Ecstasy and psilocybin are shaking up psychiatry | Hacker News Reader

Ecstasy and psilocybin are shaking up psychiatry

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Not ecstasy and psilocybin, but a few years ago, I met a psychiatrist who had worked in the armed forces and then alongside a crisis SWAT team. After decades of seeing people hit rock bottom, he learned about ketamine therapy as a treatment for treatment-resistant depression. He described it to me, a psychedelic skeptic, as “the closest thing to a miracle drug that I’ve seen in my career.”

I’m not sure why, maybe because he seemed so much like the opposite of a “woo-woo” clinician, but the way he said it stuck with me. It has been fascinating to watch this space and the forward-thinking mental health companies that have been developing in this space.

Yes, ketamine can shut off depression like a light switch. That's really, really good for the population it works for. Of course, it can also cause psychosis.

As someone who nearly got murdered in their sleep by someone on one such ketamine-caused psychosis, I think that caution is warranted when prescribing it. Waking up to take a knife away from a crying person is not something I would recommend to others.

I've heard that there are studies on a metabolite of ketamine that's supposed to avoid the psycosis. I really hope that works so we get something this powerful without the downside.

Without making light of your experience, the behavior you witnessed is simply not possible to induce with the dosing range used by licensed ketamine treatment clinics. So yes, too much of a good thing is bad.

Ketamine clinics use doses much lower than that which is used for general anesthesia, and ketamine is used for general anesthesia all over the world on a daily basis. It's on the World Health Organization's Essential Medicines List and has a very safe 50+ year track record.

Also don't take powerful drugs off-label, with no monitoring or supervision, and expect them to do the same thing they would at controlled doses in a controlled environment.

I take doctor prescribed ketamine at home. It's incredibly safe and as a bonus it's much more comfortable to be laying in your own bed.

They let people take it at home now? We had to go into a clinic and they would monitor you the entire time. There was a couch to lay on, but not much in the way of amenities.

I've been taking lozenges for over 2 years now.

We didn't! It was a licensed esketamine trial under medical supervision for treatment-resistant depression.

> Without making light of your experience, the behavior you witnessed is simply not possible to induce with the dosing range used by licensed ketamine treatment clinics.

This was a licensed esketamine (s-ketamine) trial under medical supervision which, as you might imagine, left us excluded from the trial afterwards.

So I am going to have to disagree with you regarding whether or not that is possible at theraputic doses. I realize that it's normally safe, and I hope that it helps a lot of people.

> This was a licensed esketamine (s-ketamine) trial under medical supervision which, as you might imagine, left us excluded from the trial afterwards.

Do you feel like the experts are being disingenuous with the safety of this drug? I am not taking sides here - I am genuinely curious of your opinion since you seem to know something others don't.

I feel like this is probably a rare side-effect that people should know about. I hope it doesn't affect many people, and for those it does affect, that the psychosis doesn't turn out like this.

Could you link the trial or any data about it? Genuinely curious.

I don't know specifically which trial it was, but you can google for esketamine trials because that's their brand name for s-ketamine.

Good video on the difference between infusions and nasal, and s vs r isomers. https://www.youtube.com/watch?v=ejjAszofgvA They are essentially different drugs and may explain the reaction.

> the behavior you witnessed is simply not possible to induce with the dosing range used by licensed ketamine treatment clinics

There's a growing trend of clinics prescribing take-home lozenges. Some of them are giving patients 30 or more lozenges at a time, with the expectation that they'll use them once or twice a week.

Of course, some patients take multiple doses at once. Browsing subreddits on the topic shows plenty of stories of people escalating their doses or asking for strategies to convince their doctors to prescribe more.

Unfortunately, I think it's going to get worse before it gets better. Too many unscrupulous doctors are realizing the profit potential for dispensing Ketamine prescriptions in exchange for $300, 20-minute telehealth visits.

That's terrifying. The trial we were in used esketamine dosed via inhalation. You could not take any of it home and the doctors controlled all doses.

I'd be suspicious of those who wanted more and more of the drug. It made her so dizzy and sick there's no way she'd want more.

I almost wonder if you can detect who is abusing it by how much they enjoy it...

Basically the premise of the mini-series The Night Of

Set and setting comes from Mindset and setting. Sounds like that person wasn't using K correctly (they were abusing it). I don't feel as if your anecdote applies to many others in a controlled setting.

You would be wrong about that, it was a licensed esketamine trial under strict medical supervision.

strict medical supervision is sometimes a terrifying experience. Set and setting matter but so does any drugs they are currently on. I would say that your experience is atypical.

As I understand it, the "K hole" was terrifying, the setting for taking this was a doctor's office that let you relax on a couch afterwards.

Gary Gulman talks a bit about the relief he got from it.

Unfortunately for him it was only short term relief, but it really did seem to work.

He’s doing well now, so maybe that short term relief helped in some way as part of everything else.

Are you saying he abandoned the therapy because of the short-term relief? Most people return to their depressed state when they stop taking their anti-depressants.

The doc told him he wouldn’t continue it because it wasn’t helping outside of the therapy session (and each session was quite expensive).

Did 12 sessions, after the first session I had instant relief. Even the urge to drink was completely gone. I should have gone back in for boosters but just let it slide, mostly due to the continued cost. About 3 months later I was back into a depressive state. I was able to get out of that one on my own but I don't think it would have been possible without the ketamine treatments.

It is hands down the most effective medicine to treat depression I have taken. The maintenance is the downside, however the minimal side effects are worth it.

Worked for me after I had become incredibly depressed while attempting to rescue my daughter from an abuse situation (I succeeded yay!). I went from having tunnel vision, hearing music as just noise, severe dissociation etc. to being just fine and normal two hours later.

Best bio-hack I’ve ever done.

I personally wouldn’t use it as a recreational drug often though as it does have some known side effects from habitual use and regular drug use is always a bad idea, yes folks that includes weed and alcohol.

Thank you for your story.

