Clobazam

Onfi, Sympazan, Frisium, Urbanol, Castilium

Psychoactive Class

Chemical Class

Clobazam is a long-acting benzodiazepine derivative belonging to the unique 1,5-benzodiazepine subclass, distinguishing it from the more common 1,4-benzodiazepines.¹² First synthesized in 1966¹ and patented in 1968, it was initially marketed as an anxiolytic before gaining approval for epilepsy treatment in 1984.¹² Clobazam demonstrates a more favorable side-effect profile than older benzodiazepines, with notably less sedation and memory impairment,¹² and shows a distinct addictive potential compared to its 1,4-benzodiazepine counterparts.³

Dosage & Duration

Dosage

Threshold~5 mg

Light5-10 mg

Moderate10-15 mg

Heavy15-30 mg

Bioavailability

~100%

NOTE: 20mg of Clobazam is approximately equal to 10mg of Diazepam

Duration

Onset20-40 minutes

After Effects1-12 hours

Total6-12 hours

Half-life

36-42 hours

Subjective Effects

Clobazam is a long-acting 1,5-benzodiazepine whose effects centre on anxiolysis, with sedation reported as less pronounced than that of older 1,4-benzodiazepines at comparable doses. Its unfavourable side-effect profile relative to other benzodiazepines means it is not often taken recreationally. At higher doses or in overdose the experience shifts toward drowsiness, confusion and impaired coordination, with amnesia and other cognitive impairments persisting even as tolerance develops to other effects.

Physical

Muscle relaxation and sedation are the main physical effects, accompanied at higher doses by unsteady coordination, slurred speech and lethargy.

Coordination

Sedation

Muscle relaxation

Uncomfortable

Cognitive

The headspace is primarily one of reduced anxiety, though impaired concentration, memory disruption and confusion are documented, and euphoria and disinhibition are reported in the context of misuse.

Disconnective

Emotional

Impairment

Suppressions

Visual

Reagent Testing

Loading reagent data

Expected colorimetric results are being prepared.

Pharmacology

Pharmacodynamics

Clobazam is a 1,5-benzodiazepine that acts as a positive allosteric modulator at the GABA-A receptor, binding at the benzodiazepine site to potentiate GABAergic neurotransmission.⁴² This binding increases chloride conductance in neurons, causing hyperpolarization that raises the action potential threshold and reduces neuronal firing frequency, thereby depressing central nervous system activity.² Clobazam demonstrates higher affinity for the α2 subunit of the GABA-A receptor, which mediates anxiolytic effects, compared to the α1 subunit responsible for sedation.² This subunit selectivity, along with its proposed partial agonist activity rather than full agonism, may account for its reduced sedative and amnesic effects compared to classical 1,4-benzodiazepines.³ Some additional activity at sodium channels and voltage-sensitive calcium channels has been speculated.

Pharmacokinetics

Clobazam is rapidly and extensively absorbed following oral administration, with time to peak concentrations ranging from 0.5 to 4 hours.⁴ Oral bioavailability is approximately 100% and is unaffected by food.⁴ The drug is lipophilic and distributes rapidly throughout the body with an apparent volume of distribution of approximately 100 L at steady state.⁴ Clobazam is extensively metabolized in the liver, primarily via N-demethylation catalyzed by CYP3A4 and to a lesser extent by CYP2C19 and CYP2B6, producing the active metabolite N-desmethylclobazam (norclobazam).⁴ Hydroxylation produces 4-hydroxyclobazam, facilitated by CYP2C18 and CYP2C19. N-desmethylclobazam is the major circulating metabolite, reaching plasma concentrations 3 to 5 times higher than the parent compound at therapeutic doses.⁴ The polymorphic CYP2C19 is the major contributor to N-desmethylclobazam metabolism, with poor metabolizers showing 5-fold higher plasma levels.⁴ Approximately 82% of the dose is excreted in urine and 11% in feces, with only about 2% recovered as unchanged drug.⁴

Interactions

Caution

Use caution

These combinations are not usually physically harmful, but may produce undesirable effects, such as physical discomfort or overstimulation. Extreme use may cause physical health issues. Synergistic effects may be unpredictable. Care should be taken when choosing to use this combination.

1,2-BenzodiazepineAbacavirAbametapirAbataceptAbemaciclib

TripSit

Tolerance

Full Tolerance

Tolerance to the therapeutic and anticonvulsant effects of clobazam develops with continued therapy. The rate of tolerance development varies by effect—while tolerance to seizure control may become clinically significant during long-term prophylactic use, little tolerance develops to the amnestic reactions and other cognitive impairments caused by the drug. This differential tolerance pattern is characteristic of benzodiazepines and may render long-term therapy less effective for epilepsy management.

