Medication approval journey
clonazepam (Klonopin)
Approved for Panic disorder in adults
page first published · last updated
Also answers to “the long anchor” — its codename in our videos and posts. The full codebook
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The page as written, with the clinical terms
Plain language uses the same facts, the same numbers and the same caveats. It does not leave anything out. Quotes from the FDA label are never reworded in either setting.
Before you stop or change your clonazepam dose
Stopping abruptly can be dangerous — never do it without medical supervision
Do not stop a benzodiazepine abruptly. Abrupt withdrawal can cause seizures, delirium, and can be fatal. Physical dependence develops within weeks of daily use and is not the same thing as addiction. Coming off safely is a prescriber-supervised taper measured in months, sometimes far longer, and going slower is not failure.
what the clonazepam warnings mean
label facts below are read from the clonazepam tablets FDA label on DailyMed, set id 2606ecf9-3d71-4c1c-bfda-d7d98ffc6011, version 8, effective august 27, 2026, the version the dossier above cites. this is an older-format label without numbered sections, so the brackets name the section instead. every source is linked at the end of this section. last checked 2026-10-06.
clonazepam was approved on june 4, 1975 for seizure disorders, and the panic disorder indication was added later on the strength of two trials of six to nine weeks [label, indications; approval]. about 2.2 million americans filled a prescription for it in 2024, down from about 3.5 million in 2014 [meps]. it is a schedule iv controlled substance [label, drug abuse and dependence]. its label opens with the three-part boxed warning the fda rewrote for every benzodiazepine in september 2020, and continues with warnings on suicidal thoughts that every anti-seizure drug carries, on newborns, and on the particular ways a seizure medicine can lose effect or make some seizures worse. this section says what each means in plain words, what the label itself says about tapering, what the approval trials measured and for how long, which side effects the label counts and how often, and what independent research has found since, in both directions. every number is from the label, an fda communication, or a study in the library, and each source is linked at the end.
this is information to take to a prescriber. nothing here is a reason to start, stop or change a dose on your own; with this drug the label says that stopping abruptly can cause life-threatening withdrawal and, in someone taking it for seizures, status epilepticus, and the taper quoted below is the label’s, not ours.
the boxed warning, part one: opioids
the first part says that using benzodiazepines with opioids "may result in profound sedation, respiratory depression, coma, and death", that the two should be prescribed together only when alternatives are inadequate, at the lowest doses for the shortest time, with the patient followed for slowed breathing and sedation [label, boxed warning and warnings]. the label explains why they add rather than cancel: they slow breathing through different receptors, benzodiazepines at gaba-a sites and opioids at mu receptors [label, drug interactions]. the clonazepam label itself notes that misuse "commonly involve[s] concomitant use of other medications, alcohol, and/or illicit substances", which is where the serious harm sits [label-row].
the numbers behind it are observational. among 315,428 insured american adults who filled an opioid prescription between 2001 and 2013, the share also filling a benzodiazepine rose from 9% to 17%, and those taking both had about twice the odds of an emergency visit or admission for opioid overdose [sun-2017]. across 399,230 us opioid overdose deaths from 1999 to 2017, benzodiazepine involvement rose from about 9% to 21%, and a benzodiazepine was present in one in three prescription-opioid deaths in 2017 [tori-2020]. in cdc surveillance for the first half of 2018, about 63% of opioid deaths also involved cocaine, methamphetamine or a benzodiazepine, and counterfeit pills were among the ways fentanyl reached people [gladden-2019]. none of these can prove the benzodiazepine caused the deaths; all of them count it there.
the boxed warning, parts two and three: abuse, misuse and addiction; dependence and withdrawal
the second part says benzodiazepines expose users to "risks of abuse, misuse, and addiction, which can lead to overdose or death", that abuse and misuse commonly involve other medicines, alcohol or illicit drugs, and that prescribers should assess each person’s risk before prescribing and throughout treatment [label, boxed warning]. the label adds that "even taking benzodiazepines as prescribed may put patients at risk for abuse and misuse", that misuse often but not always involves doses above the maximum, and that death "is more often associated with polysubstance use", especially with opioids and alcohol [label, drug abuse and dependence].
the third part says continued use "may lead to clinically significant physical dependence", that the risk rises with longer treatment and higher doses, and that stopping abruptly or cutting the dose quickly "may precipitate acute withdrawal reactions, which can be life-threatening", so the dose should come down by a gradual taper [label, boxed warning]. the fda required this wording on every benzodiazepine in september 2020; its point is that dependence can develop when the drug is taken exactly as prescribed, which is a reason not to stop on one’s own [fda-2020]. the label lists the acute withdrawal signs, from anxiety, insomnia, tremor, sweating, racing heart and panic attacks to the severe ones: catatonia, convulsions, delirium tremens, hallucinations, mania, psychosis, seizures and suicidality. a protracted syndrome, with anxiety, cognitive impairment, depression, insomnia, crawling-skin sensations, tremor, tingling and tinnitus, can persist beyond four to six weeks and "may last weeks to more than 12 months", and the label concedes it can be hard to tell from the return of the original problem [label, warnings; drug abuse and dependence].
on tolerance the label says it may develop to the therapeutic effect while "little tolerance develops to the amnestic reactions and other cognitive impairments" [label, drug abuse and dependence]. on how well people came off it in the trials, it reports that after the short-term panic studies patients were tapered over seven weeks "with good tolerability and a very modest clinical deterioration, without evidence of a significant rebound phenomenon", and then adds that there are not enough long-term data "to accurately estimate the risks of withdrawal symptoms and dependence" with longer use [label, drug abuse and dependence].
what the label says about tapering
quoted so that it is the label’s and not ours. for panic disorder: "treatment should be discontinued gradually, with a decrease of 0.125 mg twice daily every 3 days, until the drug is completely withdrawn" [label, dosage and administration]. for anyone: "to reduce the risk of withdrawal reactions, increased seizure frequency, and status epilepticus, use a gradual taper to discontinue clonazepam tablets or reduce the dosage. if a patient develops withdrawal reactions, consider pausing the taper or increasing the dosage to the previous tapered dosage level. subsequently decrease the dosage more slowly" [label, dosage and administration]. the warnings section adds that "a patient-specific plan should be used to taper the dose" [label, warnings].
on how long to stay on it, the label is candid: "there is no body of evidence available to answer the question of how long the patient treated with clonazepam should remain on it", and effectiveness beyond nine weeks "has not been systematically studied in controlled clinical trials", so a prescriber using it longer "should periodically reevaluate the long-term usefulness of the drug for the individual patient" [label, indications; dosage and administration]. the uk guideline for these medicines says the same in different words: do not stop abruptly, taper in steps proportionate to the current dose so the steps shrink as the dose falls, and expect that withdrawal "may take several months or more" [nice-2022]. a cochrane review of 38 trials in 2,543 long-term benzodiazepine users found no add-on medication that reliably improved the chance of stopping, leaving the gradual taper as the mainstay [baandrup-2018]. clonazepam is absorbed almost completely, peaks in one to four hours, and has an elimination half-life of 30 to 40 hours [label, clinical pharmacology].
the seizure indication: what the label says that the panic literature does not
the 1975 approval was for lennox-gastaut syndrome, akinetic and myoclonic seizures, and for absence seizures that have not responded to succinimides, alone or as an add-on [label, indications]. the label describes no controlled trial for these uses; the approval predates the era in which fda reviews were published, and the label’s seizure facts come from treatment experience [approval]. three of them matter to anyone taking it for seizures.
