A singular psychiatrist writes The Frontier Psychiatrists (plural) newsletter. Owen Muir, M.D., is not really into pills. Some people don’t love the third-person voice I use, here, in the newsletter. It is a funny conceit in my head. Having a jaunty dance while I write makes it possible to write volumes. The other item of note? I like David Foster Wallace, and he did this silly narrator sh*t all the time—when he was writing for The Atlantic and Rolling Stone. I'm just enamored of that style for personal reasons. I'm going to keep doing it. I'm sorry if it's annoying.
In my practice, I've decided not to focus on psychiatric medication, at least not the classic small-molecule drugs. Thus, I'm writing a series where I talk about individual drugs and how I think about them. For everybody else who still practices that way, it is here for them. It is intended as advice to other prescribing physicians and nurses. I think our conversations between professionals in public are better than behind closed doors, thus the newsletter publication. The first two installments are here and here. Consider supporting my work!
I have prescribed standing benzodiazepines in my entire career as an outpatient psychiatrist on two occasions1. I don’t like them.
I have, personally, been prescribed a tiny 2mg dose, Twice daily, of diazepam, by urology, for pelvic floor dysfunction. I now understand to be part of my autoimmune disease. That is a longer story. This story is about clonazepam2 (Klonopin). My prior article on Benzos, generally, is here:
All benzodiazepine medications bind to the GABA receptors, a ligand-gated chloride channel. This means that, on neurons, if GABA binds to a receptor, it opens. Calcium flows down its concentration gradient, and cells are hyper-polarized. Hyperpolarization means it's harder to make the neuron fire. Agonist means it binds to a receptor and acts as if the thing binding to it was the thing it was intended to bind to. It is the opposite of an “inhibitor.” Inhibitors hang out on a receptor and don't let it fire or be activated by endogenous chemicals in your body.
I have previously written about the combination of dextromethorphan and bupropion that together creates a new drug that is an NMDA receptor antagonist, and the important thing was that NMDA receptors are ion channels, too. That makes cells fire now.
Glycine and glutamate make cells more likely to fire, and GABA makes cells less likely to fire. That's the dance. GABA is the primary inhibitory neurotransmitter in the brain.
It’s the calm-down sauce.
Other common GABA agonists include compounds like alcohol.
Practically speaking, the differences in benzodiazepines— Klonopin, Ativan, Midozalam, and the rest—have to do with the following:
“half-life”—how long it lasts in your system before your metabolism breaks it down
Lipophilicity: how soluble a drug is in fat (a.k.a. lipids) is how quickly you can cross the blood-brain barrier, which is made up of lipids.
Active metabolites: Once the drug is broken down, is there anything left that, itself, is active in the brain or body?
Potency: per milligram, how much of a GABA agonist is it?
Cross-reactivity: At any given potency, will any other benzo work the same if you have enough of it, or not really?
Once you have these three concepts, they're largely the same. Klonopin has some serotonergic activity as well, via inducing serotonin synthesis.
Klonopin is FDA-approved for treating seizure and panic disorders.
Other indications include acute mania, which I think is pretty useful because it is a short-term treatment. It’s not a general “all the time” anxiety treatment, but it is often prescribed as such. In my home town of Brooklyn, when I last looked at the data3, it was THE most common psychiatric medicine prescription written by doctors.
Klonopin lasts a while. It's an oral medication. It is a pill, and it lasts around 12 hours. We think of it in terms of its anxiolytic uses as an anti-anxiety medicine. But it's not just that, and not approved as a generalized anxiety treatment, even. It can be used for seizures, with FDA approval. A seizure is the brain firing out of control, so having extra GABA agonism can treat or prevent a seizure. It’s also useful for essential tremor, and other neurological conditions. There are legitimate use cases outside of Psychiatry for the drug, and some people have to take it. They don't get a choice, if the underlying disorder is extremely problematic. It may be the best thing for them.
As a general psychiatric drug, I think clonazepam is garbage...my strong suspicion is not that it’s being broadly prescribed for Panic Disorder and Seizure only. It is commonly prescribed for anxiety… and taken daily. This is not to say it doesn't work. It does work. It reduces anxiety rapidly. It does that robustly, so it has FDA approval to stop a Panic Attack promptly. In the inpatient psychiatric context, it's a reasonable choice when we have to manage distress for those who feel awful and on edge. This is especially true given its anti-manic activity and sedating effects.
We get into trouble when we think about managing anxiety in the outpatient setting, and using this seductively effective drug first-line. I don't think we should be managing outpatient “anxiety,” as I have previously argued. To be very clear, it sucks to be anxious. It is awful. It can be extremely awful. Psychic anxiety, which is a way of saying VERY anxious, is one of the reliable predictors of complete suicide4. No one wants to be jumping out of their skin. It's a terrible, terrible feeling. The problem with Klonopin is that it works too well. It also comes with tremendous costs to individuals that are only evident later.
The most important problem is that you can't abruptly discontinue the drug. Once one develops physiological dependence on a benzodiazepine, abrupt discontinuation will lead to seizure and death.
