Clonazepam

What it is

Clonazepam is a long-acting benzodiazepine taken by mouth as a tablet or an orally disintegrating tablet. In the United States it is approved for certain seizure disorders and for panic disorder, and its US label carries a boxed warning covering opioid co-use, abuse and addiction, and dependence and withdrawal. It is metabolised in part by the cytochrome P-450 3A family, so drugs that induce or inhibit those enzymes change its blood levels.

What the research says

The evidence is uneven and mostly short-term. For panic disorder a Cochrane review of benzodiazepines as a class found a real but low-certainty advantage over placebo, together with more adverse effects. For epilepsy, a Cochrane review of clonazepam used on its own found the randomised evidence so thin that it concluded there is insufficient evidence to support that use. Off-label, clonazepam is widely used for REM sleep behaviour disorder, where the pooled polysomnography data are weak. Against this sit well-documented harms: dependence and withdrawal that the label calls potentially life-threatening if stopped abruptly, a raised risk of hip fracture in older people, and a raised risk of overdose when it is combined with opioids.

Evidence grade: Limited evidence.

How it works

Drug class: Benzodiazepine (positive allosteric modulator at the GABA-A receptor); an antiseizure and antipanic agent, a Schedule IV controlled substance in the US

Clonazepam works on the brain's main inhibitory chemical messenger, GABA. By enhancing GABA's activity it damps down nerve cell firing, which is thought to explain both its anti-seizure and anti-panic effects, and also its sedative effects. The label itself says the precise mechanism is not known. (Source 1)

Boxed warning

WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS; ABUSE, MISUSE, AND ADDICTION; and DEPENDENCE AND WITHDRAWAL REACTIONS

(Source 2)

What it is used for

• This is an approved indication on the US label, but a Cochrane review that looked for randomised trials of clonazepam used as the only antiseizure drug found almost nothing and rated what exists as very low certainty. In the one trial in children with absence seizures, more children dropped out on clonazepam than on ethosuximide. Evidence: limited. (Source 3)
• A Cochrane review of 24 trials of benzodiazepines against placebo found more people responded on a benzodiazepine (risk ratio 1.65, number needed to treat 4), but rated the quality of that evidence low, judged the methodological quality of the trials poor, and found more adverse effects and more dropouts for adverse effects on the drug. Evidence: limited. (Source 4)
• Clonazepam is one of the two drugs most often used first for REM sleep behaviour disorder, but in a meta-analysis of trials with polysomnography the only sleep measure that changed significantly with clonazepam was the percentage of stage 2 sleep. Melatonin, ramelteon and pramipexole each changed different measures in the same analysis. Evidence: limited. (Source 5)

Interactions

• Opioids (including prescribed painkillers) (label): Taking a benzodiazepine with an opioid can cause deep sedation, slowed or stopped breathing, coma and death. This is the first bullet of the drug's boxed warning, and an observational cohort of 2.2 million people found a higher rate of opioid-related overdose in people taking both. (Source 2)
• Alcohol (label): Alcohol adds to the brain-slowing effect of benzodiazepines. The label lists alcohol first among the substances that can potentiate this class's CNS-depressant action. (Source 6)
• Enzyme-inducing antiseizure drugs (phenytoin, carbamazepine, lamotrigine, phenobarbital) (pharmacokinetic study): These drugs speed up the breakdown of clonazepam, lowering its blood level by roughly a third. (Source 7)
• CYP3A inhibitors, including oral antifungals such as fluconazole (and, by the same pathway, any supplement or food that inhibits CYP3A) (theoretical): Anything that blocks the CYP3A enzyme family can slow clonazepam's breakdown and raise its level and effects. The label says no clinical studies of this have been done, so it is reasoning from the metabolic pathway rather than measured data. (Source 7)
• Other sedating medicines, including antipsychotics, tricyclic antidepressants and MAO inhibitors (label): These add to clonazepam's sedative effect, as does any other anticonvulsant. (Source 6)

Stopping it

• Stopping clonazepam suddenly, or cutting the dose quickly, after continued use can set off acute withdrawal that the label describes as potentially life-threatening. (Source 2)
• The label's stated way to reduce that risk is a gradual taper rather than an abrupt stop. (Source 2)
• In the trials this review summarised, a brief intervention comparable to a simple taper programme enabled about one person in three to stop, and cognitive behavioural therapy about three in four, but the review warns that an untreated psychiatric disorder may have worked against those results and that long-term outcomes were not evaluated. (Source 8)
• The same review found substitution medication gave no advantage over placebo, and warned that because abstinence was measured only over the very short term no recommendation can be made about it. (Source 8)