Cross Tolerance

Benzodiazepines, GABAergic depressants

Harm Potential

Addiction & Dependence

Psychological

High

Clobazam is a benzodiazepine with significant potential for abuse and addiction.⁴ Animal studies have shown increased reward-seeking behaviors, and abuse has been reported internationally.⁴ Even therapeutic use may put patients at risk for abuse and misuse, which often involves doses greater than recommended and concomitant use of other substances.⁴

Physical

High

Physical dependence develops from continued therapy.⁴ Abrupt discontinuation or rapid dose reduction may precipitate acute withdrawal reactions including life-threatening seizures.⁴ Acute withdrawal symptoms include anxiety, tremor, insomnia, tachycardia, and in severe cases catatonia, convulsions, delirium tremens, hallucinations, and psychosis.⁴ Protracted withdrawal syndrome may persist for weeks to over 12 months, characterized by anxiety, cognitive impairment, depression, paresthesia, and motor symptoms.⁴

Toxicity

Hepatic

Use is contraindicated or requires great care in patients with severe liver diseases such as cirrhosis and hepatitis; specific hepatotoxicity from clobazam itself is not well characterized but liver disease significantly affects drug handling.

Dermatological

Serious skin reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis can occur, particularly within the first eight weeks of treatment.⁴⁵

Respiratory

Respiratory depression can occur, particularly in overdose or when combined with other CNS depressants; use requires great care in patients with severe respiratory failure or sleep apnea.⁵

Skeletal

Administration during juvenile development in rats resulted in decreased bone density and bone length at high doses.⁴

Carcinogenicity

Possible

In rats, oral administration for 2 years resulted in increases in thyroid gland tumors (follicular cell adenoma and carcinoma) and liver tumors (hepatocellular adenoma) at mid and high doses.⁴

Evidence Basis

Human EpidemiologicalNone

Animal Models

Positive

(rat)

Psychosis Risk

Psychosis may occur as a severe withdrawal symptom during abrupt discontinuation.⁴ Paradoxical or disinhibitory reactions including agitation, confusion, and excitement may rarely occur during use or overdose.⁵ Hallucinations and delirium tremens have been reported with severe withdrawal.⁴

Seizure Risk

While clobazam is used as an anticonvulsant, abrupt discontinuation or rapid dose reduction can precipitate acute withdrawal seizures which may be life-threatening.⁴ Tolerance to anticonvulsant effects may develop with continued use, and withdrawal seizures may occur during abrupt or overly rapid withdrawal.⁵

History & Culture

Discovery and Development

Clobazam was discovered at the Maestretti Research Laboratories in Milan, Italy, with the compound first synthesized in 1966 and first published in 1969.¹ This development followed the incidental synthesis and discovery of the first benzodiazepine,…

Legality

By Country

United StatesSchedule IV

Approved by the FDA on October 21, 2011 as an adjunctive treatment for seizures associated with Lennox-Gastaut syndrome.⁸ As a benzodiazepine, it is classified as a Schedule IV controlled substance under the Controlled Substances Act, indicating accepted medical use with potential for abuse and dependence.⁸

CanadaPrescription (Schedule IV)

Approved by Health Canada in 2005 as add-on therapy for generalized tonic-clonic, myoclonic, and focal impaired awareness seizures.¹ Regulated as a controlled substance due to its benzodiazepine classification.⁷

References

Source Pages

Citations

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Clobazam

Onfi, Sympazan, Frisium, Urbanol, Castilium

Clobazam

Contents

Dosage & Duration

Dosage

Duration

Subjective Effects

Physical

Coordination

Sedation

Uncomfortable

Cognitive

Disconnective

Emotional

Impairment

Suppressions

Visual

Reagent Testing

Pharmacology

Pharmacodynamics

Pharmacokinetics

Interactions

Caution

Tolerance

Harm Potential

Addiction & Dependence

Psychological

Physical

Toxicity

Psychosis Risk

Seizure Risk

History & Culture

Discovery and Development

Legality

By Country

References

Source Pages

Citations

Further Reading

Suggest an edit

Clobazam

Contents

Dosage & Duration

Dosage

Duration

Subjective Effects

Physical

Coordination

Sedation

Uncomfortable

Cognitive

Disconnective

Emotional

Impairment

Suppressions

Visual

Reagent Testing

Pharmacology

Pharmacodynamics

Pharmacokinetics

Interactions

Caution

Tolerance

Harm Potential

Addiction & Dependence

Psychological

Physical

Toxicity

Psychosis Risk

Seizure Risk

History & Culture

Discovery and Development

Legality

By Country

References

Source Pages

Citations

Further Reading

Suggest an edit