Dr. Scott Siskind dives into the world of SSRIs in this informative article. Gain a deeper understanding of how these medications work, their effectiveness, side effects, and the process of coming off them. Siskind breaks down the common misconceptions surrounding SSRIs and provides insights into their impact on emotional processing. If you've ever wondered about the nuances of these medications or are considering them for yourself, this article offers valuable information to help guide your decision-making process.

SSRIs

Dr. Scott Siskind dives into the mechanism and usage of Wellbutrin (bupropion) as an antidepressant and stop-smoking aid. Although commonly known as an NDRI (norepinephrine and dopamine reuptake inhibitor), Wellbutrin’s effectiveness in treating depression seems to surpass this classification. Dr. Siskind explores the nuances surrounding the drug's action, comparing it to other NDRIs and highlighting patients who found relief from depression only when Wellbutrin was added to their treatment. If you’re curious about the science behind Wellbutrin's unique effects, this article will provide valuable insights.

Wellbutrin

Dr. Scott Siskind dives into the world of ADHD medication and explores the effectiveness of Adderall compared to other stimulants. He discusses typical dosages, the advantages and disadvantages of different medications in the Adderall family, potential side effects, and long-term risks. Dr. Siskind sheds light on questions like addiction, withdrawal, tolerance, and offers practical solutions for managing the infamous "crash." If you've ever wondered about the ins and outs of Adderall and its alternatives, this comprehensive article provides valuable insights for individuals seeking treatment for ADHD.

Adderall

Join Scott Siskind, MD as he delves into the fascinating world of taxometrics in psychiatry. In this thought-provoking essay, Siskind challenges the binary nature of psychiatric conditions by highlighting their continuum-like structure. He explores how this paradigm shift affects the diagnosis and understanding of mental health disorders. Discover the implications of viewing psychiatric conditions as spectra rather than distinct categories, and gain a new perspective on how symptoms can impact individual functioning. Prepare yourself for a compelling exploration of the ontology of psychiatric conditions that will challenge your preconceived notions.

Ontology Of Psychiatric Conditions: Taxometrics

Scott Siskind, MD delves into the concept of dynamical systems in the context of psychiatric conditions. He explores how these systems, which involve complex interactions between multiple variables, may provide valuable insights into understanding psychiatric disorders. Siskind discusses the idea of "attractor basins" where variables converge into unusual and persistent states without a single identifiable cause. This thought-provoking essay sheds light on a new perspective that challenges traditional approaches to mental health.

Ontology Of Psychiatric Conditions: Dynamical Systems

Dr. Scott Siskind delves into the mysterious realm of panic disorder, shedding light on its underlying causes and effective treatments. Discover why panic attacks may be triggered by false alarms in the brain's oxygen management system and how this knowledge can empower patients in their recovery. Explore the pharmacological and psychotherapeutic interventions that have proven successful in managing panic disorder. Gain practical tips for coping with panic attacks and find out what steps you can take to improve your overall well-being. Join Dr. Siskind on this enlightening journey towards understanding and overcoming panic disorder.

The short version: Panic disorder is a tendency to suffer from disabling panic attacks. These attacks are feedback loops associated with unusual bodily sensations, probably relating to a tendency for the brain’s oxygen management system to suffer false alarms and believe you are suffocating. Panic disorder usually gets better on its own, but patients don’t always want to wait the months or years this can take. SSRIs are an effective pharmaceutical treatment for panic disorder; CBT is an effective psychotherapeutic one.
The long version:
 
Contents 
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1. What is panic disorder?