- loss of effect: "in some studies, up to 30% of patients who initially responded have shown a loss of anticonvulsant activity, often within 3 months of administration", sometimes recoverable with a dose adjustment [label, precautions].
- making some seizures worse: in people with more than one seizure type, clonazepam "may increase the incidence or precipitate the onset of generalized tonic-clonic seizures (grand mal)", and taken with valproic acid it "may produce absence status" [label, precautions].
- dosing and stopping: for adults the starting dose should not exceed 1.5 mg a day in three doses, rising by 0.5 to 1 mg every three days to a maximum of 20 mg; for children up to 10 years or 30 kg, 0.01 to 0.03 mg per kg a day to start [label, dosage and administration]. the label asks for periodic blood counts and liver tests during long-term therapy, and says that because effects on physical or mental development "could become apparent only after many years", a benefit-risk judgement about long-term use is important in children [label, precautions; pediatric use].
- side effects in seizure treatment: drowsiness in about 50% of patients, unsteadiness (ataxia) in about 30%, and behaviour problems in about 25%, which the label says may diminish with time [label, adverse reactions].
the other warnings, in plain words
beyond the boxed warning, the label’s warnings and precautions sections carry:
- suicidal thoughts and behaviour: a class warning carried by every anti-seizure drug. in a pooled analysis of 199 placebo-controlled trials of 11 such drugs, median 12 weeks, 0.43% of 27,863 drug-treated patients had suicidal thoughts or behaviour against 0.24% of 16,029 on placebo, about twice the risk (relative risk 1.8, 95% ci 1.2 to 2.7) and one extra case for every 530 people treated, appearing as early as the first week. by indication, the absolute excess was 2.4 per 1,000 in epilepsy and 2.9 per 1,000 in psychiatric trials. there were four suicides on drug and none on placebo, too few to conclude anything. the label says the risk applies to all these drugs for any indication and must be balanced against the risk of untreated illness [label, warnings and table 1].
- newborns: use late in pregnancy can leave a baby sedated (slow breathing, floppiness) or in withdrawal (irritability, tremor, inconsolable crying, feeding problems). observational studies "do not report a clear association" with major birth defects; rabbit studies showed malformations at doses near the human dose [label, warnings; pregnancy]. clonazepam passes into breast milk, with reports of sedation, poor feeding and poor weight gain in infants [label, nursing mothers].
- driving and alcohol: a cns depressant; the label says to avoid hazardous activities until the effect is known, and to avoid alcohol [label, warnings; information for patients].
- paradoxical reactions: agitation, irritability, aggression, anxiety, anger, nightmares, hallucinations and psychosis "are known to occur" with benzodiazepines, more often in children and the elderly; if they do, the label says to discontinue gradually [label, precautions].
- breathing: respiratory depression; caution in people with compromised breathing such as copd or sleep apnea [label, precautions].
- contraindications: significant liver disease, acute narrow-angle glaucoma, and prior sensitivity to benzodiazepines [label, contraindications]. caution in kidney impairment, porphyria, and in anyone who has trouble handling saliva, because clonazepam can increase it [label, precautions].
- interactions: phenytoin, carbamazepine, lamotrigine and phenobarbital induce its metabolism and lower levels by about 38%; oral antifungals such as fluconazole may raise them; sertraline, fluoxetine and felbamate do not change them. the sedative effect adds to that of alcohol, opioids, barbiturates, other sleeping and anxiety medicines, antipsychotics, maois and tricyclics [label, drug interactions].
- older people: the trials did not include enough people over 65 to tell whether they respond differently; the label says to start low and watch for confusion and over-sedation [label, geriatric use].
what the approval trials measured, and for how long
the panic indication rests on two placebo-controlled trials of adult outpatients, 574 on clonazepam and 294 on placebo in all [label, clinical trials; adverse reactions]. study 1 was a 9-week fixed-dose trial of 0.5, 1, 2, 3 or 4 mg a day: "a significant difference from placebo was observed consistently only for the 1 mg/day group", the difference was about one full panic attack per week, and at the end 74% on 1 mg were free of full panic attacks against 56% on placebo. study 2 was a 6-week flexible-dose trial averaging 2.3 mg a day, with 62% panic-free against 37% [label, clinical trials]. the label turns the first result into its dosing advice: the recommended dose of 1 mg a day "is based on the results from a fixed dose study in which the optimal effect was seen at 1 mg/day. higher doses of 2, 3 and 4 mg/day in that study were less effective than the 1 mg/day dose and were associated with more adverse effects" [label, dosage and administration]. the published report of that trial, in 413 people, is in the library: doses of 1 mg and above reduced panic attacks equally well, and 1 to 2 mg gave the best balance against sleepiness and unsteadiness, which climbed at 3 to 4 mg [rosenbaum-1997].
nothing in the label is placebo-controlled beyond nine weeks, and the label says so [label, indications]. for the seizure indications the label describes no controlled trial at all [approval]. safety and effectiveness for panic disorder under 18 "have not been established" [label, pediatric use].
side effects, with the label’s numbers
in the two panic trials (574 against 294 on placebo): somnolence 37% against 10%, depression 7% against 1%, impaired coordination 6% against 0%, ataxia 5% against 0% [label, adverse reactions, table 4]. by dose, somnolence was 26% below 1 mg, 35% at 1 to 2 mg, 50% at 2 to 3 mg and 36% at 3 mg and above; dizziness 8% against 4%, memory disturbance 4% against 2%, reduced intellectual ability 2% against 0%, slurred speech 2% against 0%, nervousness 3% against 2%, decreased libido 1% against 0% [label, adverse reactions, table 3]. 17% stopped for side effects against 9% on placebo, most often for somnolence (7% against 1%) and depression (4% against 1%) [label, adverse reactions, table 2].
on the depression figure the label adds a qualification: although "depression" was reported as an adverse event in 7% against 1%, depression rating scores fell more on clonazepam than on placebo in the same trials, "suggesting that clonazepam-treated patients were not experiencing a worsening or emergence of clinical depression" [label, adverse reactions]. the seizure-treatment figures, drowsiness about 50% and ataxia about 30%, are above.
