5 ms·

As a physician with a practice in the realm of behavioral health it's been fascinating to witness the development of approaches to treatment-resistant depressio

As a physician with a practice in the realm of behavioral health it's been fascinating to witness the development of approaches to treatment-resistant depression using hallucinogenic agents. First out of the gate was ketamine (now on the market as esketamine), and currently psilocybin is being studied. It's showing promising results, however, the details re: dosing and adverse effects are still being worked out. It's an inescapable fact: ALL drugs produce side effects (at least in some recipients). Who will or won't tolerate a given drug is mostly hard to predict beyond the overall odds. Everyone in my field has seen individuals who have experienced serious harm due to use of hallucinogens including psilocybin. IMO using this class of drugs shouldn't be considered trivial. Sure, a lot of people have taken such "illicit" drugs without lasting problems, but response is a stochastic function. Odds of harm are no doubt small but as use spreads to a larger pool odds are adverse reactions will emerge. Of course people with serious depression already have major brain dysfunction and likely vulnerable to exacerbated adverse effects. Compared to normal functioning there's sharply decreased room for error. In medicine the primary rule is "above all do no harm". Absent sufficient data backing particular practices, choosing to step into new territory requires moving forward with great caution and care.

cersei 5y ago
"Of course people with serious depression already have major brain dysfunction and likely vulnerable to exacerbated adverse effects. Compared to normal functioning there's sharply decreased room for error." Is there actual evidence showing that depressed individuals are more likely to suffer adverse effects?
ProjectArcturis 5y ago
Yes, fascinating to watch, but as usual the hype outpaces the science. Two major issues not discussed in the article: 1. How do you do a placebo-controlled trial? All subjects will know the difference between psilocybin and placebo. And there are often huge placebo effects in depression trials. 2. No one has done a controlled trial with more than one dose. The best RCT so far, done by Compass, only followed patients up for 12 weeks. By that time there was still a numerical difference between drug and placebo, but it was narrowing and no longer significant. Extrapolating from the available data, the drug and placebo groups would have converged after 6 months. So what does that look like for a treatment? Do you have people trip every 3-6 months? How do you structure a Phase 3 trial to test the efficacy of, say, the 4th dose?
- username923409 5y ago
  About 1.: It's actually not so easy to assume that hallucinogen-naive test subjects will know the difference between psilocybin and placebo. Knowing the effects of a hallucinogen (i.e. reading about them) and actually experiencing the effects are quite different. At least, this is something I found surprising after experiencing a hallucinogen (or any psychoactive drug besides caffeine) for the first time.
  - robbedpeter 5y ago
    For me, the experience gave me the realization that everything is a hallucination, that all of your every day experience and thoughts are constructs, and that knowledge becomes as fundamental and intimate as the sensation of breathing or touching. If you're paying attention on psychedelics, you realize that your skull is your very own Plato's cave. Going from caffeine and occasional marijuana to mushrooms was wild. You'd have a better chance of learning how to fly a helicopter from a book than understanding what psychedelics will feel like by reading or listening. Naive users might get fooled by a niacin flush or placebo, but once you've experienced it (and paid attention) there's no way you'll mistake the real thing. It also gives you the perspective needed to appreciate music like Shpongle and hippie intellectuals like McKenna and Watts. If you haven't experienced psychedelics, you're like a blind person being told about colors. You literally can't understand it until you live through it. Like orgasms or childbirth or religious ecstasy, some things transcend mere explanation. Psychedelics are great since they give you a shortcut right into the matrix, and you're confronted with the fact that you are indeed in a simulation, and that your existence in relation to the rest of the universe isn't nearly as distinct and cleanly delineated as you thought. The radical changes in personality stem from whatever neural machinery that governs openness to experience. I think it makes sense that the change makes people less depressed and anxious. You allow yourself to pay attention to other things, and it becomes easier to avoid fixating and catastrophizing everything wrong in your life.
  - ProjectArcturis 5y ago
    True, the psilocybin effects might be different than expected, but I think absolutely everyone could tell the difference between psilocybin and a sugar pill.
recuter 5y ago
Life itself is fatal. Nothing is without risk. I'm not a health professional but I think medicine for the mentally ill is clearly overprescribed and this seems to be mostly a US thing. Although sadly, it is spreading. Times past stepping into a therapists office you'd be sent to get zapped for being a gay man or a hysterical woman and prescribed all manner of questionable treatments from cigarettes to most recently opioids. I heard those things might be bad for you too. The advice "we don't have data you should do nothing" is essentially a no-op. Useless, but you're fulfilling your primary rule, fair enough. If the advice is "we don't have data on psychedelics, they have an unknown risk factor. But we do have data on this pill with a known factor, so you should take it instead".. well. We're all adults.
- jrapdx3 5y ago
  Yup, you're an adult, you make up your own mind. If you're in my office and I recommend a medication that you decide not to accept I'm not going to twist your arm to take it. I might take calculated risks and do things myself, but when there are unknown risks due to utter lack of knowledge, you're right I wouldn't advise it for others. In my role trustworthiness is everything, it simply is wrong to do things that violate patients' trust. So true I won't take unnecessary chances with their health and well-being. Not my job to defend conduct of others of decades ago. I could argue with your comment about "overprescribing", but really I see no point debating non-issues. Discussion only means something when based on facts, IOW it always comes down to specifics, not squishy generalities.
  - recuter 5y ago
    I don't know how one can reasonably weigh between a medicine with known risks (and plausibly unknown risks!) and the unknown risks of something like psychedelics, which are not yet understood at all but anecdotatlly appear to potentially have a very high reward/risk ratio. Shrooms is not cocaine, you can't OD on the stuff. That is not to say it can't cause other types of damage. Not prescribing anything at all might be the safest course of action. And here you also say that unlike the advice you give your patients you might decide differently when it comes to yourself. > Not my job to defend conduct of others of decades ago. I'm not saying this judgmentally, there doesn't seem to be an obvious way to reconcile all these things. Your predecessors clearly also meant the best and gave the most prudent advice they could at the time. This is something to factor into the risk profile. The most trust worthy thing to do is admit that there are limits to our knowledge. But I understand why you would hesitate to provide this asterisk with your advice as a lot of people will take it poorly and rush to webmd and homeopaths as a result.
alecst 5y ago
> It's showing promising results, however, the details re: dosing and adverse effects are still being worked out. I'm gonna let out a galaxy-level eye roll when the FDA comes out with a "prescription" psilocybin x mg/kg or whatever. People have been taking mushrooms since the stone ages. The standard that these drugs have to meet is just so freaking high compared to say, Ambien, or Xanax, or Zoloft, or Prozac, which are given to at-risk populations by default.