What goes wrong

More people on a benzodiazepine reported at least one adverse effect than on placebo, and more stopped the drug because of adverse effects. (Source 4)

• Systematic review, Low certainty.
• Size: Up to 4233 participants across 24 trials.
• Who: Adults with panic disorder.
• How long: not stated.
• Result: At least one adverse effect RR 1.18 (95% CI 1.02 to 1.37); dropouts due to adverse effects RR 1.58 (95% CI 1.16 to 2.15)
• Funding: not stated.

our analyses of adverse events showed that a higher proportion of participants experienced at least one adverse effect when treated with benzodiazepines (RR 1.18, 95% CI 1.02 to 1.37; low-quality evidence).

In a trial of children with absence seizures, more children withdrew on clonazepam than on ethosuximide. (Source 9)

• Systematic review, Very low certainty.
• Size: 79 participants in this comparison; the whole review contains only two trials and 115 participants.
• Who: Children with absence seizures.
• How long: not stated.
• Result: RR 3.63 (95% CI 1.12 to 11.74)
• Funding: not stated.

Limit of this finding: This number comes from a review that found only two eligible trials, 115 participants in total. The clonazepam-versus-ethosuximide study behind this figure has never been published in full - it exists only as a conference abstract - and it reported no efficacy data at all, so nothing can be said from it about how well either drug controlled seizures. The review rated the evidence very low certainty, and the confidence interval (1.12 to 11.74) is so wide that the true difference could be slight or very large. Read it as a single weak signal that more children left the clonazepam arm, not as a settled measure of how often people stop clonazepam.

The proportion of dropouts/withdrawal was higher in the group receiving clonazepam compared to the group receiving ethosuximide (RR 3.63, 95% CI 1.12 to 11.74; 79 participants; very low-certainty evidence).

Benzodiazepine use is associated with a roughly 50% higher risk of hip fracture in older people, with the highest risk in new users. (Source 10)

• Meta-analysis, Moderate certainty.
• Size: Pooled observational studies (numbers not in the recorded passage)
• Who: Older adults.
• How long: Short-term and longer-term use analysed separately.
• Result: Benzodiazepines RR = 1.52 (95% CI 1.37-1.68); short-term use RR = 2.40 (95% CI 1.88-3.05)
• Funding: not stated.

Both BNZ, and Z-drug use respectively, were significantly associated with an increased risk of hip fracture (RR = 1.52, 95% CI 1.37–1.68; and RR = 1.90, 95% CI 1.68–2.13).

In a cohort of 2.2 million patients, people taking opioids plus benzodiazepines were more likely to have an opioid-related overdose than people taking opioids alone. (Source 11)

• Cohort study, Moderate certainty.
• Size: 2,241,530 patients.
• Who: Adults prescribed opioids, benzodiazepines and/or non-benzodiazepine sedative-hypnotics.
• How long: Retrospective follow-up.
• Result: Opioids plus benzodiazepines: 20% more likely to have an opioid-related overdose than opioids alone (p < 0.0001). All three classes: 60% more likely (p < 0.0001). This is an association, not proof of cause.
• Funding: not stated.

Those exposed to opioids and benzodiazepines were 20% more likely to have an opioid-related overdose than those exposed to opioids only (p < 0.0001).

Most people who try to stop long-term benzodiazepines without structured support do not succeed. (Source 8)

• Expert review, not systematic, Low certainty.
• Size: Randomised controlled trials of brief intervention, substitution medication and CBT (count not given in the abstract)
• Who: Long-term benzodiazepine users.
• How long: Mostly very short-term follow-up.
• Result: Without support, only 7% of misusers stop; cognitive behavioural therapy enabled about three in four of those attempting abstinence to discontinue, with abstinence measured only over the very short term.
• Funding: not stated.

Clinical practice and evidence-based reviews agree that BZ dependence is difficult to treat: without support, only 7% of misusers manage to stop taking them.

The US label states as a regulatory position that continued benzodiazepine use can cause clinically significant physical dependence. (Source 2)

• Official position, Certainty not rated.
• Size: Not applicable.
• Who: Patients prescribed clonazepam tablets.
• How long: Label revised April 25, 2023.
• Result: No numbers given; the label states risk rises with longer treatment and higher daily dose.
• Funding: Regulatory document (FDA-approved labelling submitted by Teva Pharmaceuticals USA, Inc.)