I just wanted to offer an alternative view on regular drug use. I vape marijuana every day. After college I became an alcoholic after having stayed totally sober until age 21. Binge drinking college parties left me and my friends binge drinking well after college. It was bad, though I never lost a job.

I’d tried marijuana several times and often felt overwhelmed with it. It would take me more than ten years to realize why those incidents happened - group pressure to take huge hits of marijuana left me feeling way too high. A deeply uncomfortable feeling.

But marijuana helped me quit alcohol. I do not consider it the healthiest option nor do I recommend to anyone that they consume marijuana. But I would push back that it is always a bad idea. For my health I only vape marijuana and I keep the doses very small. I know it may still lead to health problems and I hope some day I don’t feel the need to do it. But it seems to help. I’ve stopped for weeks at a time and it’s fine. But I seem to prefer having a bit of marijuana every day. And I really don’t think that’s bad for me personally. I’m a successful robotics engineer. I worked for two years at Google X robotics while consuming marijuana daily and they filed two patents for my work during that time. Since then I’ve gone off to co-found a farming robotics organization that is about to announce our open source farming robot that I designed and built pretty much all myself.

I think we should take a more open minded approach to drug use. Some people may find that certain drugs work for them. Certainly I am achieving my life goals while vaping marijuana daily. I don’t really think it’s best for me long term, but it seems to be what’s working for me now.

It’s not clear to me from your post what the upside was for daily marijuana use is. It sounds like it kept you from reaching for the bottle, which I’m supporting of; but, what does it provide for someone who is not an alcoholic?

Well you'll mostly have to take my word for it. But I think in general it helps with morning body pain, general mood, and some creativity. I'm well aware of other healthy choices I could be making to help with those things, but for whatever reason I find marijuana a convenient supplement. It is not the healthiest option but I don't consider it "bad" either.

I recently went through a similar experience.

It initially helped me to stop drinking. I pretty much swapped out alcohol for marijuana. Alcohol felt really bad for me physical, emotionally, and mentally. And marijuana doesn’t.

I found a lot of other benefits:

- unwind and integrate my brain. As an engineer my brain is constantly is “solve” mode, always thinking about problems at work or side projects. Marijuana stops that, my thoughts and brain feels much more integrated.

- easier to focus and be present with my kids. I wish that I could just sit and enjoy long periods of time with my kids, but my head is always uneasy, checking work, phone, thinking about problems. Marijuana dials that back and lets me be present and focused

- emotional introspection. I had some pretty shitty things happen to me in childhood. I’ve never really reflected on them. I’ve started to repeat some of the abusive behaviors that I experienced growing up. Marijuana has helped me to really introspect my emotions and be open to integrating that trauma

- helps relieve low level anxiety and depression, it’s uplifting. I eat low dosage edibles most nights and positive mood effects linger through the next day

- it’s just fun :$ it feels good and is recreational. Music sounds different, food tastes more intense

I never would have guessed It would be so positive for me. I smoked for a couple months In my late teens until it started making me paranoid. I never would have guessed It would provide me so much benefit. I certainly would never ever have guessed I would become a daily user in my later 30s AND it would significantly improve my quality of life

Wow, nearly the same experience here although my main aim was to alleviate the immense anxiety I faced for years. The various prescription drugs were not helping so I decided to self medicate and bought edibles when they became legal here. It was like a damn miracle. All my tension and irrational scares melted away. I just hope my use won't build up too much tolerance and the effects will last.

Are you saying that you can use one day and have a fresh engineer brain the next? In my experience the “veil” remains for days and takes close to a week to dissipate.

For about my first 3 months :) It’s starting to catch up with me already. I’m scaling back to weekends now to see if I can strike a balance. If not it’s been a huge quality of life improvement and I’d be more than happy with irregular recreational use :)

Would you consume edibles or smoke?? I just take edibles

You really nailed it as far as the reasons why I do it.

My brain is "on" ALL the time and it's hard for me to relax normally. Marijuana really helps with that.

The answer to that varies from person to person. It may provide nothing. Many people have tried it numerous times and don’t like how it makes them feel. You really just have to be the judge of that for yourself.

For me it helps slow down my brain a bit, quelling distracting thoughts and anxieties running through my head so I can focus a bit better. It’s also useful for unwinding and relaxing at the end of the day, and I find that my thoughts are a bit more creative and inventive, if a bit slower.

Set and setting are very important as well, usually it’s best at home or in other relaxed environments. Being high at work or in public is often a pretty terrible experience, for me at least.

I agree that it can help with focus. I learned to do engineering while consuming marijuana by working on personal projects in the evenings at home. I found that in the right setting and with the right dosage marijuana seems to help me achieve a "flow state" of focus. Of course, too much and you'll dash your short term memory and forget what you're working on. Its no silver bullet but I seem to have learned a lot about how to use it by now.

Are there potential lung issues with vaping that much? I.e. if you're going to do it daily, why not edibles? (If you're in a state that allows that.)

Somewhat related -- I used to drink a ton, and though I don't think I was an alcoholic, drinking was part of my life and was terrible for my mood and my weight. I'd get very drunk 2-3 times a week, and the other days I'd drink 3-4 IPAs after work, or get a six pack of really strong beer on the way home from work. Lots of drinking alone. One day I saw a coworker in the checkout line at a store after work, and all I was buying was a bottle of wine. I felt really ashamed, which is a huge red flag. Gave it up "for a month," which turned into two months, and now 6.5 years without any. I do vape/edibles/mints, but it has nowhere _near_ the allure that alcohol had, and I'll go 6 months without it, then a few days in a row, then another irregular pause, etc.

Still have dreams that I'm in some bar drinking, and in the dream I'll think, "I just drink one or two, then stop." It's so relieving waking up!

I can only imagine there are potential lung issues. I am also worried about hot vapors hitting the back of my throat, so one thing I have adapted is that I never turn up the temp of the vape to get the last few hits out. That helps.