Opiate withdrawal will not kill you. Benzodiazepine withdrawal can. The brain gets used to the presence of a GABA agonist all the time. Neurons get ready to fire in the presence of a GABA agonist all the time and acts like since it has more inhibitory stuff around… it up-regulates everything else. To keep up. So it gets ready to fire because it's so used to having the wet blanket around. Take away the wet blanket; things burst into flames.
Klonopin is no different in this regard. If taken all the time, people develop physiological dependence. Then, humans will not be able to stop it abruptly. The appropriate taper-off of a benzodiazepine, like Klonopin, can take a year. It can take more. The reason for this is that the difference between 4 mg and 3 mg is 1 mg. That's only a 25% reduction. The difference between 1 mg and 0 mg is 1 mg. But that's a 100% reduction. The tail is the slowest part, and it can feel like emergent horrible anxiety do you have what is really the withdrawal adverse effect of less Klonopin by more than your brain was expecting.
The brain is exquisitely sensitive to the percent reduction of drugs, not the total milligram reduction. No matter how slowly you taper, the end of the taper will be from something to nothing, 100%, which is hard.
I have friends who started a whole company called Outro Health, which is based on helping people taper off of antidepressant medications very slowly—because it's true for them, too. SSRI withdrawal won't kill you. Abrupt discontinuation of Klonopin, again, will kill you5. That can happen after some time, and I'm not going to get into details on how long it is because it's different for everybody, and this isn't medical advice. As a doctor, if you're going to start Klonopin, you should have a plan to taper off Klonopin from day one. More to the point, you should never start someone on Klonopin as a standing medication if you can avoid it.
I am many things in life, but a terrible Psychiatrist is not one of them. A terrible psychopharmacologist is not one of them. I hate that term. I hate it so much. I want that term to die.
Sorry. The thing I'm setting up without the above comment is the fact that people tell me all the time, yeah, but sometimes you need these medicines. What about that one case of someone's anxiety that they are demanding treatment for right now?!?
How did I—Owen Muir, M.D.— get away with only prescribing it twice, ever? Both were not for anxiety; one person had essential tremors, and the other had another neurological condition and promptly referred them to neurology.
The danger with something that works as well as Klonopin is that, as a physician, you're going to use it. And it's going to work. And then you're going to be stuck. So, I never use it. If you never start someone on a standing medication, and only ever prescribe it “as needed,” a couple of pills, and that's it; you never get yourself in that situation. It's a dangerous crutch, is my argument. And I have the privilege of making that argument because I'm a good Psychiatrist —who knows what I'm doing with medicines, more or less— if I can get away with never using it, maybe everyone else can also.
Long-term benzodiazepine use— clonazepam included—will lead to increased rates or community-acquired pneumonia6, delirium in older adults, hospital-acquired infections, and falls78, most of which happen to older people. I acknowledge that. You're probably not going to die from Klonopin as a young person. It does not mix well with alcohol. It does not mix well with opiates. It is dangerous in combination with other things.
It has a risk of memory loss, which is subtle9. Memory loss— an amnestic agent— can be so slight that most never notice it10. But it can get in the way of important tasks like studying for a board exam. It impairs your memory just a little bit. I had a colleague in medical school who had really bad OCD, which made her life pretty miserable. She was too anxious to speak up on rounds. She was prescribed a tiny amount of Klonopin, half a milligram, twice daily, every day, and changed a lot socially. She was able to talk; she was able to express her opinion. It was good for her as a medical student. It also destroyed her ability to pass a medical board exam. She passed step 1 before Klonopin. Then she took step two on Klonopin and failed it once, twice. I don't remember if she failed it a third time. She discontinued the drug with a slow taper. She passed the test. She took the next step exam and passed it next month. I did something problematic for her ability to incorporate “New Information” into long-term memory. It's not on a package insert. It's not something we warn people about. But it's real.
Klonopin is more potent than lorazepam but not as potent as alprazolam (Xanax). It has active metabolites—after a liver breaks down, more active drugs are left. This is rarely important, but every once in a while, it matters a lot.
I had a patient who is an ultra-rapid metabolizer of Ativan and has been abusing Klonopin in the outpatient setting. Ativan has no active metabolites. Klonopin is an active metabolite. That means once you break down Klonopin, your system has more benzo to wean you off even more slowly. He was admitted to a psychiatric hospital and switched to an equivalent dose of Ativan. The rare genetic variant was destroyed almost overnight. No one could figure it out; multiple trips to the emergency room, his benzodiazepine tests in a year or negative, and we had given him 9 mg a day. It didn't make any sense. This was before the commercially available test for the UGT-111 gene was published. This enzyme codes for the liver approaching and breaks down Ativan and Klonopin. The Klonopin had something extra, which was metabolized differently, so he took that and did not withdraw abruptly. With a theoretically equivalent drug, his body ripped through it so fast that the ER thought he wasn't taking anything because the blood level was below the threshold for reporting a negative result.
