring compound with a chemical structure, there are many chemically modified phenethylamines, such as 2C and NBOMe drugs, that people use and they have psychopharmacological effects, including, hallucinogenic and stimulant effects. 
• Patient’s with 2C and NBOMe intoxication may present with sympathomimetic and serotonergic toxidromes. Signs and symptoms include nausea, vomiting, tachycardia, hypertension, and hyperthermia. In severe cases rhabdomyolysis, seizures, and death can occur.
• Like most sympathomimetic drugs, cardiopulmonary monitoring and benzodiazepines are the mainstay of treatment. IV hydration and rapid cooling measures are indicated if there is concern for hyperthermia or rhabdomyolysis.
• Very high doses of benzodiazepines may be required in severe NBOMe intoxications.

References:

1. European Monitoring Centre for Drugs and Drug Addiction (2023), European Drug Report 2023: Trends and Developments, DOI: https://www.emcdda.europa.eu/publications/european-drug-report/2023_en DOI: 10.2810/161905 
2. https://isomerdesign.com/countyourculture/2010/11/02/phenethylamine-and-amphetamine/ Accessed 29 July 29, 2023.
3. David E. Nichols, William E. Fantegrossi.,Emerging Designer Drugs. In Bertha Madras, Michael Kuhar, Eds. The Effects of Drug Abuse on the Human Nervous System, Academic Press,2014,ISBN 9780124186798,https://doi.org/10.1016/B978-0-12-418679-8.01001-7. (https://www.sciencedirect.com/science/article/pii/B9780124186798010017)
4. https://isomerdesign.com/countyourculture/2010/09/28/the-halogenated-2cs/  Accessed July 30, 2023.
5. Geyer MA, Vollenweider FX. Serotonin research: contributions to understanding psychoses. Trends Pharmacol Sci. 2008 Sep;29(9):445-53. doi: 10.1016/j.tips.2008.06.006. PMID: 19086254.
6. Rickli A, Luethi D, Reinisch J, Buchy D, Hoener MC, Liechti ME. Receptor interaction profiles of novel N-2-methoxybenzyl (NBOMe) derivatives of 2,5-dimethoxy-substituted phenethylamines (2C drugs). Neuropharmacology. 2015 Dec;99:546-53. doi: 10.1016/j.neuropharm.2015.08.034. Epub 2015 Aug 25. PMID: 26318099.
7. Nikolaou P, Papoutsis I, Stefanidou M, Spiliopoulou C, Athanaselis S. 2C-I-NBOMe, an “N-bomb” that kills with “Smiles”. Toxicological and legislative aspects. Drug Chem Toxicol. 2015 Jan;38(1):113-9. doi: 10.3109/01480545.2014.911882. Epub 2014 May 1. PMID: 24785196. 
8. Halberstadt AL, Geyer MA. Effects of the hallucinogen 2,5-dimethoxy-4-iodophenethylamine (2C-I) and superpotent N-benzyl derivatives on the head twitch response. Neuropharmacology. 2014 Feb;77:200-7. doi: 10.1016/j.neuropharm.2013.08.025. Epub 2013 Sep 4. PMID: 24012658; PMCID: PMC3866097.
9. European Monitoring Centre for Drugs and Drug Addiction. Report on the risk assessment of 2C-I, 2C-T-2 and 2C-T-7 in the framework of the joint action on new synthetic drugs. Luxembourg: Office for Official Publications of the European Communities. 2004 — 136 pp. — 14.8 x 21 cm. ISBN 92-9168-181-4
10. Coelho Neto J. Rapid detection of NBOME’s and other NPS on blotter papers by direct ATR-FTIR spectrometry. Forensic Sci Int. 2015 Jul;252:87-92. doi: 10.1016/j.forsciint.2015.04.025. Epub 2015 Apr 27. PMID: 25965305.
11. Zygowiec J, Solomon S, Jaworski A, Bloome M, Gotlib A. 25C-NBOMe Ingestion. Clin Pract Cases Emerg Med. 2017 Oct 3;1(4):295-297. doi: 10.5811/cpcem.2017.5.33994. PMID: 29849316; PMCID: PMC5965197.
12. Dean BV, Stellpflug SJ, Burnett AM, Engebretsen KM. 2C or not 2C: phenethylamine designer drug review. J Med Toxicol. 2013 Jun;9(2):172-8. doi: 10.1007/s13181-013-0295-x. PMID: 23494844; PMCID: PMC3657019.
13. Gee P, Schep LJ, Jensen BP, Moore G, Barrington S. Case series: toxicity from 25B-NBOMe–a cluster of N-bomb cases. Clin Toxicol (Phila). 2016;54(2):141-6. doi: 10.3109/15563650.2015.1115056. Epub 2015 Dec 1. PMID: 26621342.
14. https://erowid.org/experiences/subs/exp_2CB.shtml Accessed July 30, 2023.
15. https://erowid.org/experiences/subs/exp_25BNBOMe.shtml Accessed July 30, 2023. 
16. Topeff JM, Ellsworth H, Willhite LA, Bangh SA, Edwards EM, Cole JB (2011) A case series of symptomatic patients, including one fatality, following 2C-E exposure. Clin Toxicol 49:526.