Edibles would be better from a health perspective, but they provide a very different effect to vaping. I do have some edible tincture which I mostly only ever have when I'm very sick and playing video games all day. But I vape a pure sativa for it's feelings of wakefulness, and it is hard to find pure sativa edibles. They do exist though, and I think some day I may switch to them. But they take much longer to take effect and they last much longer. I think they also have different psychoactive effects, but that may be down to the different strains used in the edibles I have found.

I've been there with the drinking. Good on you for going 6.5 years! In my original story I left out some details. Marijuana helped me break my nightly binge drinking habit but I continued to drink recreationally for some years. However currently it has been 10 months since I have had any alcohol and I feel great. No interest in starting back up. The plan was to go at least a year but even when the pandemic ends and parties start up again (end of this year maybe) I might just continue to abstain. Alcohol has not been good for me. I am very happy to be away from it.

You can make your own sativa edibles if you can get sativa flower or hash. Honestly, its not that complicated and using full spectrum hash makes dosing simple.

Your narrative describes alcohol and cannabis usage, on the one hand, and work achievements on the other hand. I understand that you are using that latter as a way to establish the benefits of the former, or at least to show an absence of detrimental effect.

But can you can identify why you might be reaching for psychoactive substances in the first place? Did you experience depression, anxiety, or trauma that you have been troubled by and need to blank out?

You mentioned "group pressure", but that on its own doesn't seem pervasive enough to warrant a lifestyle. Do you have any ideas about why you want to consume psychoactive substances chronically? I'm not saying you have to have a reason, or that you have to be aware of one, or that you have to share it here. I'm just curious for more information as context for your anecdotal narrative.

Does anyone else in your family use psychoactive drugs as a lifestyle choice?

My family has a history of alcohol use. The group pressure was only in college though.

I think I experience a lot of stress. I always wanted to change the world growing up, and in the last ten years (I am 36 now) I really learned a lot about how awful some aspects of the world are. I am a deep empath so I have a hard time feeling okay when I know others are suffering. And with the US economy putting the poor at such a disadvantage, I feel pretty unhappy about that stuff all the time. I am in therapy and have been for 8 years, but I still just think a lot of stuff sucks and I can't really ignore that. Just think of the 2 million people in prison in the US. That system needs to change, and it's very easy to learn about that and struggle to not feel okay on the day to day because of that knowledge.

However, marijuana helps, and is part of my coping strategy. Along with time outdoors and a lot of creative endeavors.

I also really hate working for other people, so I am always trying to start startups or something. I don't like working a regular job. But this means that even though I have high value skills, I'm always experiencing some financial stress due to my desire for independence.

I am not trying to say my work accomplishments are caused by my marijuana use, but that one can use marijuana daily and still accomplish great things. I do well despite my marijuana use. Possibly because of it, but that would be harder to prove.

To me, marijuana seems fine. I don't want to do it forever. I am finally in a good place in my career where I am doing what I want. We still have to get through the "trough of disillusionment" on our project and I suspect there will be a lot of stress for some time, but hopefully we will get more traction and the stress will die down and the pandemic will end and I can find other ways to feel okay without vaping every day.

But for now, I'm okay with it.

Thanks for responding with that extra background information.

I feel like I have a lot in common with you - high empathy and awareness of systemic economic disadvantage. I have worked from home for decades in sw dev and pub, so I had the choice to smoke pot and I found it insulated me from what I didn't like about how society is organised. Like you, I found pot helped me to concentrate on work, and liberated me with creative endeavours, although managing it isn't so simple as flicking a switch by any means.

I don't have a family history of alcohol use - the opposite. But I ran into endless legal problems 6 years ago when a major customer stiffed us for a lot of money, then 3 lawyers in a row exploited us while I was off caring full time for a relative. All the money we were owed went to lawyers fees. I ended up drinking just to get away from this awful feeling of being subjugated to injustice by the legal system.

Then 2 years ago, we sorted out the legal problems and I no longer had to dwell on it. I stopped drinking for a while, but so much of my old life had disappeared, I was left with a void. I was happier, but I started drinking again, happily.

After another year I just wanted to stop, but that was difficult. It is hard to change habits, but not impossible. I read about this subject, and learned some techniques, but my experiences taught me about the role that underlying stressors can play in the need for habits, which is why I asked you the question which you kindly responded to.

I actually quit everything 7 months ago, and soon noticed how much I love the clarity. The sobriety is like a new drug. I really dig it.

I do wonder how much the ayahuasca I imbibed in South America a few years ago has contributed to my newfound ability to appreciate sobriety, and to move on from my bad feelings about exploitative lawyers and my economic losses. I don't have any bitterness left. It's all reframed, by looking from outside myself. My empathic abilities can be applied to the lawyers who cheated us in a way that enabled me to move on. I can just see them as actors who did what they did in a way that isn't personal to me, and let it go.

I had a longer reply but I was rate limited at the time.

I just wanted to say I am glad you had that ayahuasca. I am sure it contributed. I am not religious per se but I do believe that psychedelics can provide some guidance from beyond the self.

And I am glad you quit everything 7 months ago. I quit alcohol 11 months ago and it has been so good for me.

You may appreciate psilocybin. It isn't something that is addictive IMO. The last time I tried it I had a lot of deep and serious thoughts and while it was helpful, it was also an intense experience and not the kind of thing you'd want to repeat regularly. However from what I hear it is much less intense than ayahuasca.

Check out this podcast for more info: https://psychonauts.co.za/

Thank you very much for your story too. I'm actively locked in a functional alcoholic state and have been on-and-off for almost three decades. I find I can do a month sober but then I just get back on it afterwards. I've tried weed of various types and in nearly every form factor but have been unable to shake the potency of it (makes me super paranoid and that's not a manageable side effect for me).

However, when I do have it, it's impossible for me to drink so it's hard to look past it's effectiveness in trying to treat the root issue, alcoholism.

My question to you is, what's a small dose for you and how are you vaping it?

Thanks again, I am going back on the wagon today so this thread has been particular interesting.

I have two vaporizers. A Pax3 handheld vape and an Arizer desktop tower vape.