what the research says, in both directions
in favour. the fixed-dose trial found 1 mg a day as effective as higher doses with fewer side effects, which is unusual among benzodiazepine trials in showing a floor [rosenbaum-1997]. in a 10-week trial in 75 people with social phobia, an unapproved use, 78% responded to clonazepam at a mean maximum of 2.4 mg against 20% on placebo, with more unsteadiness and dizziness; it was a single-site pilot from 1993 [davidson-1993]. in an 8-week open-label comparison in 120 people with panic disorder, clonazepam and paroxetine both reduced attacks to a fraction of a one a week, with fewer side effects reported on clonazepam (73% against 95%); open-label design can inflate such differences [nardi-2011]. a prospective cohort of 3,434 adults aged 65 and over, followed for a mean of 7.3 years, found no increased dementia risk in the heaviest benzodiazepine users and no dose-response, which argues against a causal link [gray-2016].
against, or smaller than it sounds. a case-control study of 1,796 older adults with alzheimer’s disease and 7,184 controls found past benzodiazepine use beyond three months associated with about 1.5 times the odds, rising with longer cumulative use; anxiety and insomnia can be early symptoms of dementia, so the direction of cause is unsettled and the cohort above points the other way [billioti-2014]. a meta-analysis of 13 observational studies of people who had taken benzodiazepines for about 10 years found them scoring moderately worse than controls across every cognitive domain tested (effect size 0.74) [barker-2004], which sits beside the label’s own statement that little tolerance develops to the cognitive effects. the label’s efficacy evidence for panic is nine weeks long and its seizure evidence is uncontrolled; the 30% loss of anticonvulsant effect within three months is the label’s own number [label, precautions].
the warnings, measured. the opioid warning’s size is in the three studies above: twice the odds of an overdose visit with concurrent prescriptions [sun-2017], one in three prescription-opioid deaths with a benzodiazepine present [tori-2020], and two thirds of opioid deaths involving another drug [gladden-2019]. the dependence warning’s timescale is in the uk guideline [nice-2022] and in the cochrane finding that no medicine makes stopping reliably easier [baandrup-2018]. the suicidality warning’s size is the label’s own pooled analysis: about two extra people per thousand over about 12 weeks, across the class [label, warnings].
questions to ask your prescriber about clonazepam
each one comes from a warning or a study above. they are questions, not instructions; the answers depend on a history nobody here has.
- the label says there is no evidence on how long to stay on this, and that dependence can develop even at prescribed doses. how long is the plan, and when will we review it?
- if we ever reduce or stop, the label’s schedule for panic is 0.125 mg twice daily every 3 days, slower if withdrawal appears. what would mine look like, and how would we tell withdrawal from my anxiety or seizures coming back?
- is any opioid in my life, prescribed or not, including a cough medicine or a pain pill after surgery? the boxed warning is about the combination, and both prescribers need to know.
- i take phenytoin, carbamazepine, lamotrigine, phenobarbital or an antifungal. the label says these change clonazepam levels; is anything i take on that list?
- in the panic trials, 1 mg a day worked as well as higher doses with fewer side effects. if i am above 1 mg, what is the higher dose for?
- if this is for seizures: the label says up to 30% of responders lose the effect within three months and that it can worsen some seizure types. what are we watching for, and what is the plan if that happens?
- is naloxone in the house, and do the people around me know how to use it, given what else is prescribed here?
questions people ask
- what does the klonopin (clonazepam) black box warning mean?
- it has three parts, rewritten by the fda for every benzodiazepine in september 2020. first, taking a benzodiazepine with an opioid can cause profound sedation, slowed breathing, coma and death, so the two should be combined only when alternatives are inadequate, at the lowest doses for the shortest time. second, benzodiazepines carry risks of abuse, misuse and addiction that can lead to overdose or death, and prescribers should assess that risk before and during treatment. third, continued use can cause physical dependence, and stopping abruptly or cutting the dose quickly can cause withdrawal reactions that can be life-threatening, so the dose should come down by a gradual taper. it is a warning about how the drug is used, not an instruction to stop it.
- is clonazepam addictive?
- the label says benzodiazepines expose users to risks of abuse, misuse and addiction, that even taking them as prescribed may put people at risk of misuse, and that physical dependence, a separate thing from addiction, can develop with continued use, with the risk rising with higher doses and longer treatment. dependence means withdrawal symptoms on stopping, which the label says can be life-threatening and in some people last more than a year. clonazepam is a schedule iv controlled substance. that is why the label says to taper rather than stop.
- what are the most common clonazepam side effects?
- in the label’s panic trials: somnolence 37% vs 10% on placebo, depression 7% vs 1%, impaired coordination 6% vs 0%, ataxia 5% vs 0%, dizziness 8% vs 4%, memory disturbance 4% vs 2%. somnolence rose with dose, to 50% at 2 to 3 mg a day. in seizure treatment the label reports drowsiness in about 50% of patients, unsteadiness in about 30% and behaviour problems in about 25%. the label says little tolerance develops to the memory and cognitive effects.
- what happens if you stop clonazepam suddenly?
- the label says abrupt stopping or a rapid dose cut after continued use can cause acute withdrawal reactions that can be life-threatening, including seizures, and in someone taking it for seizures can cause more seizures or status epilepticus. its own taper for panic disorder is a decrease of 0.125 mg twice daily every 3 days until the drug is completely withdrawn, pausing or stepping back up if withdrawal appears and then going more slowly. a protracted syndrome can last weeks to more than 12 months. a taper plan belongs with a prescriber.
- can you take clonazepam with opioids or alcohol?
- the boxed warning says benzodiazepines with opioids may cause profound sedation, respiratory depression, coma and death, and that the combination should be reserved for people with no adequate alternative, at the lowest doses for the shortest time. the label also says to avoid alcohol. in the studies behind the warning, people filling both prescriptions had about twice the odds of an overdose emergency visit, and a benzodiazepine was present in one in three prescription-opioid overdose deaths in 2017. the person who can make sure both prescribers know is the patient.
- does clonazepam cause dementia?
- unsettled, and the two best studies point in opposite directions. a 2014 case-control study of 1,796 older adults with alzheimer’s disease found past benzodiazepine use beyond three months associated with about 1.5 times the odds, rising with longer use. a 2016 prospective cohort of 3,434 adults aged 65 and over, followed for 7.3 years, found no increased dementia risk in the heaviest users and no dose-response, which argues against causation; anxiety and insomnia can be early symptoms of dementia that lead to a prescription years before diagnosis. what is better established is that long-term users score worse on cognitive tests while taking the drug, and the label says tolerance to those effects is limited.
- how is clonazepam different from xanax (alprazolam)?
- both carry the same 2020 boxed warning and the same dependence and withdrawal language, and both are schedule iv. the label facts that differ: clonazepam has an elimination half-life of 30 to 40 hours, is approved for seizure disorders as well as panic disorder, and its label recommends 1 mg a day for panic because higher doses in the fixed-dose trial were less effective with more side effects. the alprazolam label has its own explainer on this site, with its own taper wording and side-effect tables [alprazolam-explainer]. nothing in either label is a reason to prefer one drug; that is a prescriber’s decision.
sources for this section
the library rows link to our one-page summary of each study, with the original paper, its funding and our evidence grade on that page.