All of which is to say, Klonopin can get weird. It is sedating. It's hypnotic, which is to say it puts you to sleep, but that effect wears off pretty quickly, too. And then you're just tired but not sleeping and not remembering things.
I don't think a lot of it is worth it as a long-term drug for anxiety. I would rather clinicinan spend more time figuring out why people are anxious and addressing that underlying psychological and physical problem, which is often obsession, trauma, etc., sometimes it's even physiological problems like super ventricular tachycardia!
I think Klonopin works well enough that we can skip the explanation or the understanding. And we shouldn't do that because it's not the best treatment. It's not great doctoring. It makes us feel like we're doing a good job because we provide relief, and we create a long-term problem, and we should do less of that.
Once, was Klonopin
Basit H, Kahwaji CI. Clonazepam. In: StatPearls. StatPearls Publishing, Treasure Island (FL); 2022. PMID: 32310470.
two years ago
Oquendo, M. A., Galfavy, H., Burke, A., Grunebaum, M. F., Sher, L., Sullivan, G. M., Sublette, M. E., Mann, J., & Lafer, B. (2018). Are comorbid anxiety disorders a risk factor for suicide attempts in patients with mood disorders? A two-year prospective study. European Psychiatry : The Journal of the Association of European Psychiatrists, 47, 19. https://doi.org/10.1016/j.eurpsy.2017.09.005
once you have physiological dependence
Paul, K. J., Walker, R. L., & Dublin, S. (2015). Anticholinergic Medications and Risk of Community-Acquired Pneumonia in Elderly Adults: A Population-Based Case–Control Study. Journal of the American Geriatrics Society, 63(3), 476-485. https://doi.org/10.1111/jgs.13327
Deano, J. (2016). Fall Prevention in Acute Psychiatric Patients.
Stevenson, D. G., Decker, S. L., Dwyer, L. L., Huskamp, H. A., Grabowski, D. C., Metzger, E. D., & Mitchell, S. L. (2010). Antipsychotic and Benzodiazepine Use Among Nursing Home Residents: Findings From the 2004 National Nursing Home Survey. The American Journal of Geriatric Psychiatry: Official Journal of the American Association for Geriatric Psychiatry, 18(12), 1078. https://doi.org/10.1097/JGP.0b013e3181d6c0c6
Noé Contreras-González, Bernarda Téllez-Alanís, Reyes Haro, Ulises Jiménez-Correa & Adrián Poblano (2015) Executive dysfunction in patients with chronic primary insomnia treated with clonazepam, Neurological Research, 37:12, 1047-1053, DOI: 10.1080/01616412.2015.1114740
Ghosh, C., Hossain, M., Puvenna, V., Martinez-Gonzalez, J., Alexopolous, A., Janigro, D., & Marchi, N. (2013). Expression and functional relevance of UGT1A4 in a cohort of human drug-resistant epileptic brains. Epilepsia, 54(9), 1562-1570. https://doi.org/10.1111/epi.1231
Ghosh, C., Hossain, M., Puvenna, V., Martinez-Gonzalez, J., Alexopolous, A., Janigro, D., & Marchi, N. (2013). Expression and functional relevance of UGT1A4 in a cohort of human drug-resistant epileptic brains. Epilepsia, 54(9), 1562-1570. https://doi.org/10.1111/epi.12318
As a patient I personally have found clonazepam to be an extremely beneficial drug with few side effects (though I am unquestionably physically dependent on the drug).
I was prescribed it for REM Sleep Behavior Disorder which sounds really lame and banal but is actually pretty dangerous. Your muscles doesn’t get paralyzed during REM sleep and so whatever body movements you make or anything you say while dreaming becomes sleepwalking/sleepwalking.
I always had it and it led to some weird situations but I didn’t seek medical treatment until I apparently told my gf I was going to murder her and pinned her down with one of my arms. That was pretty terrifying so I was down for whatever.
Melatonin is first line but it did nothing for me. So after I got a sleep study and confirmed it they prescribed clonazepam as it’s the only other medication used to treat REM SBD. I feel like other benzos would probably would too but idk.
I can’t really tell much difference between lorazepam and clonazepam. Diazepam felt much more sedating and euphoric but also cognitively impairing. I absolutely hate Xanax as I blackout at subtherapeutic doses (0.25 mg will annihilate my memory for the evening). I’ve never blacked out on clonazepam and unless I take it during the day I don’t feel tired or cognitively dull. I also have Bipolar and it def does help mania but I don’t think it’s the best drug for that purpose bc a lot of ppl find benzos so addictive.
I suppose I’m lucky in that I really don’t enjoy benzos much. It improves my sleep quality and prevents me from hurting myself or others - that’s all I was looking for and once I developed a tolerance that’s about all I get out of it. I strongly dislike taking a dosage so high that I’m even slightly impaired or intoxicated.
I simultaneously agree with nearly everything you said. And, I wish you would further emphasize the important role that benzos can play in treating acute mania. I work with seriously psychotic individuals who require weeks of multiple antipsychotics + benzo to break through their mania. Its real.