I am currently vaping Oakland store-bought "shake" weed which says it is 12.79% THC, so its on the low potency side. I use a pure sativa so it does not make me feel sluggish (an "indica" will provide "couch-lock" which is an all body effect that makes you want to sit down and not move - so I avoid those). Be warned that sativa is the type that can cause high anxiety. It varies by strain, and you can look up reviews of different strains on leafly.com or weedmaps.com

Both vape devices I own have a "bowl" for filling with ground flower. I tend to replace the bowl in each approximately once every three days right now with low potency flower. The dosage of drug falls off exponentially with the freshness of the bowl so the first hit on a newly packed bowl will be MUCH stronger than the last hit of the old bowl - something to be very careful with as you can get yourself trying to take a big draw off an old bowl, then you replace it, and suddenly if you're not careful to re-adjust your dosage it will be too much. So be careful there.

I basically have a small dose when I wake up with my morning coffee, then puff on my handheld vape during the day being careful to regulate so that I can still write software (and puffing a bit more if I have an hour of mechanical robot assembly to work on or something mindless). And then I have a bit more than those lower doses in the evening after I've gotten home and settled in.

I have roommates that vape using weed-concentrate on a torch-heated quartz crystal which is why I say my dose is small. I go through way less product than them. Because potency builds over time, even my conservative hits are probably larger than what you would want.

I highly recommend the vape for long term use. But a pipe or whatever you have on hand is fine to try for now. If you want to experiment with marijuana without having too much, here is what I would recommend:

Get some low potency hybrid (mixed indica sativa) weed. Look up reviews of the strain on leafly.com or weedmaps.com and make sure it is not one that will trigger paranoia.

Then, take the TEENYIEST amount you can imagine (the size of a pea or less), and smoke it. Then have no more the rest of the night. It is not necessary to combust the entire sample. Just take one hit. You will feel it, but I believe one small hit of low potency marijuana will not cause the anxiety effects I have known.

I suspect that would be okay for you. You may want to have a friend or loved one around to monitor you, although marijuana is relatively safe.

It is worth it to quit alcohol. In my original story I did not mention that I continued to drink recreationally for a long time, but marijuana did help me break my binge drinking. However for 2020 I decided to quit drinking for at least one year. That started in March 2020 and it has been 10 months without alcohol. I am VERY happy for it. I feel so much better. I do not want alcohol and I am not planning to try it when one year is up.

You can do this. My email is in my profile if you'd like to follow up with me in a month or two. I am curious if this helps you.

I wish you the best, and I love you.

Wow, thank you so much for that detailed information and kind support, really appreciate it!

I have an Arizer handheld but I think I've just been packing it too much, so I'll dial it way back and start small.

Really, thank you so much again :)

Marijuana may be the solution for you but I highly recommend checking out The Sinclair Method. There is an awesome book [1] about it and also a great Reddit community [2] for support.

Long story short, your brain is addicted to the endorphin rush that results after consuming alcohol. You can abstain for a period of time but due to the alcohol deprivation effect your urges to drink alcohol only increase as you abstain for longer periods of time (hence the AA mantra "Once an alcoholic, always an alcoholic.") The Sinclair Method gets around this by attacking your brains relationship with the alcohol endorphin rush. Long story short, you take an opioid antagonist (endorphin blocker) before you drink, typically Naltrexone or Nalmefene, which slowly trains your brain to no longer associate alcohol with pleasure. Check out the book for more information.

I was a heavy drinker and alcohol was destroying my life and after 4 months of TSM, I was drinking at a safe level and now one year later I am completely sober. I could continue to drink if I wanted to, with Naltrexone, but at this point I am ready to start a new life without alcohol and leave that all in the past. I believe 40% of TSM users choose to abstain completely and the other 60% choose to drink socially in moderation. It is up to you, which highlights the power of this system. Having complete control over my drinking after being out of control for years is nothing short of a miracle.

(You may also run into systems where you take Naltrexone on days that you don't consume alcohol. This is something different, and it may work for you, but my experience is with TSM which requires you only take Naltrexone before drinking)

[1] https://www.dropbox.com/s/60fs7gmvbyzs1kk/Cure%20for%20Alcoh... [2] https://www.reddit.com/r/Alcoholism_Medication/

Thanks for your information! I've tried so many different meds over the years and I honestly can't recall my reaction to Naltrexone but I know I've tried it and think it didn't jive with my SSRI medication.

Thanks so much though, I'm going back to the GP tomorrow so I'll read up on the links you provided and see if the GP can give me another run at it (or at least remind me why I didn't stick to it last time!)

Really appreciate the support, thanks again :)

How long were you in that state before the ketamine? That’s fascinating. Wondering if length of time in a state like that affects odds of permanent reversal.

The Center for Transformational Psychotherapy in SF leverages ketamine as part of their treatment, to good effect. Hopefully continued use and research will continue to mainstream its use (when appropriate).

Ketamine is a not uncommon thing in psych today. It is routinely prescribed. The problems are that it does seem for most people the effect is short lived (weeks) and psychosis is a thing (the poster below saying it’s never an issue even in pain setting is simply mistaken). The thing is that neither of these are uncommon problems for psych meds in general so ketamine shouldn’t be singled out for this, but it’s more complicated then some of the armchair docs here make it seem.

There is continuing research into regimens that might minimize the tachyphylaxis, but it’s an ongoing problem.

>psychosis is a thing

Looking through Google scholar + personal experience I don't see evidence that this is an issue for non-schizophrenics.

You need to look harder. Schizophrenia and psychotic features are relative contraindications for use of ketamine per APA guidelines. “It is unclear whether patients with depression that is not treatment- refractory or patients with other psychiatric illnesses are ap- propriate candidates for ketamine treatment, and extreme caution must be exercised in patients with psychotic or substance use disorders.”

Side-effects associated with ketamine use in depression: a systematic review, Short 2018.

To summarize: A review of 60 studies found dissociation and psychotomimetic effects >70 percent of the studies at varying rates. And note that the time courses of observation were variable. Furthermore most of these studies excluded participants with psychotic features or known psychotic disorder.

But for any provider considering ketamine this is literally top of the list in consideration of adverse effects.