 
2. What is the usual prognosis of panic disorder?

 
3. What pharmacological treatments work for panic disorder?

 
4. What psychotherapy works for panic disorder?

 
5. What can I do when I’m having a panic attack?

 
6. Anything else I should do?



1. What is panic disorder?
To vastly oversimplify: panic disorder is a false alarm in the brain’s suffocation detection system, plus a series of feedback loops that make the false alarm worse and prevent it from being fixed.
I realize this isn’t the standard explanation given in textbooks. But it’s a theory Professor Donald Klein proposed in Archives of General Psychiatry in 1992, it’s been supported by many experiments since then, it makes sense of various otherwise-inexplicable phenomena, and I think it should be better-known than it is. Also, when I explain it to patients with panic disorder, they usually feel better and recover more quickly, because part of the problem with panic attacks is a feeling of helplessness and not knowing what’s going on. I believe Professor Klein explained what was going on back in 1992 and that it’s worth explaining his model to the public.
Your brain has a collection of cells called the “central chemoreceptor” that checks the level of carbon dioxide in the blood. If there’s too much carbon dioxide, the central chemoreceptor tries to get you to breathe harder. If for some reason this doesn’t work, the chemoreceptor activates a “suffocation alarm”, telling the rest of your brain that you’re suffocating and it should drop everything else and try to solve this problem. If you’ve ever been in a situation where you’ve been low on air, you know what this feels like. Sudden, extreme panic. The feeling of suffocating (not really like any other feeling, very unpleasant), and the replacement of normal breathing with desperate gasping. Increased circulatory activity in case oxygenated blood just isn’t isn’t reaching your brain properly – that means fast, pounding heartbeat. A desire to get out of whatever situation you’re in and run outside (if you’re suffocating, probably the situation you’re in is some kind of cave or fire or something with no air supply). These are most of the symptoms of panic attacks, with the remainder being explained by general sympathetic activation.
Making people breathe air artificially enhanced to have extra CO2 can provoke panic attacks. This effect is stronger in relatives of people with panic disorder, even those who have never had the condition themselves, suggesting that they have genes for being more sensitive to carbon dioxide and the possibility of suffocation. Some of the genes involved in carbon dioxide sensing seem to predispose for panic disorder, although the studies involved are preliminary and should be confirmed with more modern genetic research tools.
(not-so-fun fact: scientists first discovered the central chemoreceptor by investigating a condition called Ondine’s Curse, where patients with certain kinds of neurological damage lose their natural drive to breathe: they could still breathe by consciously choosing to do so, but the moment they forgot, they would suffocate. Obviously this condition is extremely fatal; if nothing else, sufferers will die upon falling asleep. Panic disorder is a sort of opposite of Ondine’s Curse; Curse patients don’t feel like they’re suffocating even if they are; panic disorder patients feel like they’re suffocating even when they’re not).
Exactly how this overactive suffocation alarm produces panic attacks is a little murkier, but here’s one possible model: at some point, the normal ebb and flow of weird sensations in the body passes the threshold for setting off an oversensitive suffocation alarm. The suffocation alarm sounds a weak signal, which causes bodily sensations to become more deranged – eg faster heart rate, higher sympathetic activation. The suffocation alarm incorrectly interprets its own downstream effects as further evidence of suffocation (“there’s a fast heart rate, something must be really wrong!”) and sounds a stronger signal. This intensifies in a vicious cycle: stronger suffocation alarm means more deranged bodily signals means stronger suffocation alarm. 
What are these deranged bodily sensations and how do we stop them? Probably there are many of them, and the central chemoreceptor takes inputs from all sorts of other bodily systems before deciding how much you are suffocating. One unusually ironic one that’s gotten a lot of attention is hypocapnia – not having enough carbon dioxide. Because the false suffocation alarm provokes hyperventilation (increased breathing, gasping for air), by the middle of a panic attack, patients usually have much too much oxygen, and much too little carbon dioxide, in their blood. This causes its own set of problems, and the chemoreceptor is totally incapable of distinguishing the problems of too little carbon dioxide from the problems of too much carbon dioxide, so it just notices things are getting worse and tries to make you breathe even harder (I don’t understand why evolution let this system get this stupid, but here we are). This is probably why deliberate attempts to decrease oxygenation (eg breathing into a paper bag) seem to help panic attacks. They might also work by giving the brain an “explanation” for its otherwise confusing sensations. When the suffocation alarm goes off, higher brain centers are able to think “Yeah, of course she’s got too much carbon dioxide, she’s breathing into a paper bag”, and then it doesn’t panic as much as it would otherwise.
Probably it is actually much more complicated than this. The part I always stress with my patients is that panic attacks are a specific type of false alarm. They don’t mean anything is actually going wrong. They’re happening for a very specific reason: your body thinks you are suffocating, and is trying to give you a level of freaked-out-ness appropriate to that situation. Many patients, if they concentrate closely enough on the sensations of panic, are able to explicitly perceive them as the feeling of suffocating. This can paradoxically be reassuring – if you’re in a normal well-ventilated place, you know you’re not suffocating and you can understand the false-alarm nature of the scary feelings.
2. What is the usual prognosis of panic disorder?
I can’t back this up with formal studies, but I’ve found people with panic disorder fall into three groups.
The smallest group is people who have had it ever since they were old enough to notice, have it consistently all the time, and will probably continue having it unless something changes. This situation seems pretty rare.
A somewhat larger group is people who have it when other problems get really bad. Depressed people who get panic attacks during the worst parts of their depression (and never once their depressive episode is over). Anxious people who get it during a stressful life event that makes them extra-anxious. My guess is that depression, anxiety, and so on activate the sympathetic nervous system in a way that the chemoreceptor interprets as a little bit of extra evidence of suffocation. With this “bonus”, it’s much more common for other small fluctuations to get over the threshold, set it off, and precipitate a panic attack. These people will stop having panic attacks once their anxiety or depression gets better.
The largest group are people who never had panic attacks until [incident], then [incident] gave them a very bad panic attack, and ever since [incident] they’ve continued to have panic attacks regularly. Sometimes [incident] is a traumatic event, sometimes it’s a random panic attack that came completely out of nowhere, but most often it involves using recreational drugs (even usually-considered-harmless drugs like small amounts of alcohol, marijuana, or LSD). Probably these drugs created weird internal sensations that confused their chemoreceptor, and their chemoreceptor decided to err on the side of caution and set off a suffocation alarm. Whatever the [incident], it “kindled” a temporary tendency toward panic attacks (if you’ve read the section on predictive coding, it produced some evidence that suffocation is common in the environment leading to a high prior on suffocation that has to be unlearned). The good news is you’ll unlearn this prior with time. This group of people tend to have very frequent panic attacks just after [incident], gradually declining in frequency and severity over the course of a few months to a year, and eventually recover completely. Sometimes there will be another incident some time in the future that will start the process over again, sometimes there won’t be.
Panic attacks often go away on their own, especially if an underlying cause is resolved. When they don’t, treatment is usually effective. Patients usually don’t feel like they have an effectively-treatable condition in the middle of a panic attack, but psychiatry’s track record here is usually pretty good.
3. What pharmacological treatments work for panic disorder?
There are two goals here. The first is an acute treatment you can take when you’re having a panic attack and want it to stop right now. The second is a maintenance treatment you can take to prevent panic attacks from happening at all.