- clonazepam tablets prescribing information, fda label on dailymed (set id 2606ecf9-3d71-4c1c-bfda-d7d98ffc6011, version 8, effective august 27, 2026; remedyrepack, anda 075150): boxed warning; indications and usage; dosage and administration; contraindications; warnings (table 1); precautions, including drug interactions, pregnancy, nursing mothers, pediatric use and geriatric use; adverse reactions (tables 2 to 4); drug abuse and dependence; clinical pharmacology (clinical trials)
- drugs@fda, nda 017533 (klonopin), approved june 4, 1975; no fda review of the original application is published, as for most approvals of that era
- ahrq medical expenditure panel survey, prescribed medicines public-use files 2014 (hc-168a) and 2024 (hc-254a): people with at least one clonazepam purchase, weighted; computed by veisund, method on the usage section of this page
- fda drug safety communication, september 2020: fda requiring boxed warning updated to improve safe use of benzodiazepine drug class (library row)
- the clonazepam label’s boxed warning, read for the library: misuse commonly involves alcohol or street drugs, and that is where the deaths are (dailymed spl version 6, december 2025, a different labeler’s copy of the same text) (library row)
- sun ec, et al. association between concurrent use of prescription opioids and benzodiazepines and overdose: retrospective analysis. bmj 2017 (library row)
- tori me, larochelle mr, naimi ts. alcohol or benzodiazepine co-involvement with opioid overdose deaths in the united states, 1999 to 2017. jama network open 2020 (library row)
- gladden rm, et al. changes in opioid-involved overdose deaths by opioid type and presence of benzodiazepines, cocaine, and methamphetamine, 25 states, 2017 to 2018. mmwr 2019 (library row)
- national institute for health and care excellence. medicines associated with dependence or withdrawal symptoms (ng215), 2022 (library row)
- baandrup l, et al. pharmacological interventions for benzodiazepine discontinuation in chronic benzodiazepine users. cochrane database of systematic reviews 2018 (library row)
- rosenbaum jf, et al. clonazepam in the treatment of panic disorder with or without agoraphobia: a dose-response study of efficacy, safety, and discontinuance. journal of clinical psychopharmacology 1997 (the label’s study 1) (library row)
- davidson jr, et al. treatment of social phobia with clonazepam and placebo. journal of clinical psychopharmacology 1993 (library row)
- nardi ae, et al. psychopharmacotherapy of panic disorder: 8-week randomized trial with clonazepam and paroxetine. brazilian journal of medical and biological research 2011 (open-label) (library row)
- gray sl, et al. benzodiazepine use and risk of incident dementia or cognitive decline: prospective population based study. bmj 2016 (library row)
- billioti de gage s, et al. benzodiazepine use and risk of alzheimer’s disease: case-control study. bmj 2014 (library row)
- barker mj, et al. cognitive effects of long-term benzodiazepine use: a meta-analysis. cns drugs 2004 (library row)
- what the alprazolam (xanax) warnings mean, the companion explainer on this site: the same 2020 boxed warning, that label’s taper wording and side-effect tables
How long the clonazepam trials actually ran
The longest trial behind the clonazepam approval ran 9 weeks.
The gap between how long the trials ran and how long people actually take these medications is the single most important thing on this page. It is not evidence that longer use is unsafe or ineffective. It is evidence that longer use was not what got tested.
People often stay on these drugs for far longer than the trials ran. The panic disorder trials ran 6 to 9 weeks. For the seizure use the 1975 approval covered, the label describes no trial at all.
That does not mean longer use is unsafe. It does not mean the drug stops working either. It means longer use was never the thing that got tested.
If you have been on it a long time, that is a fair thing to ask your prescriber about.
Boxed warning: risks from use with opioids
The strongest warning the FDA puts on a label, often called a black box warning. It is reproduced below word for word, not summarised.
This is the strongest warning the FDA can put on a drug label. Some people call it a black box warning. We copied it word for word. We did not shorten it and we did not soften it.
The clonazepam boxed warning covers risks from use with opioids; abuse, misuse, and addiction; dependence and withdrawal reactions.
The warning below covers three things. First, taking this drug with an opioid can cause deep sedation, slowed breathing, coma, and death. Second, it can be abused and misused. That can lead to addiction, overdose, and death. Third, taking it day after day can lead to physical dependence. Stopping fast after that can set off withdrawal. The label says that withdrawal can be life threatening, so it says to come off slowly.
The FDA’s own words follow, copied exactly.
WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS; ABUSE, MISUSE, AND ADDICTION; and DEPENDENCE AND WITHDRAWAL REACTIONS Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation (see WARNINGS and PRECAUTIONS ). The use of benzodiazepines, including clonazepam tablets, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes. Before prescribing clonazepam tablets and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (see WARNINGS ) . The continued use of benzodiazepines, including clonazepam tablets, may lead to clinically significant physical dependence. The risks of dependence and withdrawal increase with longer treatment duration and higher daily dose. Abrupt discontinuation or rapid dosage reduction of clonazepam tablets after continued use may precipitate acute withdrawal reactions, which can be life-threatening. To reduce the risk of withdrawal reactions, use a gradual taper to discontinue clonazepam tablets or reduce the dosage (see DOSAGE AND ADMINISTRATION and WARNINGS ) .
FDA label effective August 27, 2026 — read the full label on DailyMed
What clonazepam is FDA approved for, and the trials behind it
Approved for seizure disorders (Lennox-Gastaut syndrome, akinetic and myoclonic seizures, and absence seizures unresponsive to succinimides); the panic disorder indication was added later in 1975, under application NDA 017533. Source: FDA Drugs@FDA.
The 1975 approval was for seizure disorders, and no public FDA review of that application exists — reviews from that era were not published. The label's seizure data come from treatment experience, not from any described controlled trial; the trials summarized below supported the panic-disorder indication added two decades later.
The panic-disorder indication rests on two double-blind, placebo-controlled trials of 6 to 9 weeks, pooling 574 patients on clonazepam and 294 on placebo. In the 9-week fixed-dose study, 74% of patients receiving 1 mg/day were free of full panic attacks at endpoint versus 56% on placebo; in the 6-week flexible-dose study (mean dose 2.3 mg/day) the figures were 62% versus 37%. The label describes no controlled trials for the seizure indication the 1975 approval covered.
A large gap first. The 1975 approval was for seizure disorders. No public FDA review of that application exists, because reviews from that time were not published.
The label’s seizure data come from treatment experience. They do not come from any trial it describes. The trials below supported the panic disorder use, added two decades later.
The FDA approved clonazepam in 1975. The approved use was seizure disorders. The panic disorder use came later. The file number is NDA 017533. The source is Drugs@FDA, the FDA's own database.
Two trials against a placebo backed the panic disorder use. Nobody in them knew who got the drug (double-blind). They ran 6 to 9 weeks. Together they held 574 people on the drug and 294 on a placebo.