This review doesn't say all that much. I just took another look at it and it merely reports what % of the studies mention those effects without effect sizes or anything of the sort.

Also they clump psychotomimetic and dissociation effects together which is really weird as ketamine is a dissociative. It's literally the highest number in their analysis (72%) because dissociation is to be expected from a dissociative.

The point with referring to a review article/meta is that you are free to look at the references themselves. Adverse effects secondary to dissociation can obviously be troublesome for some using in a professional clinical setting, which is what this is about..

Anyway, in medicine statements of the form “x never happens unless y” or it “only” happens in certain circumstance are always wrong. The data is not perfect but your implication that only schizophrenics experience adverse effects is not only an idiotic statement on its face you can easily find case reports refuting it.

I didn't say it never happens. Everything is correlated but if the risk is extremely small, as I believe it is here for non-shizophrenics then I don't consider it a concern. And others definitely experience dissociation for example, that's not something I am questioning.

Ketamine treatment for depression doesn’t require a psychedelic experience. Many clinics prefer to keep doses low enough to avoid full psychedelic experiences. Of course, some clinics blast patients with excessive doses and send them into full-blown psychedelic trips, but it’s definitely not necessary for the anti-depressant effect.

Ketamine’s effects on depression are almost certainly mediated by something other than any psychedelic effects. Ideally we’ll find a safer medication which accomplishes the same thing without disorienting the patient

Unfortunately, the effects of this therapy are rather short lived. There’s a growing industry of ketamine clinics that are happy to continue charging patients for endless ketamine infusions. Some offer outpatient prescriptions of ketamine. However, repeated treatment isn’t quite as effective as tolerance develops.

The best approach appears to be using ketamine as a way to kickstart more sustainable, long-term depression treatments, such as therapy programs.

There's a growing industry of therapy clinics that are happy to continue charging patients for endless sessions. Some offer anti-depressants and anti-psychotics. However, repeated treatment isn't quite as effective as the wrong mix of drugs are prescribed, the therapy re-enforces the trauma, and it is quite costly for patients to afford.

I've done both back then, those stuff really changed my life perspective in terms of depth.

Recreationally some of them can be misused (ketamine, extasy), but for the medically desperate I'm hella convinced these substances deserves more research.

I don't know. Every generalist doctor I have known got a alt phase aound 50. Homeopathiy, bach's flower, essential oils, etc. I chalk it up to "they have seen bad stuff and can't help some of their patients going through rough times and they look up for alternatives and settle for something for a few years".

Good to see the blanket anti-drug hysteria of the last century being slowly dismantled.

> Placebo controls pose another challenge because the drugs have such powerful effects.

This is fascinating and something I haven't considered before. Are there other example of major studies that have inherent difficulty forming a control group like this?

Relevant XKCD: https://xkcd.com/1462/

Equally related yet much less relevant XKCD: https://xkcd.com/790/

That suggests to me that Randall Munroe has never taken psychedelics.

Spiders and inability to scale things is one of the most common types of hallucination that is common to all paychedelics.

I found this fascinating as well. Sounds like a hard problem to solve - I'm skeptical and surprised that "niacin, which elicits a physical sensation — usually a flushing response in the skin" was effective as a placebo

I can't imagine it would be an effective placebo with any person who has ever had prior psychedelic experience, once enough time has passed. Perhaps in the pre-peak period where it's already kind of fuzzy when the effects start to kick in, but not anywhere near the peak

It's a challenge, but it's hardly a show-stopper.

Studies can use active placebo to make patients feel something dramatic. Some times they use drugs like Xanax which induce noticeable sedated states, for example.

Double-blind, placebo controlled studies are the gold standard, but not the only option. It's common to compare against another known-good treatment option. For example, you might structure the study such that one group receives 16 weeks of standard therapy, while the second group receives 16 weeks of the same therapy, but with the addition of of psychedelic sessions on weeks 8 and 12. If the psychedelics have a positive impact, you would expect greater divergence between the two groups after the psychedelic sessions.

Sadly, current studies don't actually point to a significant benefit from psychedelics when compared to standard therapy sessions. In the last study I viewed the used therapy with a few psychedelic sessions, it appeared that the vast majority of improvement came strictly from the therapy, before the psychedelics were even introduced. In fact, from the graph of patient improvement I couldn't tell if the psychedelics had any effect at all. The study basically showed that psychedelics didn't make therapy worse than normal, but that's about it.

Methyline Blue is tricky to test because it really does turn things super blue. Interestingly, this is sometimes used as a powerful placebo in other studies, since it sure does convince people they aren't taking a sugar pill! https://en.m.wikipedia.org/wiki/Methylene_blue#Placebo

Having had severe diagnosed depression and having also taken MDMA at parties and with friends, I see why it is, if not a miracle drug, then at least a powerful and potent tool. I credit it with much of my quality of life today.

Rant - it's not Ecstasy, it's MDMA. Ecstasy is a street drug. I wish these reporters would get their facts straight. Also, I did a guided therapeutic session two years ago and it was sublime. Top three experiences of my life. Transformative. This stuff needs to be legalized at least for prescription use, minimum.

Yeah the street drug often contains amphetamines or other stimulants. MDMA might be one ingredient, but often isn't.

“People get locked into disorders like depression because they develop this system of thinking which is efficient, but wrong,”

<-- I take some issue with the above statement and I'm very surprised to see it came from a doctor! I'm a neuroscience grad student and would like to do research on psychedelics in the future, therefore this article was an interesting read otherwise. Coincidentally I also suffer from a state of depression, and have been for years. Mostly I can do fine but some times I can't even get out of bed until the evening, and on many nights I wasn't convinced I'd live to see the next day.

The way the sentence above is presented, to me, feels like people suffer from depression just as a result of thinking "wrong". I'm sure your judgement is clouded by such a serious mental condition in some ways. But in others, I like to think that I with my depressive POV might have more realistic view points on some things than an unaffected person. I would hate to not even have this one tiny little advantage from all this, and that in fact I'm not "sadder but wiser" [than some]. Am I wrong?

