Clobazam

Clobazam — commercially available as Frisium or Onfi — is a prescription benzodiazepine medication. It was developed initially as an anxiolytic but is more commonly prescribed as a muscle relaxant today.

Clobazam has a different chemical structure than “traditional” 1,4 benzodiazepines, which have nitrogen atoms in the 1 and 4 positions. Instead, clobazam is classified as a 1,5 benzodiazepine similar to drugs like arefendazam and lofendazam.

Clobazam has a unique mechanism of action and is thought to carry a lower risk of side effects such as rebound insomnia or anxiety (unconfirmed).

IUPAC Name: 7-chloro-1-methyl-5-phenyl-1,5-benzodiazepine-2,4-dione

Other Names: Onfi, Frisium, Urbanol

Metabolism: The major metabolic pathway of clobazam involves N-demethylation, primarily by CYP3A4 and to a lesser extent by CYP2C19 and CYP2B6.

Duration of Effects: Intermediate-Acting (6–12 hours). Clobazam is rapidly and extensively absorbed following oral administration. The time to peak concentrations of clobazam tablets under fasted conditions ranged from 0.5 to 4 hours after single- or multiple-dose administrations. The relative bioavailability of clobazam tablets compared to an oral solution is approximately 100%. The estimated mean elimination half-lives (t½) of clobazam and N-desmethylclobazam were 36-42 hours and 71-82 hours, respectively.

Dosage: Proper dosage is determined on a case-by-case basis.

How Does Clobazam Work?

Like most other benzodiazepines, clobazam is a positive allosteric modulator at the GABA-A receptors.

Wondering what that means? We’ll break it down for you.

Benzodiazepines exert their inhibitory effects on the brain and central nervous system (CNS) by interacting with GABA molecules at receptor sites along the CNS. Specifically, they bind to the GABA-A receptors at a site different from where GABA-A binds and potentiate the GABA-A neurotransmitter’s natural activity [1].

Benzodiazepine’s action upon GABA-A receptors increases the opening frequency of the chloride channel in the neuron, allowing chloride atoms to enter and hyperpolarize the neuron. Clobazam, specifically, also increases the production of the GABA transporter [2].

The hyperpolarization of the neuron’s membrane potential alters the electric charge inside it and makes it less likely the neuron will fire an action potential. Reduced action potential activity means reduced overall brain activity. This inhibitory effect gives benzodiazepines their anxiolytic, hypnotic, sedative, muscle relaxant, and anticonvulsant effects.

What Makes Clobazam Unique?

The most meaningful differences between benzodiazepines lie in the nitty-gritty of how they interact with GABA-A and other neurotransmitters to exert their inhibitory effects. Even slight differences in their mechanisms of action lead to significant variations in their effects and side effects.

GABA-A receptors are made up of five subunits, each one typically having αsubunits, two βsubunits, and one γsubunit [3]. Each subunit has multiple types.

These drugs are still not well understood, but we do know something about how clobazam differs when compared to traditional benzodiazepines. We know the α1 subunit mediates sedative effects while the α2 subunit controls anxiolytic effects; all αsubunits mediate anticonvulsant effects [4].

Additionally, clobazam binds in the junction between the α and γ2 subunits. It also has increased selectivity for α2 subunits over α1 subunits when compared to 1,4 benzodiazepines. It’s been suggested that this is why clobazam exhibits a decreased likelihood of causing sedation. Also, the selective binding may explain clobazam’s decreased potential to cause tolerance (theoretical) [5].

Is Clobazam Safe? Risks & Side Effects

To understand the danger one is risking when taking clobazam, it is key to understand the inherent risks in all benzodiazepine use and how they have taken their toll on the United States in recent years.

Benzodiazepine Misuse Statistics

The current situation regarding benzodiazepine use is quite alarming when one considers the dangers they represent. However, the problem has flown under the radar largely due to the severity and alarm caused by the opioid crisis. Still, there is a good argument to be made that a corresponding benzodiazepine crisis has also developed.

In a 2020 survey, the CDC showed how benzodiazepines were involved in 12,290 deaths in the US. Another National Institute on Drug Abuse (NIDA) study shows that 16% of opioid overdose deaths also involved benzodiazepines.

Looking at the broader trend, we can see how benzodiazepine-related deaths have increased steadily since 1999. They leveled off around 2010 but started climbing once again in 2014, mainly because of the explosion in concomitant opioid use. United States health authorities have recognized the seriousness of this trend and are taking strong action to reign in the explosion in opioid and benzodiazepine misuse. In 2016, the FDA warned healthcare professionals and consumers about the risks of mixing opioids with benzodiazepines and other CNS depressants.

Clobazam Misuse

Like all prescription drugs, clobazam use does imply certain risks. First of all, the United States classifies it as a Schedule IV drug under the Controlled Substances Act — despite its approved medical uses, it still carries the potential to develop physical dependence and withdrawal symptoms.

There is almost no data on how clobazam fits into the larger picture regarding benzodiazepine misuse. It is essential to understand the trends surrounding popular benzodiazepines with large numbers of prescriptions and a reputation for recreational abuse, such as clonazepam and alprazolam. However, compared to these popular benzodiazepines, clobazam misuse is almost a non-issue.