The continued use of benzodiazepines, including clonazepam tablets, may lead to clinically significant physical dependence.

What the evidence supports

Across 24 randomised trials, benzodiazepines produced more treatment responses than placebo in panic disorder, with a number needed to treat of 4, but the review rated this evidence low quality. (Source 4)

• Systematic review, Low certainty.
• Size: 4233 participants across 24 studies (2124 randomised to benzodiazepines, 1475 to placebo)
• Who: Adults with panic disorder, with or without agoraphobia.
• How long: Not stated in the recorded passage; trials were short-term.
• Result: Response RR 1.65 (95% CI 1.39 to 1.96), NNTB 4 (95% CI 3 to 7); dropout RR 0.50 (95% CI 0.39 to 0.64), NNTB 6 (95% CI 5 to 9); remission RR 1.61 (95% CI 1.38 to 1.88)
• Funding: not stated.

The estimated risk ratio (RR) for a response to treatment was 1.65 (95% confidence interval (CI) 1.39 to 1.96) in favour of benzodiazepines, which corresponds to an estimated number needed to treat for an additional beneficial outcome (NNTB) of 4 (95% CI 3 to 7).

What the evidence does not support

In the same review, benzodiazepines did not beat placebo on the change-score analysis for depression symptoms. (Source 4)

• Systematic review, Very low certainty.
• Size: Subset of the 24 trials reporting depression change scores.
• Who: Adults with panic disorder.
• How long: not stated.
• Result: Depression change score SMD -0.22 (95% CI -0.48 to 0.04); social functioning change score SMD -0.32 (95% CI -0.88 to 0.24)
• Funding: not stated.

With the exception of the analyses of the change score data for depression (SMD -0.22, 95% CI -0.48 to 0.04) and social functioning (SMD -0.32, 95% CI -0.88 to 0.24), all secondary outcome analyses showed an effect in favour of benzodiazepines compared to placebo.

A Cochrane review found the randomised evidence for clonazepam used alone to treat epilepsy is too thin to support the practice. (Source 3)

• Systematic review, Very low certainty.
• Size: Two small trials; the ethosuximide comparison included 79 participants.
• Who: People with newly diagnosed epilepsy, including children with absence seizures.
• How long: not stated in the recorded passage.
• Result: No difference in efficacy or tolerability versus carbamazepine in mesial temporal lobe epilepsy; dropouts/withdrawal higher on clonazepam than ethosuximide, RR 3.63 (95% CI 1.12 to 11.74)
• Funding: not stated.

There is currently insufficient evidence to support the use of clonazepam as monotherapy treatment for epilepsy.

Where the evidence is mixed

The same Cochrane review judged the trials it pooled to be of poor methodological quality. (Source 4)

• Systematic review, Low certainty.
• Size: 24 studies.
• Who: Adults with panic disorder.
• How long: not stated.
• Result: 20 of 24 studies at high risk of bias in at least one domain; all studies at unclear risk of bias in at least three domains.
• Funding: not stated.

We assessed the overall methodological quality of the included studies as poor. We rated all studies as at unclear risk of bias in at least three domains.

A meta-analysis of drug trials for REM sleep behaviour disorder measured by polysomnography reported that the one sleep variable clonazepam changed significantly against baseline was the percentage of stage 2 sleep; the paper's text and its own figure disagree about which way that change went. (Source 5)

• Meta-analysis, Low certainty.
• Size: 13 eligible studies out of 454 identified.
• Who: Patients with REM sleep behaviour disorder.
• How long: not stated in the abstract.
• Result: Percentage of stage 2 sleep [4.00 (95% CI = 0.90 to 7.10)] compared with baseline, recorded here exactly as printed. The paper calls this a significant decrease, but the point estimate it prints carries no minus sign and its confidence interval lies entirely above zero.
• Funding: not stated.

Limit of this finding: Treat the direction of this result as unresolved. The paper says clonazepam was found to significantly decrease the percentage of stage 2 sleep, but the number it prints in the same sentence, 4.00 with a confidence interval of 0.90 to 7.10, is entirely above zero, which is how an increase is written. Every other estimate in that sentence that goes with a word like reduce does carry a minus sign, so this is the journal's own inconsistency and not a copying slip; it was checked on two independent copies of the paper. A reader should take from this only that stage 2 sleep changed by a statistically significant amount, and should not rely on the paper's wording for whether it went up or down.