There's been a fair bit of research on "depressive realism", the hypothesis that depressed people's view of reality is actually more accurate and it's "normal" people who have a system of thinking which is efficient, but wrong:

https://en.wikipedia.org/wiki/Depressive_realism

I think that this may be an example of the tension between what's accurate vs. what's adaptive. There are a number of other social phenomena - like lying, exaggeration, overconfidence, risk-taking, perceptual bias, etc. - where individuals espouse views that are wrong because being wrong is more effective (in the sense of better social status or reproductive success) than being correct. Depression is likely the inverse of that: depressed people see the world accurately, but all of the mechanisms biasing toward survival involve distorting our perception of the world.

YES. Thanks for saying this. I reflect on this a lot when I try to imagine how I should "expect" the society to tend toward some pseudo-stability... A related TED talk by Donald Hoffman has stuck with me: https://www.ted.com/talks/donald_hoffman_do_we_see_reality_a...

> Well, I hate to break it to you, but perception of reality goes extinct. In almost every simulation, organisms that see none of reality but are just tuned to fitness drive to extinction all the organisms that perceive reality as it is. So the bottom line is, evolution does not favor veridical, or accurate perceptions. Those perceptions of reality go extinct.

Written format: https://www.quantamagazine.org/the-evolutionary-argument-aga...

Interesting, but what does it mean? The example of the steak makes no sense (it's a steak, not "fitness") and what does it mean to be "tuned to fitness" instead of reality? If perception of reality goes extinct, how do you reach the steak?

The whole section makes no sense to me.

heh sorry, maybe it wasn't as strong a primer as I was recalling, since there's lots of noise around the message I was cherry-picking for my comment :)

This one's more to-the-point maybe: https://www.youtube.com/watch?v=WcgbLwn_yYE

It's basically saying at every level of existence and perception, actors that see fake versions of reality outcompete and drive to extinction actors that spend energy trying to see truth (and as a corollary, try to socialize truth). Shortcuts always win. Like not just one given level we might try to look at, like our mental heuristics, but at EVERY level.

At its core, it's basically saying "truth" is not energetically favoured in systems.

This gives me tons of pause for thought, in that I wonder how a truism like this might play out at the cultural level of organization, where evolution remains a force at play. I feel aware of the power of stories and lies to create simple narratives at all levels -- is this a manifestation of this sort of information energetics playing out? For e.g., the overton window being a constrained version of truth that [previously] created stability. Or the fact that democracy doesn't appear to actually function according to the folk theory we all tell ourselves, but maybe the simple (fake) story of democracy is what makes it work.[1] Or how we deceive about our own internal state in order to keep social homeostasis with others. Or that truth maybe doesn't have enough benefit to survive unless it has the cover of larger lies/deceptions to offset its penalty...? So what lies allowed the dominance of science to operate up til now, and how might we be shifting that balance within our new digital landscape?

I dunno, I have some background in this stuff, but haven't been in academia for a bit, so it's a bit armchairy :)

[1]: https://www.amazon.ca/Democracy-Realists-Elections-Responsiv...

I've watched the second video and it still makes no sense to me.

"if you have an organism that sees reality as it is, competing with an organism that sees none of reality but is just tuned to what's called the fitness in the environment"

The fitness in the environment? As I understand it, fitness is a property of the individuals, not of the environment. It's defined ex post as the reproductive success of an individual. What does being "tuned to fitness" mean? I imagine (but can only guess) it means something like "being served a pre-digested version of reality that maximises some signal-to-noise ratio". But that means that someone else is doing the job of actually parsing the relevant information in the environment before feeding it to an organism.

The second issue I have is with the concept of "reality". Is there even such a thing? Real is what, in some sense, reflects useful properties of the environment- and it's still an approximation. Is the steak real? Or are its proteins real? Or the atoms of which it is composed? Or the chemical bounds between them? Or the quarks? Or where it came from? Or its colour? Or its relation with our digestive system?

In the video he makes the example of a file: is it "real" that the file is an icon sitting in the middle of the screen? Well, for some uses it is. For others it's sitting somewhere in the filesystem. For other uses, it's a series of non-contiguous blocks. For others still, it's magnetic fields on a disc surface. For others, it's an abstract entity that can be printed on a sheet of paper or sent via email or encrypted. All these things are real, yet none really captures the ground truth of the thing, which is possibly unknowable.

Hm. Ok, these are good questions. I did biochemistry, where we kinda talked about "fitness" a lot -- I haven't unrolled it in awhile, so you've got me thinking. Let me try...

Fitness is a property of the relationship between an actor and the environment -- the human and the gazelle in the savanna. It's not a property of the gazelle or the human or the savanna. It's purely relational. One actor seeing fitness is it having (and seeing) connections with others that allow its structure to "persist". Persist to the next generation in biological evolution, and to the next tick of the simulation for thermodynamic evolution. But yeah, it's all about volatile structures persisting.

So for the sake of this thought experiment -- you could imagine a god-view that sees "reality" to some degree of resolution. For the sake of capping the distance down the stack our minds wander, your current understanding of the world could be the god view. From the point of view of human actors 1000 years ago, it essentially is. The point is, you know of more than can be perceived by the actors under observation (technically, the gazelle, the human, and even the geology of the savanna are structural "actors" undergoing [thermodynamic] evolution, but it's easier to just focus on the human).

As I understand, the idea that fitness outcompetes reality is that the view of the fitness relationship will always drive out the view of "reality", which is more complex. That the complexity of reality is unfavored and unstable to perceive. That when an actor unwraps the "next layer" of the god-view, it will entropically always fail to resemble the previously perceivable appearance, all the way down. And we can dig deeper and learn more truth, but it's perhaps not entropically favoured to try to fully operate according to that truth (e.g., a rationalist society without reductive belief systems). The white lie will be favoured. Those who distort will always be aligning themselves more with the universe than those who strive for truth. And to the extent truth seems to have won, it's perhaps only because some equilibrating distortion was balancing out the equations of the larger system.