The most common acute treatment is Xanax (alprazolam). This stops panic attacks pretty effectively. Its main downside is that it’s potentially addictive, but in practice people rarely get addicted if they take it 2-3x/week or less, so this is a good choice for people whose panic attacks are less frequent than that. If someone’s panic attacks are more frequent than that and they want something they can still take long term, my second-line choice is Vistaril (hydroxyzine). This is still pretty good but it can sometimes make people sleepy, which is annoying if they have a panic attack in the middle of the day.
A secondary downside to all acute treatments for panic attacks is that some people worry it inhibits the learning process. That is, part of treating panic disorder is convincing your lizard brain that panic attacks aren’t as scary as it thinks, breaking the feedback loop where panic causes worse panic and so on. But if you always take medication as soon as you start feeling a panic attack, then you never get a chance to habituate to the state of being in a panic attack. 
I am pretty liberal on this one; I think part of the process of learning not to be scared of a panic attack is knowing that you could stop it if you wanted to. Somebody who knows they have a medication that could help them at any time, but who’s going to try to sit through the panic attack to get “the full experience”, is in a much safer and better place to learn something than the person who’s freaking out because they’re stuck in a panic attack they can’t control. Also, a lot of people’s panic attacks will go away on their own, or with the help of maintenance medication, after a while anyway. So I usually try to get somebody stabilized on an acute medication that works for them first, and then once they feel like things are in control, talk about whether they might want to try experiencing the panic attacks so they can habituate. Often the problem is mostly solved by then in any case and we don’t have to worry about that.
The usual dose for Xanax for panic attacks is 0.5 mg; if you’re a bigger person, or your attacks are unusually bad, or that doesn’t work, you can go up to 1.0 mg. If it takes too long to work, you can crush it into a powder and let it sit under your tongue until it gets absorbed by the blood vessels there, which will make it work faster than forcing it to go through your stomach and digestive tract. The usual dose of Vistaril is 25 – 50 mg, same story.
The most common maintenance treatment is antidepressants. For some reason, almost all antidepressants (except maybe Wellbutrin) treat panic attacks pretty much in proportion to how well they treat depression. As with depression, start with SSRIs. I’ve never had any panic attack patients need to go further than this, but in theory you would probably escalate to tricyclics or MAOIs if this didn’t work. Anxiolytics like buspirone and pregabalin should probably work too, but realistically SSRIs are really good for this and it rarely requires getting fancy.
You can pick whichever individual SSRI you would normally pick for depression, use the same dose as in depression, and expect it to take the same amount of time to work as depression. Strange, huh? My guess is this has something to do with SSRIs’ ability to blunt emotions breaking the negative feedback loops involved in panic disorder, but I don’t have a really clear understanding here.
4. What psychotherapy works for panic disorder?
Most people benefit from a course of cognitive-behavioral therapy centered on exposure.
The cognitive-behavioral therapy teaches you things about panic attacks. You learn that they can’t actually hurt you. You learn some coping strategies for what to do when you’re having them (eg breathing exercises). You learn to recognize negative thoughts (“I’m never going to be able to deal with this”) and transform them into positive ones (“I’m gradually working on learning how to deal with this”).
Once the CBT has made you more able to deal with panic attacks, you start the exposure therapy, which is intended to make you stop having them. Exposure therapy works especially well if your panic attacks have a clear trigger, like socializing or going outside. You and your therapist work together to make an “exposure ladder”, starting with easier things and moving to harder things. For example, if someone had panic attacks upon being out in big crowds, their ladder might look like:
1. Go outside the house into my front yard
2. Go on a walk to the corner store and buy milk
3. Go to the big local supermarket and do a grocery run late at night when nobody’s there
4. Go to the big local supermarket and do a grocery run at midday when everybody’s there
5. Go to the shopping district and browse some of the stores
6. Go to a sports game at a packed stadium
The idea is: first you go outside the house into your front yard. You repeat this every day. Probably this will make you uncomfortable but not cause a panic attack. Or maybe it will make you have a mild panic attack, but you will use the techniques you learned in cognitive-behavioral therapy to not let it get to you as much. Your brain will learn that going into the front yard isn’t that scary, and after a while it will stop making you so uncomfortable. You will have “unlearned” a little bit of your fear of open places.
After going into your front yard barely causes any distress at all, you move on to the next phase, going on a walk to the corner store and buying milk. Again, this will make you uncomfortable – but given the unlearning you did in the last step, this is probably a small enough step forward that it won’t cause a panic attack either. You repeat this every day and after a while it stops making you so uncomfortable, and then you move on to the next step, and so on.
Some people make this work without a therapist’s help. This is great, but you want to be careful, because if you do the exposure too quickly, or without having done the part where you learn how to cope with panic attacks, then you can have very bad panic attacks during the exposure and accidentally make your brain further-learn that things are scary, instead of unlearning it. If you’re going to go this route, I strongly recommend David Burns’ book When Panic Attacks, which is a great guide to everything you need to know about panic disorder and how to plan an exposure therapy course for it.
Other psychotherapies might also work for panic disorder, but are less tested, and I know less about them.
5. What can I do when I’m having a panic attack?
If you’ve talked to your doctor and have a special medication for stopping panic attacks, like alprazolam or hydroxyzine, you may want to use that (see above for some considerations for why or why not).
If you’re trying to get through it without medications, different people will find different things are helpful. But here are some options you might want to try:
1. Do anything that causes strong bodily sensations other than the sensations of panic. Taking a very cold (or very hot) shower has worked for a lot of people. 
2. Experiment with what you can and can’t do while having an attack. Most people having a panic attack assume they are completely incapacitated, can’t think straight, some people don’t even think they can walk. David Burns makes these people do jumping jacks, complicated mental math problems, and whatever else they say they’re not capable of. I’ve talked to patients who say they’re lying in bed because they think they can’t stand up without falling over, and made them go on walks around their house, which they are perfectly capable of. During a panic attack, your body is lying to you. Call its bluff. This will make you less afraid, less incapacitated, and it’s part of the process of learning to reinterpret your panicky feelings and eventually defuse them. Just don’t do anything where you could potentially seriously hurt yourself (like driving a car). You would probably be completely capable of driving safely, but I wouldn’t want you to freak out and decide to give up in the middle of the highway.
3. Exercise is a combination of strong bodily sensations and experimenting with what you’re capable of doing; predictably, it can be pretty helpful.
4. Do breathing exercises. I recommend learning the exercise before a panic attack so you’re ready when one happens; this one is pretty good; if you’re into yoga, you can also try nadi shodhana breath. My guess is that the actual features of the breathing exercise you’re doing matter less than the fact that you’re breathing mindfully (plus a little placebo effect).
5. A friend of mine swears that eating honey, especially letting it sit on their tongue and the roof of their mouth, reliably aborts their panic attacks. I don’t know if this is a sub-example of “anything that causes strong bodily sensations”, and I’ve never heard of anyone else trying this. If you try it, let me know.
6. Anything else I should do?
I want to recommend a second time David Burns’ book When Panic Attacks. Because panic attacks involve a feedback loop that passes through your thoughts and emotions around having a panic attack, understanding what they are is half the battle. This book gives you a better understand and has more good advice for dealing with them.