In the 9-week set-dose study, 74 out of 100 people on 1 mg a day had no full panic attacks at the end. On the placebo it was 56 out of 100.
In the 6-week study the dose could move and averaged 2.3 mg a day. There it was 62 out of 100 against 37.
- Trials
- 2 placebo-controlled trials (panic disorder)
- Duration
- 6 to 9 weeks
- Participants
- 574 patients on clonazepam vs 294 on placebo
- Compared against
- Placebo
The effectiveness of clonazepam tablets in the treatment of panic disorder was demonstrated in two double-blind, placebo-controlled studies of adult outpatients who had a primary diagnosis of panic disorder (DSM-IIIR) with or without agoraphobia.
Verbatim from the clonazepam FDA label, Clinical Pharmacology (Clinical Trials) section, effective August 27, 2026 — read the full label on DailyMed.
Side effects of clonazepam in the approval trials
Incidence among 574 patients on clonazepam versus 294 on placebo, pooled from the two 6- to 9-week panic-disorder trials. For the original seizure indication the label gives no comparative rates — only that in treatment experience drowsiness occurred in approximately 50% of patients, ataxia in approximately 30%, and behavior problems in approximately 25%. The label itself cautions that trial figures cannot be used to predict side-effect incidence in usual medical practice.
Read the limits first. These numbers are pooled from the two panic disorder trials. Those ran 6 to 9 weeks. 574 people took the drug and 294 took a placebo.
For the first use, seizures, the label gives no side-by-side rates. It says only what came up in treatment experience. About 50 out of 100 people got drowsy. About 30 out of 100 had trouble with balance and coordination (ataxia). About 25 out of 100 had behavior problems.
The label warns that you cannot use trial figures to predict side effect rates in ordinary care.
- Somnolence (37% vs 10% on placebo)
- Dizziness (8% vs 4%)
- Upper respiratory tract infection (8% vs 4%)
- Depression (7% vs 1%)
- Fatigue (7% vs 4%)
- Coordination abnormal (6% vs 0%)
- Ataxia (5% vs 0%)
- Memory disturbance (4% vs 2%)
- Sinusitis (4% vs 3%)
- Nervousness (3% vs 2%)
The most frequently occurring side effects of clonazepam tablets are referable to CNS depression. Experience in treatment of seizures has shown that drowsiness has occurred in approximately 50% of patients and ataxia in approximately 30%.
From the clonazepam FDA label, Adverse Reactions section, effective August 27, 2026 — DailyMed.
More from the clonazepam label: drug abuse and dependence
Schedule IV controlled substance
Clonazepam is a Schedule IV controlled substance. The label describes it as a benzodiazepine and CNS depressant with a potential for abuse and addiction, noting that even taking benzodiazepines as prescribed may put patients at risk for abuse and misuse.
FDA label, Drug Abuse and Dependence section.
Stopping requires a gradual taper
Continued therapy may produce physical dependence, and abrupt discontinuation or rapid dose reduction can precipitate acute withdrawal reactions, including seizures, which can be life-threatening. The label describes a protracted benzodiazepine withdrawal syndrome that persists beyond 4 to 6 weeks and may last weeks to more than 12 months.
FDA label, Drug Abuse and Dependence section.
What happened when trial patients stopped
After the short-term panic trials, patients were withdrawn gradually over a 7-week downward-titration period; the label reports good tolerability and a very modest clinical deterioration, without evidence of a significant rebound phenomenon. It adds that data are insufficient to accurately estimate the withdrawal and dependence risks of long-term use in panic disorder.
FDA label, Drug Abuse and Dependence section.
How many Americans take clonazepam
Survey-based federal estimates, published with a lag of about two years. They count prescriptions filled, not outcomes.
These are federal survey numbers. They come out about two years late. They count prescriptions filled. They do not tell you if the drug helped.
- 11,861,003
- prescriptions in the United States (2024), refills included
- 2,154,594
- people filling them (2024), ± 428,478 (95%)
Prescriptions are down 44% from 2014 to 2024, a change larger than the survey’s margin of error. Whatever you decide about clonazepam, you are deciding alongside about 2,154,594 other people in 2024.
Prescriptions by year: 2014 21,021,489 · 2015 21,817,868 · 2016 18,675,680 · 2017 20,708,621 · 2018 17,064,643 · 2019 15,578,495 · 2020 14,758,212 · 2021 14,197,548 · 2022 11,711,066 · 2023 10,614,830 · 2024 11,861,003.
Prescriptions are down 44 percent since 2014. About 2.2 million people in the United States took it in 2024.
Correction (29 September 2026). An earlier version of this section took its numbers from ClinCalc DrugStats, a third-party site that republishes this survey; we now compute them from AHRQ’s public-use files ourselves.
Source: AHRQ Medical Expenditure Panel Survey (MEPS), Prescribed Medicines public-use files, 2014 (HC-168A) through 2024 (HC-254A), computed by veisund. People with at least one purchase where the Multum generic name (RXDRGNAM) equals the drug, weighted by the year’s person weight; purchases include refills. Standard errors by Taylor linearization on VARSTR/VARPSU. AHRQ’s reliability rule: a year is not shown when fewer than 60 survey respondents reported the drug or the relative standard error is over 50%. AHRQ cautions that its 2018 questionnaire redesign and the 2020–2022 pandemic years make year-to-year comparisons less certain.
What people report to the FDA about clonazepam
Read this before the numbers.
Anyone can file an adverse event report — patients, doctors, manufacturers — and nobody verifies that the drug caused what was reported. There is no denominator: tens of millions of prescriptions generate reports at an unknowable rate, and reporting rises with news coverage, not necessarily with harm. Counts below are report volumes, not rates, and cannot be compared between drugs. The FDA itself says not to use this data to make medical decisions — we show it because you deserve to see what is in the public record, with its limits stated plainly.
Read this before the numbers.
Anyone can send a report to the FDA. Patients can. Doctors can. Drug makers can. Nobody checks that the drug caused what the report describes.
There is also no bottom number. Tens of millions of prescriptions turn into reports at a rate nobody knows. Reports go up when a drug is in the news, and that is not the same as more harm.
So these are counts of reports. They are not rates. You cannot use them to compare one drug with another. The FDA itself says not to use this data to make medical choices.
We show it because it is on the public record, and you should get to see it with its limits named.
- 159,283
- reports mentioning clonazepam, all time
- 108,457
- filed as serious (a report-level flag covering every drug and outcome in the report)filed as serious. That flag covers the whole report, and one report can name more than one drug and more than one outcome.
Most-reported reactions
- Drug ineffective13,982
- Fatigue10,473
- Nausea9,818
- Anxiety8,896
- Headache8,763
- Depression8,232
- Pain8,226
- Off label use8,039
- Dizziness7,402
- Insomnia7,122
“Drug ineffective” ranking this high is worth noticing: a report of not being helped counts as an adverse event too, and people file them in large numbers.
It is worth noticing how high “drug ineffective” ranks. A report that the drug did not help counts as an adverse event too. People file a lot of them.