Sorry that I'm giving this sort of interpretation. I'm certainly taking leaps beyond the source material here, and I recognize it might be very frustrating how I'm speaking about this if you're a certain sort of respectful concrete thinker. That's understandable, but I suppose not where I'm at right now -- untangling the threads I'm pulling on feels a bit overwhelming to me as well. So yes, you'd be fair to disregard if how I'm able to deliver right now doesn't fit your own models of the universe :)

At risk of sharing more than you care to dive into, I suspect the topics in these articles are informing how I process this: https://nautil.us/issue/9/time/life-is-a-braid-in-spacetime https://knowm.org/thermodynamic-computing/

Anyhow, be well! Sorry if I failed to answer satisfactorily, but I genuinely appreciated your great prompts!

Consider the 2x2 matrix and the two types of error in it:

* Optimistic think is correct in good environment

* Optimistic think is wrong in bad environment

* Pessimistic think is correct in bad environment

* Pessimistic think is wrong in good environment

An optimistic thinker being wrong in a bad environment will result in inability to expect bad events. In our modern world, he will probably be robbed of his wealth. Since he thinks optimistically, he will keep trying and succeed to some extent.

A pessimistic thinker being wrong in a good environment will chronically fail to take advantage of opportunities. While everybody else is fucking and getting rich, the pessimist is in paranoid survival mode afraid to do anything but hunker down for the worst, which never comes.

Which error is WORSE is determined on average by how good or bad the world is. If you think the world is more good over time, the pessimist error is worse. If you think the world is more bad over time, the optimist error is worse. Your views might depend on where in the world exactly you live, but I consider the world to have vastly and measurably improved, forever and so far, since we began our existence on this rock billions of years ago.

Therefore, I choose optimism. If I'm wrong and am robbed (which I've been!), it's still the correct play. Like when you play poker; you calculate the odds, make the play, and even if when the cards hit the table you see you could've won more with a different play, that doesn't matter, because you play the odds. The outcome of probability doesn't change the strategy!

> I would hate to not even have this one tiny little advantage from all this

How is what you describe an advantage? Based on what you've said it does not sound to me, a third party reader, that this advantage is bearing any fruit.

This is talking in the abstract of course. If one were in an oppressive authoritarian regime bent on murdering you, one would be both sad and right, but one should also be mad too. So there must exist correct yet sad understandings of the world. But surely if you see people in the exact same situation as you, and you think them fools for being happy. That sounds wrong? Are they missing an immediate danger which your sadness is allowing you to take advantage of or escape?

How can an advantage exist which does not lead to action but rather self-harming inaction?

I think the sentence you take issue with suffers from poor phrasing while being essentially correct. Its a maladaptive state, which makes it 'wrong' and being energy efficient makes it, well, efficient.

Related: See (hear) author Michael Pollan's 2018 Fresh Air interview on NPR about his experiments with mushrooms, LSD and other psychedelics while researching his book, "How to Change Your Mind."

https://www.npr.org/2019/05/24/726085011/reluctant-psychonau...

I find it entertaining that lsd and mushrooms is a no no in the US, while drugs like Ambien that often cause somnambulism are "safe" to treat sleep problems.

It's all regulatory capture, lobbying money from big pharma industrial complex - likely tied to the prison industrial complex who are happy to fill prisons, along with a few other complexes.

This actually does help. The problem I have is it all returns years later which is why some people have LSD once a year or shrooms once a year or whatever. I'd love to trial this in a clinical situation but it's gonna be a long time until we see that I imagine.

The Imperial College London trials looked at this. In the first trial, people were given 1 dose of psilocybin, and while some people recovered fully, many went back to being depressed after some months. In the second trial, they gave people 2 doses spaced a few weeks apart, and focused more on integration after the experience. They had much more success in sustained recovery with that. Here’s a podcast episode all about it if anyone’s interested (soundcloud link at the bottom of the page): https://www.mindmanifestpodcast.com/news/sureshmuthukumarasw...

I think I'm going to sign up for one of these, or just start trying things (I heard ketamine is also effective) in March.

I've had severe clinical depression on and off for 12 years now. I've had all the SSRIs, none worked. I've tried the SNRIs and they worked a bit 8 years ago, but aren't working at all now. I started lithium a week ago, that's not having much effect so far (dose should be reviewed next week). I think the latest term in the US is Major Mood Disorder.

Only around 30% of people with depression ever find an antidepressant that works for them. So for all the SSRIs, SNRIs, Tricyclics and other, the SUM effectiveness is 30%.

There's really very little left on the menu and I have no expectation it will work.

So, anyone got any experience with self treatment?

There are less known causes of depression, where medications won't help - for example, if I ask you did you ever have ear infections as a child and were any of them painful - if your answer is yes, then I'd direct you to a specific therapy and a book that explains how that can lead to blocks in development and a depressed nervous system.

Ayahuasca has helped me, MDMA as well, and a sound therapy I did in my early 20s dramatically shifted my life - as to what I'm referring to in my previous paragraph; prior to the sound therapy, which you can actually do a diagnostic audiogram to check for imbalances in hearing to confirm an issue, I would have been considered to have Aspergers - though never formally diagnosed, after the sound therapy I connected to emotion and my body again that I didn't know I was partially to fully disconnected/blocked from, which had an effect of hypersensitivities as well.

I’ve actually struggled a lot with depression and had many many painful ear infections as a child. Do you mind sharing that information on the book and therapy with me? Thanks!

The book is called "Hearing Equals Behaviour: Updated and Expanded" - can be found on Amazon - and the sound therapy is called Berard AIT or Auditory Integration Training; unfortunately there are people who claim to offer it, or have "at home" sessions they'll sell you where you rent equipment - however it's not the same high-end equipment that should be used, so "buyer beware." There are other sound therapies on the market that are reaching mainstream via well-written books, however the actual products they released don't seem to actually follow the AIT protocol and logically they shouldn't have anywhere near the same level of efficacy due to a few factors. I do know of a gentle old man in Montreal, Quebec, who was trained directly by Dr. Berard.