Panic Disorder

Dr. Scott Siskind delves into the world of Body-Focused Repetitive Behaviors (BFRBs) such as hair-pulling and skin-picking, shedding light on their complex nature and potential treatments. Drawing connections to anxiety and OCD, this intriguing article explores the genetic and primitive brain factors that contribute to BFRBs. Dr. Siskind outlines various approaches to managing these behaviors, including treating underlying anxiety, implementing practical measures to prevent the behavior, engaging in psychotherapy, and considering medication options. Discover how these insights may offer relief and a deeper understanding of BFRBs' mysterious nature.

The short version: BFRBs like skin-picking and hair-pulling are probably distantly related to obsessive-compulsive disorder. There are no silver bullet treatments, but it can be helpful to treat associated anxiety or to restrict practical access to the relevant body part (either through clever hacks or various high-tech products). Any anxiety or OCD medication can be mildly effective against BFRBs, and the supplement n-acetylcysteine (start with 500 mg twice a day, titrate up after one month) seems especially promising.
The long version:
 
Contents 
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1. What are body-focused repetitive behaviors?

 
2. How can you treat BFRBs?

 
3. Where can I learn more about BFRBs?



1. What are body-focused repetitive behaviors?
Body-focused repetitive behaviors include compulsive hair-pulling, skin-picking, and nail-biting. Some people include compulsive lip-biting, cheek-biting, and joint-cracking. These come from the same place as the universal urge to pick at a scar, but for some people they can be constant, overwhelming, and disabling.
We don’t know exactly what’s going on here. We know the condition is partly genetic, because relatives of patients have 5-10x elevated risk of being patients themselves. We know that the condition is deeply rooted in primitive brain areas, because many different kinds of animals have BFRBs – monkeys pull their hair, birds pull their feathers, dogs compulsively lick their paws to the point of damaging them. And we know that anxiety is by far the most important risk factor; most people’s urges to pick or pull wax or wane with their anxiety levels.
The psychiatric establishment classifies BFRBs as an obessive-compulsive-spectrum disorder, along with OCD and hoarding, based on all of these tending to co-occur in the same people and families. But other researchers think they’re more closely related to “stereotypies” like when autistic people bang their heads or rock back and forth. And they may even have some relationship to the strange motor behaviors seen in people who overuse dopaminergic medications – for example, after abusing methamphetamine, some people will compulsively brush their hair, lick their nails, etc. At this point the whole condition is still kind of a mystery, even moreso than usual in psychiatry.
2. How can you treat BFRBs?
There are at least four treatment options for BFRBs, all of which can be pursued in parallel. First, treating the underlying anxiety. Second, taking pragmatic measures to prevent the behavior. Third, psychotherapy. Fourth, medication. Moving through them in order:
First, you can treat anxiety.
Almost all BFRBs get worse with underlying anxiety, and get better when the patient feels like their life is calm and stress-free. Often they get so much better that no other treatment is needed. We know much more about treating anxiety than we do about treating BFRBs, and it’s usually safer and has fewer side effects, so anything you can do to decrease anxiety is a first-line treatment here. Quitting your stressful job or breaking up with your abusive partner will be much better for you in the long run, in terms of BFRBs and everything else, then taking some exciting high-tech medication.
Second, you can take direct steps to prevent yourself from engaging in the behavior.
This gets complicated, because BFRB patients have very different experiences of how voluntary their behaviors are. Some people feel like they do their behaviors completely automatically, without thinking about it, and as soon as they notice the behavior they’re able to stop. Other people do it almost like an addiction, where they know what they’re doing but can’t stop.
If you’re more of the first type – you just don’t notice when you’re doing it – take steps to notice. My favorite such step is the HabitAware bracelet ($149). You put it on your dominant hand, and when your hand gets too close to the part of your body you’ve programmed in – eg your hair or your face – the bracelet vibrates and then you realize what you’re doing.
A few of my patients have gotten good results with fake nails – the same kind people use for fashion. These make it really hard to bite your nails or effectively pick at your skin; certainly it makes trying to do these things more noticeable. I’ve never used these and honestly I have no idea how they would interact with hair-pulling. You can also just get really bad-tasting nail polish. 
If you have problems with lip, tongue, or cheek biting, you can buy mouth guards. Something like this one should be fine. Here’s a paper talking more about how to make this solution work.
Finally, eliminating the thing you want to pick at may be easier than stopping yourself from picking. If you pick at your nails because they have snags or hangnails, you can use moisturizing cream to have fewer of those. The most common way to get a complete cure for acne-related skin-picking is to cure the acne; I realize this is easier said than done, but there are many more good acne medications than there are good BFRB medication. And if you’re really the sort of person who likes cutting Gordian knots, the most radical solution for trichotillomania is to either cut your hair so short that you can’t pull it effectively, or shave your hair entirely and buy a wig. This obviously isn’t the right solution for everyone, but the people who really need it really need it.
If you can’t eliminate the target body features, and seeing them is a trigger for you, you can also consider just getting rid of mirrors.
Third, you can get psychotherapy.
The most commonly recommended therapy for BFRB is habit reversal training (abbreviated HRT, but be very careful using the abbreviation since it can also stand for the hormone replacement therapy used in gender change; people who just ask their doctor for “HRT” may end up getting more than they bargained for!). HRT focuses on raising awareness of the behavior, coming up with a competing response (eg when you get the urge to bite your nails, you clasp your hands together in a prayer-like position in front of you instead), and getting social support for these things. It works about as well as anything does for this condition, ie not great.
Fourth, you can use medication. 
I recommend this as a last-line option, because medication doesn’t work great for these kinds of conditions. Still, there are some possibilities.
Studies disagree over whether SSRI antidepressants work for BFRBs. I assume they work a little, because they work a little for anxiety, and anything that decreases anxiety will also decrease BFRBs.
Some studies suggest that clomipramine, an older antidepressant, works best of all. This is very plausible, because it increases serotonin levels more than SSRIs, and probably works better than SSRIs for anxiety – and, again, anything that decreases anxiety will also decrease BFRBs.
Some studies show that antipsychotics help with BFRBs. This is also very plausible, because antipsychotics are sedative, are anxiolytic, and generally decrease all behaviors. I’m agnostic as to whether they have any special anti-BFRB potency beyond this. It’s not completely implausible that they do – remember that methamphetamine abuse can cause BFRB-like behaviors, methamphetamine increases dopamine – and antipsychotics block dopamine – so they might at least be targeting the right system. Still, as usual antipsychotics should be your last-line treatment only for when you are very desperate.
Naltrexone is an opioid antagonist that seems to help with many addictive and compulsive behaviors. Some people speculate that it might help with BFRBs because BFRBs involve opiates in some way – maybe pulling your hair or picking your skin causes pain which releases endorphins which make it addicting. I find this theory a little implausible, but some small studies have given it a little support, especially in people who have a personal or family history of opioid or other addiction. If that’s you, maybe this is worth a try.
Anecdotally, many people have stories of totally random drugs being magic bullets that completely stop their BFRBs. I’ve seen people who swear by bupropion or valproate – neither of which has any business being on a list like this – and say nothing else has worked for them. I think this is probably related to anxiety. Any medication that you need will make your life better and make you less anxious, and being less anxious will help BFRBs.
N-acetylcysteine is an over-the-counter supplement you can buy at Whole Foods or online (eg here). This is the only substance I can recommend for BFRBs without at least a little bit of embarrassment. It works in studies, has few side effects, and seems to be genuinely addressing the root problem instead of decreasing anxiety or behaviors in general or something like that. See eg this article. If you want to use the same dosing protocol as in the most successful studies, take 500 mg twice a day (total 1000 mg/day) for a month, then 1000 mg twice a day (total 2000 mg) for another month, then go up to 1500 mg twice a day (3000 mg a day) after that. This will be much more than whatever vitamin company sold you the NAC recommends, and might involve taking six large pills a day, but that’s the right way to take it according to the studies. If you don’t feel any better after three months, give up and try something else. Ask your doctor before starting NAC, especially if you take anything else or have any co-occuring health problems. You may want to avoid drinking large amounts of alcohol when on NAC.
3. Where can I learn more about BFRBs?
Try the TLC Foundation For Body-Focused Repetitive Behaviors website.