Source: FDA Adverse Event Reporting System (FAERS), via openFDA, openFDA dataset refreshed 2026-07-30 (the refresh date of the query endpoint, not the date reports run through).
Drug interactions listed on the clonazepam label
The FDA label’s interactions section, verbatim. A pharmacist checking your actual medication list beats any published list — including this one.
Below is the part of the FDA label that lists other drugs. It is copied word for word.
No list on the web can see what else you take. A pharmacist can. Ask one to check your full list.
Read the label’s interactions section
Drug Interactions: Effect of Concomitant Use of Benzodiazepines and Opioids: The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at GABA A sites, and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists. Limit dosage and duration of concomitant use of benzodiazepines and opioids, and follow patients closely for respiratory depression and sedation. Effect of Clonazepam on the Pharmacokinetics of Other Drugs: Clonazepam does not appear to alter the pharmacokinetics of carbamazepine or phenobarbital. Clonazepam has the potential to influence concentrations of phenytoin. Monitoring of phenytoin concentration is recommended when clonazepam is co-administrated with phenytoin. The effect of clonazepam on the metabolism of other drugs has not been investigated. Effect of Other Drugs on the Pharmacokinetics of Clonazepam: Literature reports suggest that ranitidine, an agent that decreases stomach acidity, does not greatly alter clonazepam pharmacokinetics. In a study in which the 2 mg clonazepam orally disintegrating tablet was administered with and without propantheline (an anticholinergic agent with multiple effects on the GI tract) to healthy volunteers, the AUC of clonazepam was 10% lower and the C max of clonazepam was 20% lower when the orally disintegrating tablet was given with propantheline compared to when it was given alone. The selective serotonin reuptake inhibitors sertraline (weak CYP3A4 inducer) and fluoxetine (CYP2D6 inhibitor), and the anti-epileptic drug felbamate (CYP2C19 inhibitor and CYP3A4 inducer) do not affect the pharmacokinetics of clonazepam. Cytochrome P-450 inducers, such as phenytoin, carbamazepine, lamotrigine, and phenobarbital induce clonazepam metabolism, causing an approximately 38% decrease in plasma clonazepam levels. Although clinical studies have not been performed, based on the involvement of the cytochrome P-450 3A family in clonazepam metabolism, inhibitors of this enzyme system, notably oral antifungal agents (e.g., fluconazole), should be used cautiously in patients receiving clonazepam because they may impair the metabolism of clonazepam leading to exaggerated concentrations and effects. Pharmacodynamic Interactions: The CNS-depressant action of the benzodiazepine class of drugs may be potentiated by alcohol, narcotics, barbiturates, nonbarbiturate hypnotics, antianxiety agents, the phenothiazines, thioxanthene and butyrophenone classes of antipsychotic agents, monoamine oxidase inhibitors and the tricyclic antidepressants, and by other anticonvulsant drugs.
FDA label for clonazepam, effective August 27, 2026 — DailyMed.
Label history: when this label changes, it is recorded in What changed.
Who pays for clonazepam
Two claims datasets and one survey, covering different populations with different instruments — they cannot be reconciled by arithmetic, and where their sum crowds the all-payer estimate, that is a finding about the estimates rather than a percentage.
- Medicare Part D
- Read the under-65 group correctly before the numbers: Medicare before 65 means the disabled and dual-eligible population — among the sickest, highest-need people in the program — and reading their utilization as typical adult use would be a category error. The beneficiary total sums brand-level rows, so treat it as an upper bound on distinct people. 1,315,917 beneficiaries filled 8,856,358 claims in 2024 — 925,485 aged 65 and over, and 390,432 under 65.
- Medicaid
- At least 3,836,777 prescriptions in 2024 — a floor, because 151 of 670 national data rows are suppressed for privacy and contribute zero. Medicaid covers more children than any insurer in the country and publishes no age split — how much of this number is pediatric use is not knowable from public data.
- All payers (survey estimate)
- A survey estimate from 139 respondents, which we computed from AHRQ’s MEPS 2024 Prescribed Medicines file (people with at least one purchase, weighted; purchases include refills), puts the whole country at 11,861,003 purchases and 2,154,594 people in 2024. Subtracting the public programs from it would produce a number for everyone else — and we do not print that number, because subtracting a survey from claims counts manufactures precision that does not exist.
- The population nobody counts
- The commercially insured working-age adult — statistically, the likeliest person to be reading this page — is the one population with no public per-drug count anywhere. Private claims data exists and is sold, but nothing a patient can check is published. For children the record is thinner still: no public source counts pediatric use of clonazepam specifically; the closest the public record comes is condition-level treatment rates for children, which we have traced for one condition in how childhood ADHD got counted.
Sources: Medicare Part D Prescribers — by Geography and Drug, data.cms.gov, National rows, data year 2024 (published with ~17-month lag). Medicaid State Drug Utilization Data 2024, data.medicaid.gov, national aggregate rows. Retrieved 2026-09-01.
Who has been paying for clonazepam, 2019–2024
Medicare Part D
Claims, all ages — the one payer with a public per-drug series.
9,580,495 → 8,856,358 claims
Medicare under 65
Beneficiaries, not ordinary working-age adults: Medicare before 65 means the disabled and dual-eligible population. A gap is a suppressed split, not zero.
536,255 → 390,432 beneficiaries
Medicaid
A floor each year — small-cell rows are suppressed federally and excluded from the sum.
4,071,469 → 3,836,777 prescriptions (floor)
Commercially insured adults
No public dataset publishes per-drug commercial claims for any year — the absence is the finding, and it is rendered, not interpolated. The population this library most wants to inform is the one with no public per-drug series, in any year — insurers and PBMs hold that data privately. What the federal surveys do measure — how many adults take these medications at all — is on the adult-usage page.
Sources: Medicare Part D Prescribers by Geography and Drug (data.cms.gov, national rows, per data year); Medicaid State Drug Utilization Data (data.medicaid.gov, national rows). Claims, fills and beneficiaries are different units — compare each series only with itself.
The clonazepam approval, step by step
Step 1
What the approval was actually based on
Which studies did the FDA rely on, how long did they run, and who was in them?
Study 1 was a 9-week, fixed-dose study involving clonazepam doses of 0.5, 1, 2, 3 or 4 mg/day or placebo... A significant difference from placebo was observed consistently only for the 1 mg/day group. The difference between the 1 mg dose group and placebo in reduction from baseline in the number of full panic attacks was approximately 1 panic attack per week.
FDA-approved labelling, Clinical Trials: (from a generic manufacturer's label — the brand application has no current label on file, so this text is FDA-cleared but is not the original approval document) — read the label on DailyMed
Our reading
Read the effect size, because it is stated plainly and almost never repeated: about one fewer panic attack per week. And of five doses tested, only 1 mg/day separated from placebo consistently — the higher doses did not do better. The study ran nine weeks, of which six were at a fixed dose. Clonazepam is prescribed for years. Note also where this quote comes from: the brand label is gone and this text is a generic filer's, headed "Clinical Trials:" with no section number, because the drug predates the rule that created section 14.
