Status determination of benzimidazoles – Canada.ca

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This guidance document provides a general overview of how Health Canada determines the status for benzimidazoles under the CDSA. Please note that this guidance is subject to change upon availability of new scientific evidence. It bears emphasis that this document is published for informational purposes only. It is not a comprehensive account of how status decisions are made, and is not a substitute for status decisions made by the Science Division of the Office of Drug Policy and Science.

In order to ensure the accurate status of any substance of interest, please contact: status-demandedestatut@hc-sc.gc.ca.

About benzimidazoles

A benzimidazole is a simple chemical structure found in a great variety of substances. A subset of benzimidazole-containing substances are opioids, some of which can be very potent – more than morphine and sometimes more than fentanyl. Non-opioid benzimidazoles are not captured under the CDSA. From this point forward “benzimidazoles” refers to benzimidazole opioids.

Benzimidazoles were originally developed to reduce pain but were never approved for medical use in Canada. Benzimidazoles also induce euphoria (feeling high), which gives them the potential to be used improperly and to be addictive. Overdoses can be fatal. Consumption of benzimidazoles is especially dangerous when used at the same time with alcohol and other drugs that slow down brain activity (such as, other opioids, sedatives, anxiety medications, muscle relaxants).

Benzimidazoles are controlled in Canada under Schedule I, item 13 to the CDSA under the heading “Benzimidazoles, their salts, derivatives and salts of derivatives.“

3 benzimidazoles are explicitly listed in the act:

• clonitazene
• etonitazene
• bezitramide

Many other structurally similar substances also have the potential to induce psychoactive and toxic effects similar to the benzimidazoles listed under the CDSA. For instance, isotonitazene, metonitazene, protonitazene, etodesnitazene, and brorphine have been found on the Canadian illegal drug market. These substances are controlled under item 13 even though they are not explicitly listed.

Substances classified as benzimidazoles under the CDSA

The status confirmation process includes a scientific review with respect to Schedule I, item 13 to the CDSA. This scientific assessment is based on the chemical structure and the chemical synthesis of the substance. Core structures have been defined to confirm whether a substance belongs to the benzimidazole class, and therefore controlled under the CDSA. These core structures capture substances that are chemically related and expected to be psychoactive. As the 3 substances explicitly listed under this listing are structurally diverse, 2 core structures have been developed. They are based on the structural elements of benzimidazole opioids currently listed under the CDSA as well as currently available scientific information related to benzimidazoles, including structure-activity relationships and pharmacological activity.

Figure 1. Etonitazene-related benzimidazoles

Core Structure	Group	Substitutions
Figure 1 – Text description The etonitazene-related benzimidazole core structure includes a 1-aminoethyl-benzimidazole skeleton whether or not substituted on the phenyl moiety of the benzimidazole ring with nitrogen substituents (R1). The 1-aminoethyl nitrogen is substituted at positions R2 and R3. A linker (X) on position 2 of the benzimidazole ring, whose composition may vary, is further substituted at positions R4 and R5. See in-text bullets for possible substitutions.	x	x is comprised of 1 or 2 carbons (x=1 or 2), an oxygen, or a sulfur atom. (x=1), with no substitution, is most commonly observed
	R1	Hydrogen or any substitution, including nitro, amino, or substituted alkyl amines.
	R2	Hydrogen or any substitution, including alkyls, or a heterocycle linked between R2 and R3.
	R3	Any substitution, including alkyls, or a heterocycle linked between R2 and R3.
	R4	Aromatic or heterocyclic rings, whether or not further substituted, for example with hydrogen, alkoxy, alkyl, amino, halogen, hydroxyl, nitro, or sulfide groups. Alkoxy phenyl substitutions are most commonly observed
	R5	Hydrogen, or any substitution, including alkoxy, alkyl or amide.

Figure 2. Bezitramide-related benzimidazoles

Core Structure	Group	Substitutions
Figure 2 – Text description Figure 2 – Text description The bezitramide-related benzimidazole core structure includes a 1-(4-piperidinyl)-2-benzimidazolone skeleton. A linker (X) on the nitrogen of the piperidine ring, whose composition may vary, is further substituted at positions R1, R1‘ and R1”. Substitutions may occur at position 3 and on the phenyl moiety of the benzimidazole ring (R2 and R3 respectively). See in-text bullets for possible substitutions.	R1, R1‘, R1”	Dependent on the number of carbon atoms found within the alkyl chain (x) and where the underlined C (carbon atom) is substituted with R1 groups
	(x=C)	R1	Unsubstituted aromatic and variously substituted aromatic rings including but not limited to halogenated phenyl, alkylated phenyl, phenyl ether, and benzodioxan.
		R1‘	Hydrogen
		R1”	Hydrogen or variously substituted alkyl groups
	(x=(CH2)2C)	R1	Hydrogen or any substitution including carbonyl, carboxamido, hydroxyl and/or cyano.
		R1‘, R1”	Unsubstituted or variously substituted aromatic rings.
	R2	Hydrogen or any substitution including alkyl halides, hydroxyalkyls, lower-alkoxy#, lower-alkyl#, lower-carbonyl#, and/or nitrile.
	R3	Hydrogen or any substitution including alkoxy, alkyl, and halogens.
	Piperidine	The piperidine ring can be substituted, such as 1,2,3,6-tetrahydropyridine ring.

# 1 to 5 carbons per functional group

Controlled benzimidazoles identified in Canada include isotonitazene, metonitazene, protonitazene, etodesnitazene (also known as etazene), butonitazene, N-pyrrolidino etonitazene (also known as etonitazepyne), flunitazene, metodesnitazene, 5-aminoisotonitazene, and brorphine.