Body-Focused Repetitive Behaviors

Dr. Scott Siskind dives into the world of supplements, exploring their similarities to medications and the importance of understanding their potential effects. He demystifies the supplement industry and provides insights on how to find the right supplements for your individual needs. Learn about the differences between various extracts of the same supplement and gain guidance on supplements for mental health conditions such as anxiety and depression. Discover the intricacies of the supplement and medication distinction, and unravel the truth behind the supplement industry's approach to FDA regulations.

The short version: Supplements are purportedly-bioactive chemicals that haven’t been formally approved as medications by the FDA. They aren’t ontologically different from medications, and sometimes they’ll have significant amounts of evidence supporting them, but they are less-thoroughly-tested and require more care. Because everyone has different neurochemistry, different supplements will work for different people. I sometimes recommend l-theanine, silexan, and Zembrin for anxiety, and Zembrin, 5-HTP, and SAM-e for depression.
The long version:
 
Contents 
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1. What’s the difference between supplements and prescription drugs?

 
2. What is the difference between different extracts of the same supplement?

 
3. How do I know which supplement is right for me?

 
4. What are the best supplements to try for my condition?

 
5. How can I learn more about supplements for mental health?



1. What’s the difference between supplements and prescription drugs?
Some people place moral value on the supplement/medication distinction. Either supplements are “all-natural” and drugs are “artificial poisons”, or plant-derived supplements are “woo” and drugs are “real medicine”. I don’t think either of these views stands up to serious scrutiny. Supplements and drugs are both chemicals. In one case, the chemical usually (but not always) comes from a plant; in the other, it usually (but not always) comes from a factory.
Here are two chemical structures. One is 5-HTP, a naturally-occurring supplement you can buy at your local Whole Foods. The other is fluoxetine, the active ingredient in Prozac. Can you tell by looking at them which is which? Which is “natural” and which is “artificial”? Which is for kooky hippies, and which is for serious scientifically-minded adults?