Thanks. I didn't really have any ear infections as a child. It's useful for me to know there are still things to try that worked for others.

Painful ear infections is one hypothetical source of disruption to the nervous system, it's possible, probably, that other extremely painful experiences during childhood - when there's rapid nervous system development - could also impact/block development - cause development delays or reduction in capability or hyper/hypo-sensitivities. But yes, it can be comforting to know there are more options out there to explore.

I'm in the same boat as I went through multiple antidepressants with nothing to show for taking them over the last few years.

The way I turned it around was self medication with microdosing THC. Not sure where you are but where I live weed edibles are legal and I can ensure that I always take the same dose. Depending on how I feel I consume 2.5 mg of THC every other day and occasionally do a weekend blast with 10mg. Since I do that no more than once per week I can still get high on mere as little as 7.5mg and it gives me a mood boost for a couple of days and if I hit the funk I'll microdose with 2.5mg once per day. Been doing this for a few months and it's working like a charm. I hope I don't build up tolerance and lose the effect over time.

I tried like 8 antidepressants and never found one that helped me. I also tried psychedelics and they didn't help me, though the dose probably wasn't high enough.

What helped was intensive daily group therapy and behavioural modifications, as well as becoming more social.

Depression has many causes. Good luck finding yours.

Thanks, I am glad you seem on the right path!

Fostering PLURalism? https://news.ycombinator.com/item?id=25963589

I thought the infographic of # trials per year is really interesting - amazing that in January 2021 there have been 12 trials, when there were 11 in 2019 and 17 in 2020

>"He explained that he would have on hand a drug that could neutralize the hallucinogen, if necessary."

How is right now the first time I have heard of this?

Because it doesn’t exist.

What they really mean when they say something like this is a high dose benzodiazepine.

They might be referring to an antipsychotic like olanzapine https://pubmed.ncbi.nlm.nih.gov/26216558/

This echoes the popular wisdom that benzos can only mollify hallucinations to make them bearable, and then force a black-out at higher dosage. Antipsychotics (like Seroquel & Olanzapine) on the other hand make the visuals and 'shadow people' (hallucinations resulting from lack of sleep) disappear, forcefully flinging people back to a semblance of reality, and then to uncomfortable sleep.

Maps.org founder Rick Doblin's recommendation if someone is having a bad experience with Ayahuasca [or other psychedelic] is to give them a half therapeutic dose of MDMA; therapeutic dose is 100-125mg.

A veteran of the 60's here. Silly-cybin was definitely the hallucinogen of choice. Nary a bad time and days upon days of sweetness and light afterwards. I can readily understand how it might be efficacious for depression. LSD however, normally left you feeling like your dog had died. And ecstacy, at least outside of some secluded lab, didn't exist on the street...

I’m torn on this.

On one hand I see the value in helping people who are sick, which is clearly a good.

On the other hand I’ve seen how casually antidepressants can be consumed and seen them offered in social contexts and can’t help but suspect that pervasive mind-altering drugs could have a negative effect on society.

Reminds me very much of Brave New Worlds Soma

The Psychedelics ETF PSYK hit the Canadian market the day this was published. Nice timing.

I just picked up some psilocybin and I’m very curious to try it got the first time. My PTSD compounds my depression and fuels my anxiety. Very interested to see where this research goes.

Best of luck stranger! Perhaps explore starting with a microdose see how you feel on that before scaling up.

More rediscovery of avant-garde technology and ideas from the 1960s.

best thing ever for my chronic depression was a hit of E at a furry con, it basically kicked me out of a loop I'd been in for years and I've never been back in it since.

What a unique experience, and quite good that it had that effect! What was that like?

I spent all night wandering around the hotel with a couple of friends who I would later end up in a relationship with, babbling about some deep deep holes in my brain. Several times I said that I felt wonderful and amazing, and that I was not allowed to go looking for this stuff again for at least a year, as I could see how it could get addictive.

This was something like fifteen years ago and I still haven’t had any urge to hunt down more. If I need it badly enough I figure it will show up in my life again.

(Also it was at a furry con, which I guess is kind of a weird and magical space for most people; it was far from my first one, and there’s a strong component of work to them for me as I’m an artist who spends most of them hanging out behind a table drawing stuff!)

I love these they, basically turn into: "when I was absolutely ripped on [blank] I discovered I could fly, am genius, nobel prize when" gold

EDIT: breaking news, Crack cocaine discovered to hold the secrets of the universe, says man on crack cocaine.

Your argument appears to be that people under the influence of a drug aren't able to accurately judge its positive benefits due to being intoxicated. But that doesn't really apply if a person is reflecting on an event from years prior, does it? A lot of the responses here are about a drug having a long-lasting effect on their depression, for example, which doesn't seem to fit with your theory.

Trauma causes your mind/body to bury its sensitive and vulnerable parts under a survival cocoon - metaphorically, a way of thinking that helps you cope.

Psychoactives like MDMA, LSD, psilocybin, ketamine, and others temporarily confuse and override your normal mode of thinking, revealing and releasing buried truths.

For me personally I was surprised that such strong emotions of love and empathy could even exist, and I vowed to tap into that channel which the drug unlocked after its effects had waned. I can still, years later, activate those emotions on command by consciously choosing to do so.

I had a similar experience. I used to turn my nose up at recreational drug use, because I thought of it as a purely pleasure-seeking activity. One day, I took some MDMA out of curiosity, and found that within a few hours I had a strong sense of empathy for everyone else in the room. It amazed me that it was even possible to feel that way -- I actually wanted to interact with people rather than shy away from them. It left a strong impression on me, and made me wonder whether some people naturally walk around feeling that way by default.

Just wait until they start unlocking Ayahuasca en masse...

https://archive.is/1IkV3

Will be interesting when we begin to simulate these effects in artificial neural networks.

That reminds me of this

https://slatestarcodex.com/2019/05/09/is-there-a-case-for-sk...

Which tries to point out almost all treatments work and don't work and almost all papers that claim to do are by the true believers of the treatment.

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