Step 2
The approval
When was it approved, under what application, and by whose review?
- Approved
- June 4, 1975
- Application
- NDA017533
- Review
- PRIORITY
- Original sponsor
- Roche
- Holds it now
- Cheplapharm
- Label submissions since
- 51
Source: openFDA Drugs@FDA, original application ORIG-1
Step 3
What was added after it was on the market
Which warnings arrived only after millions of people were already taking it?
The FDA strengthened the benzodiazepine warning in 2020
45 years after approval
In September 2020 the FDA required the boxed warning on every benzodiazepine to be rewritten. The wording matters: physical dependence can develop even when the medication is taken exactly as prescribed, and stopping abruptly or dropping the dose quickly can cause withdrawal reactions that include seizures and can be life-threatening.
This is not a claim that the medication is bad or that you should stop taking it. It is the opposite. It is the reason not to stop on your own. The FDA's own instruction to prescribers is to taper gradually rather than stop, and to reassess dose and duration over time.
Worth asking
How long is the plan for me to be on this, what does my taper look like if we decide to come off, and how will we tell withdrawal apart from my original anxiety coming back.
The clonazepam label says misuse commonly involves alcohol or street drugs, and that is where the deaths are
50 years after approval
The first thing the FDA requires on a clonazepam label is not about clonazepam alone. It is about what it is taken with.
Significant findings
KLONOPIN prescribing information (H2-Pharma, December 2025), boxed warning: "Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for patients for whom alternative treatment options are inadequate."
Then the sentence that reaches past prescriptions: "The use of benzodiazepines, including Klonopin, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes."
The Warnings section gives the evidence and the instruction: "Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone. If a decision is made to prescribe Klonopin concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use, and follow patients closely for signs and symptoms of respiratory depression and sedation."
The word "illicit" on a label matters because street opioids now mean fentanyl, which is stronger and less predictable than anything a prescriber measures out. A benzodiazepine on board removes the margin.
Worth asking
If you take clonazepam or any benzodiazepine, the honest question is not whether a drink or a pill is "okay" but which combinations the label says kill: opioids of any kind, including counterfeit pills, and alcohol. If you are going to use, the label's own logic is the harm reduction: lowest dose, not alone, naloxone within reach. Never stop a benzodiazepine abruptly; the same label warns that withdrawal can be life threatening.
Step 4
What independent research has found since
What has been learned by people who were not selling it?
Opioid users who also filled a benzodiazepine had about twice the odds of an overdose visit
42 years after approval
The label says the combination is dangerous. This is the study that put a number on it, in the year before the FDA required the boxed warning.
Significant findings
Sun and colleagues (BMJ, 2017) analysed claims for 315,428 privately insured people aged 18 to 64 who filled at least one opioid prescription between 2001 and 2013. Concurrent use meant the two prescriptions overlapped by at least one day. "9% of opioid users also used a benzodiazepine in 2001, increasing to 17% in 2013 (80% relative increase). This increase was driven mainly by increases among intermittent, as opposed to chronic, opioid users."
On the outcome: "Compared with opioid users who did not use benzodiazepines, concurrent use of both drugs was associated with an increased risk of an emergency room visit or inpatient admission for opioid overdose (adjusted odds ratio 2.14, 95% confidence interval 2.05 to 2.24; P<0.001) among all opioid users." The odds ratio was 1.42 for intermittent opioid users and 1.81 for chronic users.
The authors' own conditional: "If this association is causal, elimination of concurrent benzodiazepine/opioid use could reduce the risk of emergency room visits related to opioid use and inpatient admissions for opioid overdose by an estimated 15% (95% confidence interval 14 to 16)."
Worth asking
Two things this study is not. It is not a trial, so it cannot prove the benzodiazepine caused the overdoses; people prescribed both may differ in ways claims data cannot see. And it is not about street drugs; every exposure was a filled prescription from a doctor. That second point is the useful one. Both drugs came through a pharmacy, which means a pharmacist can see both. If you take either, ask the pharmacist to check for the other.
Two thirds of opioid overdose deaths in 25 states also involved cocaine, methamphetamine or a benzodiazepine
44 years after approval
The question "is it okay to mix" has a public health answer in the surveillance data: most opioid deaths are already mixtures.
Significant findings
Gladden and colleagues (MMWR, 2019) describe opioid overdose deaths in 25 states participating in the CDC's State Unintentional Drug Overdose Reporting System, comparing January to June 2018 with the previous half year. The background: "From 2013 to 2017, the number of opioid-involved overdose deaths (opioid deaths) in the United States increased 90%, from 25,052 to 47,600. This increase was primarily driven by substantial increases in deaths involving illicitly manufactured fentanyl (IMF) or fentanyl analogs mixed with heroin, sold as heroin, or pressed into counterfeit prescription pills."
The findings: "overall opioid deaths decreased 4.6%"; decreases were in prescription opioid deaths without illicit opioids; and "IMF deaths, especially those with multiple illicit opioids and common nonopioids, increased. Consequently, IMF was involved in approximately two-thirds of opioid deaths during January-June 2018. Notably, during January-June 2018, 62.6% of all opioid deaths co-occurred with at least one common nonopioid drug."
The nonopioid drugs counted were cocaine, methamphetamine and benzodiazepines, detected in the person who died. The report's conclusion: efforts must "address polysubstance misuse with opioids."
Worth asking
Two things this report establishes. Counterfeit pills, including ones sold as Xanax or oxycodone, may be fentanyl; the report says so in its first paragraph. And the deaths are mostly combinations, not single drugs. If you take a prescribed benzodiazepine or stimulant and also use cocaine or pills from outside a pharmacy, the relevant number is not the interaction between your two drugs but the fentanyl you did not know was there. Fentanyl test strips and naloxone are the practical questions.
Benzodiazepines were present in a third of prescription opioid overdose deaths in 2017; alcohol in one in seven
45 years after approval
The label says benzodiazepines plus opioids kill. This is the count.
Significant findings
Tori, Larochelle and Naimi (JAMA Network Open, 2020) analysed every opioid-involved poisoning death in the CDC's WONDER database from 1999 to 2017: "399 230 poisoning deaths involved opioids, of which 263 601 (66.0%) were male, and 204 560 (51.2%) were aged 35 to 54 years."
Alcohol: "Alcohol co-involvement for all opioid overdose deaths increased nonlinearly from 12.4% in 1999 to 14.7% in 2017. By opioid subtype, deaths involving heroin and synthetic opioids (eg, fentanyl; excluding methadone) had the highest alcohol co-involvement at 15.5% and 14.9%, respectively, in 2017."
Benzodiazepines: "Benzodiazepine co-involvement in all OODs increased nonlinearly from 8.7% in 1999 to 21.0% in 2017. Benzodiazepines were present in 33.1% of prescription OODs and 17.1% of synthetic OODs in 2017."