The supplement/drug distinction is best thought of as dividing two legal routes by which a chemical becomes part of the health care industry. In the first route, a drug company decides it looks interesting, spends billions of dollars testing it and convincing the FDA to approve it. In the second route, someone who is not a drug company decides it looks interesting, spends fifty cents designing a cool-looking bottle to put it in, and markets it as a supplement.
Most chemicals that take the first route tend to be novel – that is, some drug company just invented them. Why? Because if they already existed, the drug company would have a harder time patenting them, and wouldn’t be able to make as much money off selling them. So most plant-based and natural compounds can’t make it through the first route, although there are some complicated exceptions.
Most chemicals that take the second route tend to be natural – you can’t legally market something as a supplement unless it’s found in nature. I think this was originally intended because politicians thought it was fair to let people sell garlic or turmeric or whatever without FDA approval, but didn’t want to give the same guarantees about artificial chemicals. But supplement companies have gotten pretty creative – it turns out lots of things are found in nature somewhere, and once you find it in nature you are free to use a factory to actually manufacture it. Some supplement companies skirt the law and sell interesting health-related chemicals that aren’t found in nature, and sometimes the FDA turns a blind eye to this.
The advantages of the drug route are that the FDA is pretty strict and requires a lot of studies, so most things that get approved as drugs are safe and effective. The disadvantages of this route are that it costs billions of dollars to get anything through it. Drug companies will only ever submit a few chemicals to the FDA – ones which are new and unique enough to be patentable, carefully-studied enough that approval is likely, and popular enough that they can make a lot of money off of them.
The advantages of the supplement route are that the barriers to entry are so low that any chemical that could be a supplement probably is. There are only a few classes of prescription anxiety drugs, and they mostly affect the serotonin system. But there are dozens of different anti-anxiety supplements, which work through all sorts of fascinating and exotic mechanisms that no currently-existing drug matches. Lemon balm inhibits GABA transaminase, which is a really exciting mechanism of action for an anxiolytic. L-theanine probably antagonizes glutamate receptors directly! They are much cheaper than drugs, and you don’t need to have good insurance and see a doctor once a month and go to the pharmacy every time you want to refill them. 
On the other hand, most of them probably don’t work, and a few of them might kill you.
This isn’t to say that “drugs are evidence-based but supplements aren’t”. Some supplements have dozens of studies looking at them – this meta-analysis alone references 27 different studies of St. John’s wort (for comparison, there are only four studies of the FDA-approved prescription drug Spravato). On the one hand, the FDA does have pretty strict criteria for its studies and they’re often better than the studies some random person does of a supplement. On the other, studies for the FDA are usually done by a pharmaceutical company doing everything it can to bias results in their own favor. So I think it’s fair to say that it’s a good rule-of-thumb that drugs are usually backed by more evidence than supplements. But it’s not a hard-and-fast law of nature, and you actually have to look at the studies before forming strong opinions.
There are definitely real differences between drugs and supplements. But the differences aren’t fundamental. They’re downstream of the economic incentives that caused a chemical to get classified in one bin rather than the other. Whether or not you would be best served by a supplement or medication depends on your situation. I usually start with real drugs, just because I think they’re usually stronger and have more evidence behind them. But this is a relative distinction, not an absolute one. My first choice for treating anxiety would usually be an SSRI. But if that doesn’t work, my second choice might be silexan, a supplement derived from lavender. If that doesn’t work, my third choice might be pregabalin, a drug sold by Pfizer as Lyrica. Why? Because (I think) the risks/benefits/evidence calculation favors SSRIs over silexan and silexan over pregabalin. Based on the needs of a particular patient I might change this order around or add some other things into it. The fact that SSRIs and pregabalin are drugs and silexan is a supplement matters only insofar as it means that the studies supporting SSRIs and pregabalin are marginally better quality – and the studies for silexan are quickly catching up.
(to rub in how arbitrary all of this is: silexan is sold as a prescription medication in Germany. In the US, because of our slightly different laws around what sorts of things should be drugs vs. supplements, it’s sold over the counter as a supplement.)
If you don’t have insurance, or otherwise find it hard to manage the demands of doctors and pharmacies, that might be another reason for you to prefer supplements over prescription medications.
2. What is the difference between different extracts of the same supplement?
Some supplements come from plants. You don’t want to eat a whole plant. And if they just ground up the plant and put the powder in a capsule, you would end up eating a lot of ground-up stems and leaves and bugs and barely any of the chemicals you want. A coffee plant ground into a powder and encapsulated would have so little caffeine you’d have to take a few hundred capsules just to feel a mild buzz. So part of the job of a supplement company is to find a way to process the plant in order to extract the chemical you want.
But a lot of the time we don’t know which chemical we want, or there are different ways of getting the chemical, or we want more than one chemical, or different people might want different chemicals. So different researchers or supplement companies will process the plant in different ways, and get an end result with different amounts of different chemicals in them. These end results are called “extracts”.
So for example, ashwagandha is an Indian herb sometimes used to treat anxiety. One of the best-known ashwagandha extracts, KSM-66, starts with the roots (but not leaves) of the ashwagandha plant, treats them with milk to leach out certain chemicals, and ends up with a “full-spectrum” extract that contains most of the chemicals in the original plant matter. Sensoril, a competing ashwagandha extract, starts with both leaves and roots, treats them with water to leach out certain other chemicals, then standardizes the results to have consistent levels of a class of chemicals called withanolides. Even though both extracts start with the same plant, they end up being chemically pretty different. Although there haven’t been any studies, the conventional wisdom among users is that KSM-66 is more stimulating, and Sensoril is more calming.