In comparison to baseline, clonazepam was found to significantly decrease the percentage of stage 2 sleep [4.00 (95% CI = 0.90 to 7.10)] in RBD patients.

Where the research disagrees

Whether the short-term benefit of benzodiazepines in panic disorder is worth the long-term risk of dependence

• Cochrane review authors (Breilmann and colleagues, 2019), systematic-review of 24 randomised trials, rated low quality: The estimated risk ratio (RR) for a response to treatment was 1.65 (95% confidence interval (CI) 1.39 to 1.96) in favour of benzodiazepines, which corresponds to an estimated number needed to treat for an additional beneficial outcome (NNTB) of 4 (95% CI 3 to 7). (Source 4)
• US FDA-approved labelling for clonazepam tablets (2023), position, a regulator's boxed warning rather than a trial result: The continued use of benzodiazepines, including clonazepam tablets, may lead to clinically significant physical dependence. (Source 2)

How much

• Reference intake: There is no reference intake for a prescription medicine. Dosing is set by the prescriber. As a regulatory position, the US label (revised April 25, 2023) states for panic disorder: "The initial dose for adults with panic disorder is 0.25 mg twice daily. An increase to the target dose for most patients of 1 mg/day may be made after 3 days." (Source 12)
• Upper limit: As a regulatory position, the seizure-dosing section of the same label states: "Maximum recommended daily dose is 20 mg." The panic-disorder section states separately that some patients "may benefit from doses of up to a maximum dose of 4 mg/day." (Source 13)
• Studied: A fixed-dose study in panic disorder found the optimal effect at 1 mg/day, with 2, 3 and 4 mg/day less effective and associated with more adverse effects. (Source 12)
• Studied: The Cochrane panic disorder review pooled 24 trials of benzodiazepines as a class against placebo; doses of individual drugs are not given in the recorded abstract. (Source 4)

A common belief, and what the research shows

The belief: Clonazepam is a mild, routine pill for nerves or sleep that you can simply stop when you no longer need it.

What the research shows: The US label's boxed warning states that "Abrupt discontinuation or rapid dosage reduction of clonazepam tablets after continued use may precipitate acute withdrawal reactions, which can be life-threatening." and the review literature is blunt about how hard stopping is: "Clinical practice and evidence-based reviews agree that BZ dependence is difficult to treat: without support, only 7% of misusers manage to stop taking them."

Questions and answers

What is it?

Clonazepam is a benzodiazepine medicine, taken by mouth, that is approved in the US for some seizure disorders and for panic disorder. It is a controlled substance because it can be misused and can cause physical dependence. The US label carries a boxed warning about opioid co-use, abuse and addiction, and dependence and withdrawal. (Source 2)

What does it do in the body?

It boosts the effect of GABA, the brain's main calming chemical messenger, which slows nerve cell firing. That is thought to be behind both its anti-seizure and anti-panic effects, and also the drowsiness it causes. The label states the precise mechanism is not known. (Source 1)

Is it good or bad for you?

It depends on the condition and on how long it is used. In panic disorder a Cochrane review found more people responded on a benzodiazepine than on placebo, but rated that evidence low quality and found more adverse effects on the drug. For epilepsy used on its own, a Cochrane review found insufficient evidence. Over months and years the picture shifts towards harm: dependence, withdrawal, hip fracture in older people, and overdose risk with opioids. (Source 4)

How do you get more of it?

Clonazepam is a prescription-only controlled medicine; there is no food or supplement source and no way to obtain more of it outside a prescription. The label sets out how a prescriber titrates the dose, starting low and increasing slowly. (Source 12)

If it is harmful, what reduces it?

If clonazepam is causing harm, the evidence is that it should be reduced gradually rather than stopped outright, because abrupt stopping can trigger dangerous withdrawal. In the trials summarised by a 2025 narrative review, a brief intervention comparable to a simple taper got about one person in three off benzodiazepines and cognitive behavioural therapy did considerably better, though follow-up was short. (Source 2)

Why might someone be low in it or missing it?

This question does not apply in the usual sense: clonazepam is a manufactured medicine, not a nutrient or an organism, so nobody is naturally low in it. The closest real situation is that blood levels fall when another drug speeds up its breakdown. (Source 7)

Which whole foods contain it or feed it?