The state-level pattern: "State-level rates of binge drinking were significantly correlated with alcohol co-involvement in all OODs (r = 0.34; P = .02). State benzodiazepine prescribing rates were significantly correlated with benzodiazepine co-involvement in all OODs (r = 0.57; P < .001)."
Worth asking
Co-involvement means the drug was found at death, not that it caused the death, and death certificates undercount what was not tested for. Even so, one in three prescription opioid deaths with a benzodiazepine present is the number behind the boxed warning. If you take a benzodiazepine and any opioid is in your life, prescribed or not, the question for your prescriber is whether naloxone is in the house and whether the people around you know how to use it.
Higher benzodiazepine doses went with non-response to ketamine for depression, above 8 mg diazepam-equivalent
45 years after approval
Ketamine, from a clinic or from the street, works on the same brain systems benzodiazepines quiet. This study asked whether the sedative blunts the antidepressant.
Significant findings
Andrashko and colleagues (Frontiers in Psychiatry, 2020) analysed 47 patients with major depression who had not responded to at least one antidepressant and received a single infusion of racemic ketamine, 0.54 mg per kilogram, on top of their existing medication. "Thirteen patients (28%) reached ≥ 50% reduction in MADRS within one week after ketamine administration. Nineteen (40%) patients took concomitant benzodiazepines on a daily basis."
"The doses of BZDs were significantly higher in nonresponders (p=0.007). ROC analysis distinguished responders from nonresponders by a criterion of >8mg of diazepam equivalent dose (DZ equivalent) with a sensitivity of 80% and a specificity of 85% (p<0.001)." Patients above that dose had "a significantly worse outcome" on day 3 and day 7.
"The results of the study indicate that concomitant benzodiazepine treatment in higher doses may attenuate ketamine's antidepressant effect." A 2015 letter by Frye, Blier and Tye in the Journal of Clinical Psychopharmacology, read for this wave, reported the same pattern under the title "Concomitant benzodiazepine use attenuates ketamine response".
Worth asking
Forty seven patients and a retrospective split, so the cut-off is a hypothesis, not a rule. The direction is consistent across the two reports, and it matters in both settings: a person paying for ketamine treatment while on a moderate benzodiazepine dose may be paying for less effect, and a person using street ketamine on top of a benzodiazepine is combining two sedatives, which the esketamine label in this wave addresses directly. If ketamine treatment is on the table, the question for the clinic is what your benzodiazepine dose is in diazepam-equivalents and whether that changes the plan. Any change to the benzodiazepine is the prescriber's, with a taper; the same drugs cause dangerous withdrawal if stopped abruptly.
Withdrawal from these medications can take months, and NICE says so
47 years after approval
NICE guideline NG215 covers safe prescribing and managed withdrawal for five groups of medication: opioids, benzodiazepines, gabapentinoids, Z-drugs and antidepressants. It is the closest thing there is to an official answer on how coming off actually goes.
It states that withdrawal can be difficult and may take several months or more, that symptoms vary widely in type and severity, that they affect both physical and mental health, and that they can be delayed in onset and can persist. Two recommendations are worth quoting to a prescriber. Do not stop a medicine abruptly except in exceptional medical circumstances. And taper using a slow, stepwise reduction proportionate to the current dose, so the decrements get smaller as the dose gets lower — not a fixed cut each time.
That last detail is the one most commonly missed. Gabapentinoids are the exception in the guideline and are reduced by a fixed amount at each step.
Worth asking
Can we write the taper down, what size are the steps near the end, and how long do I hold at each step before the next reduction.
Benzodiazepine use and risk of incident dementia or cognitive decline: prospective population based study
41 years after approval
Following 3,434 adults aged 65+ for a mean of 7.3 years (797 developed dementia), the heaviest benzodiazepine users had no higher dementia risk than non-users — only minimal users showed a slight elevation — which argues against benzodiazepines causing dementia.
Worth asking
The evidence on benzodiazepines and dementia points both ways — how do you weigh it for someone my age, and does it change how long I should stay on clonazepam?
Benzodiazepine use and risk of Alzheimer's disease: case-control study
39 years after approval
Comparing 1,796 older adults with Alzheimer's disease to 7,184 matched controls, past benzodiazepine use was associated with higher Alzheimer's risk, and the association strengthened with longer cumulative use — an association that cannot by itself prove the drugs cause dementia.
Worth asking
I've been on clonazepam for more than a few months — given the unresolved question about benzodiazepines and dementia, is it worth working out a gradual tapering plan?
Clonazepam in the treatment of panic disorder with or without agoraphobia: a dose-response study of efficacy, safety,…
22 years after approval
In 413 people with panic disorder randomized to placebo or five fixed doses of clonazepam, daily doses of 1 mg and above reduced panic attacks equally well, and 1-2 mg/day gave the best balance of benefit against side effects such as sleepiness and unsteadiness, which climbed at 3-4 mg.
Worth asking
I'd like to check my clonazepam dose — am I in the 1-2 mg range where benefit plateaus, and if I'm above it, is the extra dose doing anything but adding side effects?
Treatment of social phobia with clonazepam and placebo.
18 years after approval
In a 10-week double-blind trial of 75 outpatients with social phobia, 78% responded to clonazepam (mean maximum dose 2.4 mg/day) versus 20% on placebo, with more unsteadiness and dizziness in the clonazepam group.
Worth asking
If clonazepam is helping my social anxiety, what's the longer-term plan — is this a bridge to something like an SSRI or therapy, or are we staying on it?
Treatment of social phobia with clonazepam and placebo. — Davidson JR, et al. (1993)
Psychopharmacotherapy of panic disorder: 8-week randomized trial with clonazepam and paroxetine
36 years after approval
In 120 adults with panic disorder randomized to clonazepam or paroxetine for 8 weeks, both drugs reduced panic attacks (0.1 vs 0.5 attacks per week at endpoint), and fewer clonazepam patients reported side effects (73% vs 95%).
Worth asking
Between a benzodiazepine like clonazepam and an SSRI like paroxetine, which is the better long-term strategy for my panic attacks given dependence risk?
Step 5
What still is not known
Which questions you might reasonably have has nobody answered yet?
- One fewer panic attack per week, at one specific dose, over nine weeks. Is that the size of benefit you were told to expect?
- The higher doses were not better than 1 mg/day. If you are above that, what is the reason?
- Physical dependence on benzodiazepines develops within weeks. The trial barely outlasted the window in which it begins, and the boxed warning about it was not strengthened until 2020.
Deciding about clonazepam?
- Side-effect rates from clonazepam's own label — drug vs placebo, with every caveat the label attaches
- How long every medication's approval trials ran — clonazepam beside every other drug in the library, from the same FDA record
- 12 questions to ask before starting a psychiatric medication — each with the study behind it
- Already on it? The 10-question annual review — including the honest case for staying
- How long every drug here was tested before approval — one chart, all medications
Open clonazepam (Klonopin) in veisund
The app has the full approval journey, the resources behind it, and people working through the same questions.