Some supplements – like melatonin or magnesium – don’t involve any plant matter, and so none of this applies to them. Other supplements do involve plant matter, and when you’re using these you have to be careful to use a reliable extract. One good rule of thumb is to find the studies that convinced you that this supplement might be useful in the first place, and see what extract they used. Often there’s a “gold standard” extract that all the studies are done on, and your safest course is to find a supplement company that sells that extract. This can sometimes require a little bit of detective work.
3. How do I know which supplement is right for me?
Even more than with medications, different supplements work for different people.
Cynics would say this is because supplements are placebo, or get credit when people recover on their own – and if this happens randomly, then it will be pretty random which supplement you’re on when that happens. There’s some truth to this.
But on the broader scale, this is little different than what happens with regular medication. Only about a third of people improve on any given antidepressant. Some people will do very well on SSRIs and have no response to bupropion; other people will do very well on bupropion and have no response to SSRIs. Everyone’s biochemistry is different, and apparently similar conditions (eg depression) may have very different causes in different people. So for example, we know some depression is caused by thyroid hormone deficiency, and these cases respond very well to thyroid hormone; other cases are unrelated to the thyroid and don’t respond at all to thyroid hormone. We have less understanding of what underlying differences cause different response to SSRIs vs. bupropion, or one supplement vs. another – but probably these differences exist.
The only way to figure out which supplements work for you is trial and error. Try a supplement, see if it works, if it does then keep it, and otherwise move on.
This is very different than the advice for, eg, omega-3 supplementation for heart disease, where you don’t really know how much heart disease risk you have or how omega-3s are affecting it, and you take the supplement based on large studies that suggest it works in the general population. Psychiatric conditions are convenient in that you know whether you have them or not – you are the best expert about how depressed or anxious you are, or whether you’re getting better or worse. You take omega-3s or multivitamins because you have faith in the studies behind them. You should take mental health supplements because you have personal evidence that they’re working for you.
(that doesn’t mean the studies are useless; they should guide which supplements you think are most likely to work, and which ones you take first).
So treat every supplement you take as an experiment. Any experiment is better than nothing, but careful experiments are best of all. If you want to be careful change one thing at a time: don’t start a supplement at the same time you’re starting another supplement (or a new exercise routine, or a new job). Consider recording any subjective data (eg how you feel on a scale of 1-10) and objective data (eg how many panic attacks you have per week, how many hours of sleep you get per night) to see whether it changes before and after starting the supplement.
If you start a supplement and feel better, it could be because of the supplement – or it could be coincidence. You can certainly just accept that you’re feeling better and not change anything. But if you’re going to continue taking the supplement long-term, consider confirming your first impression by eg stopping the supplement and seeing if your problems come back, then restarting and seeing if they go away again.
4. What are the best supplements to try for my condition?
The following are my opinions only. These lists should be considered starting points for experiments: ie things that are most likely to work. You can’t skip the experimenting step. Many of these won’t work for you, but some might. 
You should not take any of these just on my recommendation. You should use my recommendation as a starting point to learn more about each of these substances, including the studies for and against, the potential risks, the potential interactions, and the correct dose. I’ve gotten you started with short commentary, and eventually I hope to have writeups about all of these which will give you the information you need to know. But until I do, please look into these more carefully before trying them.
A few of these are especially complicated or require some more advanced knowledge; I’ve marked these with letters instead of numbers and put them at the bottom outside the main sequence.
For anxiety, I would go:
1. L-theanine. Simple to use, cheap, fast, effective.
2. Silexan. Well-studied, effective.
3. Zembrin. Simple to use, cheap, effective, probably just an herbal SSRI.
4. Ashwagandha. Make sure you get a calming extract and take it regularly.
5. Bacopa. Make sure you get a calming extract, and expect some risk of being oversedated.
6. Magnesium. Make sure you get a non-laxative form. Dose will vary by person.
X. Selank. Russian intranasal peptide. Very effective. For especially knowledgeable users only.
Y. Kava. Polynesian psychoactive drink. Some formulations are much better than others. For especially knowledgeable users only.
For depression, I would go:
1. 5-HTP. Serotonin precursor, decent evidence. Don’t use with any other serotonergic or serotonin-affecting medication unless you know what you’re doing.
2. Zembrin. Simple to use, cheap, effective, probably just an herbal SSRI.
3. SAM-e. Folate cycle chemical. Some studies in support. Tends to cause nausea.
4. L-methylfolate. FDA approved prescription substance as “Deplin”, but also sold as a supplement.
5. Polygala tenuifolia. Weird Chinese herb, seems to have antidepressant effect through unclear route.
Other people’s lists of favorite supplements might look completely different; this territory is still mostly unexplored.
5. How can I learn more about supplements for mental health?
examine.com is a great site that will tell you a little about anything.
I’ve drawn some of my conclusions about supplements above from various small surveys of supplement users, including this one and this one.
Supplement-related communities, like r/supplements, r/nootropics, r/depressionregimens and Longecity include some incredibly well-informed researchers and experts in the field, and also some total garbage. Read at your own risk.