No whole food contains clonazepam or feeds it. It is a synthetic benzodiazepine available only on prescription. We searched the Cochrane reviews for clonazepam in epilepsy and benzodiazepines in panic disorder, the Heliyon meta-analysis of drugs for REM sleep behaviour disorder, and the US label, and none describes a dietary source. (Source 1)

We searched: Cochrane CD013028 (clonazepam monotherapy for epilepsy), Cochrane CD010677 (benzodiazepines versus placebo for panic disorder), Heliyon 2022 meta-analysis of pharmacotherapies for REM sleep behaviour disorder, and the DailyMed clonazepam label

What happens if you do not have it?

If someone has never taken it, nothing happens; it is not something the body needs. If someone has been taking it for a while and it is stopped suddenly, the label warns of acute withdrawal reactions that can be life-threatening. In epilepsy, stopping any antiseizure drug abruptly risks seizures returning. (Source 2)

How can you test for it?

We found no validated routine test for clonazepam levels in the literature we reached. Blood levels can be measured in toxicology, and the label reports that enzyme-inducing drugs lower plasma clonazepam by about 38%, so a measurable plasma concentration exists, but no source we fetched describes a clinically validated monitoring test with a target range. (Source 7)

We searched: DailyMed clonazepam label (clinical pharmacology and drug interactions), Cochrane CD013028, Cochrane CD010677

References

1. DailyMed, U.S. National Library of Medicine (FDA Structured Product Label). CLONAZEPAM tablet - CLINICAL PHARMACOLOGY, mechanism of action (Teva Pharmaceuticals USA, Inc.). 2023. Read the source
2. DailyMed, U.S. National Library of Medicine (FDA Structured Product Label). CLONAZEPAM tablet - BOXED WARNING (Teva Pharmaceuticals USA, Inc.). 2023. Read the source
3. Cochrane Database of Systematic Reviews. Clonazepam monotherapy for treating people with newly diagnosed epilepsy (Authors' conclusions). 2022. PMID 35187637, DOI 10.1002/14651858.CD013028.pub3. Read the source
4. Cochrane Database of Systematic Reviews. Benzodiazepines versus placebo for panic disorder in adults. 2019. PMID 30921478, DOI 10.1002/14651858.CD010677.pub2. Read the source
5. Heliyon. The treatment efficacy of pharmacotherapies for rapid eye movement sleep behavior disorder with polysomnography evaluation: A systematic review and meta-analysis. 2022. DOI 10.1016/j.heliyon.2022.e11425. Read the source
6. DailyMed, U.S. National Library of Medicine (FDA Structured Product Label). CLONAZEPAM tablet - PRECAUTIONS, Drug Interactions, CNS depressants (Teva Pharmaceuticals USA, Inc.). 2023. Read the source
7. DailyMed, U.S. National Library of Medicine (FDA Structured Product Label). CLONAZEPAM tablet - PRECAUTIONS, Drug Interactions, cytochrome P-450 (Teva Pharmaceuticals USA, Inc.). 2023. Read the source
8. Journal of Behavioral and Cognitive Therapy (Elsevier). A narrative review of strategies for discontinuing long-term benzodiazepine use and methodological recommendations: Is a success rate of only one in three patients sufficient? (abstract). 2025. DOI 10.1016/j.jbct.2025.100533. Read the source
9. Cochrane Database of Systematic Reviews. Clonazepam monotherapy for treating people with newly diagnosed epilepsy (Main results). 2022. PMID 35187637, DOI 10.1002/14651858.CD013028.pub3. Read the source
10. PLOS ONE. Benzodiazepines, Z-drugs and the risk of hip fracture: A systematic review and meta-analysis (abstract, Results). 2017. DOI 10.1371/journal.pone.0174730. Read the source
11. Journal of General Internal Medicine. Risk of Overdose with Exposure to Prescription Opioids, Benzodiazepines, and Non-benzodiazepine Sedative-Hypnotics in Adults: a Retrospective Cohort Study. 2020. PMID 31919729, DOI 10.1007/s11606-019-05545-y. Read the source
12. DailyMed, U.S. National Library of Medicine (FDA Structured Product Label). CLONAZEPAM tablet - DOSAGE AND ADMINISTRATION, panic disorder in adults (Teva Pharmaceuticals USA, Inc.). 2023. Read the source
13. DailyMed, U.S. National Library of Medicine (FDA Structured Product Label). CLONAZEPAM tablet - DOSAGE AND ADMINISTRATION, seizure disorders in adults (Teva Pharmaceuticals USA, Inc.). 2023. Read the source