General Notes On Supplements

Discover the ancient South African herbal medication, Kanna, and its modern extract, Zembrin, designed to alleviate depression and anxiety. Although the exact pharmacology of Kanna remains a mystery, anecdotal evidence from enthusiasts supports its mood-enhancing effects. Scott Siskind, MD, dives into the history and traditional use of Kanna, shedding light on its various applications, from sedative to stimulant. Learn about the limited scientific research surrounding Zembrin and how it can potentially improve your well-being. If you're seeking relief from depression and anxiety, with no contra-indications, this thought-provoking article may offer valuable insights.

The short version: Kanna is a traditional South African herbal medication. Zembrin is an extract of kanna marketed for people with depression and anxiety. Kanna is probably an SSRI with additional PDE4 activity, though its pharmacology still isn’t exactly clear. If you’re depressed or anxious and have no contradindications, you might benefit from taking Zembrin 25 mg daily, which you can get here. 
The long version:
 
Contents 
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1. What’s the evidence that Zembrin works?

 
2. What is the pharmacology behind Zembrin?

 
3. How do I take Zembrin, and what should I expect?



1. What’s the evidence that Zembrin works?
A long history of traditional use, anecdotal evidence from users, and a tiny and unsatisfying handful of real studies.
The San (“Bushmen”) of South Africa have traditionally used kanna in various ways; depending on dose and preparation, it can be an anxiolytic, intoxicant, narcotic, stimulant, or sedative. An early European explorer wrote:
There is a root, gathered in the Hottentot Countries, called Kanna; which is in such Esteem among the Hottentots for its great vertues that they almost adore it…they look upon it as the [greatest] Chearer of the Spirits, and the [noblest] Restorative in the world. They will give [almost] any Thing in exchange for it, and will, any of ’em, run Twenty Miles upon an Errand, or perform a hard Day’s Work, for a very small Bit of it…
I have often seen the effects of Kanna upon Hottentots. They chew and retain it a [considerable] Time in their Mouths. But taking generally too much of it at a Time, it drowns ’em in Intoxications. They chew it not long, before their spirits [visibly] [rise], their Eyes brighten, their Faces take a jovial Air, and they [Sport] and wanton under a [thousand] gaieties of Imagination. But in the End it [Strips] ’em of their [Senses], and throws ’em into the [wildest] Deliria.
San (and some Europeans in South Africa) continue to use the plant more or less the same way up to the present. In the late 20th and early 21st century, Nektium Pharmaceuticals, working with locals and ethnobotanists, came out with Zembrin, the first standardized extract of kanna. I don’t have a great understanding of this process, except that (according to Nigel Gericke), the locals pointed out plants that were “tamer” and less likely to cause intoxication and weird drug-like effects, and the pharma company iterated until they had something that supposedly preserved the mood-lifting properties without the “wildest Deliria”.
Reports from Zembrin users are pretty positive. Anyone who looks into it comes across stories like “I started taking Zembrin last wek and I feel like it has already changed my life” or “Last week I began taking [Zembrin] and it’s been the most effective thing I’ve tried so far.” We need to be careful with these kinds of stories – thanks to the placebo effect everything has a few people who say it’s amazing – but Zembrin seems to produce more than its share. In 2020 I surveyed 852 users of mental health related supplements. Zembrin received the highest rating of 37 substances studied (although some complications in how the questions were asked make it hard for me to say this with certainty; I’ll link the survey once it’s published). 
There are several terrible studies that probably shouldn’t be treated as much more than anecdotal evidence. Among these are some studies by Japanese veterinarians with hilarious titles like Clinical application of South African tea on dementia dog, lots of case reports, and trials of safety where some people offhandedly mention it seems efficacious.
The only study I can really endorse is Effect of Zembrin® on Brain Electrical Activity in 60 Older Subjects after 6 Weeks of Daily Intake. A Prospective, Randomized, Double-Blind, Placebo-Controlled, 3-Armed Study in a Parallel Design. It does a placebo controlled trial on EEG results, and finds Zembrin produces EEG changes consistent with decreased anxiety and improved well being – but EEG findings are kind of easy to manipulate and not really trustworthy. However, the authors also gave subjects the HAM-A anxiety questionnaire before and after the study, and they found the group taking Zembrin improved significantly. In particular, the placebo group’s anxiety was 9.3, the Zembrin 25 mg group was 6.65, and the Zembrin 50 mg group was 6.37. The 50 mg group was barely inside the significance threshold (p = 0.03) and the 25 mg group barely outside of it, but realistically these numbers are very similar and probably justify the standard 25 mg dose.
I don’t know of any credible studies that explicitly show Zembrin does not work. If you know of any other useful Zembrin studies I should include here, please let me know.
Overall I admit the scientific evidence for Zembrin is relatively weak. I base my interest primarily off anecdotal reports, surveys of users, and its interesting pharmacology.
2. What is the pharmacology behind Zembrin?
The only really extensive look at this question suggests it is a dual serotonin reuptake inhibitor and PDE4 inhibitor. From Pharmacological actions of the South African medicinal and functional food plant Sceletium tortuosum and its principal alkaloids:
The extract was a potent blocker in 5-HT transporter binding assays (IC50 4.3 μg/ml) and had powerful inhibitory effects on phosphodiesterase 4 (PDE4) (IC50 8.5 μg/ml), but not other phosphodiesterases…The activity of the sceletium tortuosum extract on the 5-HT transporter and PDE4 may explain the clinical effects of preparations made from this plant.

A serotonin reuptake inhibitor is better known as an SSRI. If this study is correct, Zembrin works the same way as the most common class of antidepressants. This would be exciting, since Zembrin is off-patent, unregulated, and available without prescription.
The PDE4 inhibition is also exciting. PDE4 (phosphodiesterase 4) is an enzyme that plays a role in “second messengers”, chemicals that help receptors and different parts of a cell communicate with each other. PDE4 inhibitors had previously been identified as potentially promising antidepressants, but were dropped because the best-known example caused severe vomiting. In 2009 a team of researchers wrote a paper arguing that a dual SSRI/PDE4 inhibitor might be an especially powerful antidepressant, since PDE4 might be involved in compensating for the effects of SSRIs. If Zembrin were such an agent, that would be exciting and justify further study and use.
But although the pharmacology lines up with this, there are still some things that confuse me. The San used kanna to get high. There is no dose of SSRIs that will make you high, and I’ve never heard claims that PDE4 should be able to do this either. That suggests whatever was making the San high was unrelated to the SSRI/PDE4 properties of Zembrin. But is it just a coincidence that a drug that can be used to become euphoric and sedated also has antidepressant/anti-anxiety properties? I would expect that Zembrin would help treat depression and anxiety through some much weaker version of whatever was making the Khoi-San high. But I don’t think anyone has discovered this chemical yet. So I’m not sure what’s going on here.
Also, Zembrin seems to at least sometimes work immediately (SSRIs take a month) and have low rates of sexual side effects (SSRIs have a high rate). It’s possible that this is the PDE4 inhibition doing its job, but I’m not sure. This substance really does not “feel” SSRI-like (aside from its ability to treat depression and anxiety), so I’m not sure what to think here.
A few teams (1, 2) find scattered evidence that Zembrin has at least some effect on AMPA receptors, current relevance unclear.
3. How do I take Zembrin, and what should I expect?
If you’re currently dealing with depression or anxiety, are not bipolar, aren’t taking any medications that might interact with it (eg MAOIs, 5-HTP), and haven’t had previous bad reactions to SSRIs, taking Zembrin might be a reasonable choice.
Since Zembrin is already a proprietary extract, there’s no real difference between brands; I recommend one that’s inexpensive and doesn’t have too many other things mixed in. This Doctor’s Best Calm-Z supplement is fine.
The usual dose is 25 mg (one capsule) once a day. The one small study that investigated this didn’t find much advantage to going higher. Expect to feel effects sometime between a few days and a few weeks. There are few known side effects, but a theoretical risk of sexual side effects. There are no actual reports of withdrawal, and some anecdotal reports of people stopping long-term use without noticeable withdrawal, but in theory an SSRI-like discontinuation syndrome is possible.

Kanna / Zembrin

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