cersei 5y ago

"Of course people with serious depression already have major brain dysfunction and likely vulnerable to exacerbated adverse effects. Compared to normal functioning there's sharply decreased room for error." Is there actual evidence showing that depressed individuals are more likely to suffer adverse effects?

ProjectArcturis 5y ago

Yes, fascinating to watch, but as usual the hype outpaces the science. Two major issues not discussed in the article: 1. How do you do a placebo-controlled trial? All subjects will know the difference between psilocybin and placebo. And there are often huge placebo effects in depression trials. 2. No one has done a controlled trial with more than one dose. The best RCT so far, done by Compass, only followed patients up for 12 weeks. By that time there was still a numerical difference between drug and placebo, but it was narrowing and no longer significant. Extrapolating from the available data, the drug and placebo groups would have converged after 6 months. So what does that look like for a treatment? Do you have people trip every 3-6 months? How do you structure a Phase 3 trial to test the efficacy of, say, the 4th dose?

username923409 5y ago
About 1.: It's actually not so easy to assume that hallucinogen-naive test subjects will know the difference between psilocybin and placebo. Knowing the effects of a hallucinogen (i.e. reading about them) and actually experiencing the effects are quite different. At least, this is something I found surprising after experiencing a hallucinogen (or any psychoactive drug besides caffeine) for the first time.
- robbedpeter 5y ago
  For me, the experience gave me the realization that everything is a hallucination, that all of your every day experience and thoughts are constructs, and that knowledge becomes as fundamental and intimate as the sensation of breathing or touching. If you're paying attention on psychedelics, you realize that your skull is your very own Plato's cave. Going from caffeine and occasional marijuana to mushrooms was wild. You'd have a better chance of learning how to fly a helicopter from a book than understanding what psychedelics will feel like by reading or listening. Naive users might get fooled by a niacin flush or placebo, but once you've experienced it (and paid attention) there's no way you'll mistake the real thing. It also gives you the perspective needed to appreciate music like Shpongle and hippie intellectuals like McKenna and Watts. If you haven't experienced psychedelics, you're like a blind person being told about colors. You literally can't understand it until you live through it. Like orgasms or childbirth or religious ecstasy, some things transcend mere explanation. Psychedelics are great since they give you a shortcut right into the matrix, and you're confronted with the fact that you are indeed in a simulation, and that your existence in relation to the rest of the universe isn't nearly as distinct and cleanly delineated as you thought. The radical changes in personality stem from whatever neural machinery that governs openness to experience. I think it makes sense that the change makes people less depressed and anxious. You allow yourself to pay attention to other things, and it becomes easier to avoid fixating and catastrophizing everything wrong in your life.
- ProjectArcturis 5y ago
  True, the psilocybin effects might be different than expected, but I think absolutely everyone could tell the difference between psilocybin and a sugar pill.

recuter 5y ago

Life itself is fatal. Nothing is without risk. I'm not a health professional but I think medicine for the mentally ill is clearly overprescribed and this seems to be mostly a US thing. Although sadly, it is spreading. Times past stepping into a therapists office you'd be sent to get zapped for being a gay man or a hysterical woman and prescribed all manner of questionable treatments from cigarettes to most recently opioids. I heard those things might be bad for you too. The advice "we don't have data you should do nothing" is essentially a no-op. Useless, but you're fulfilling your primary rule, fair enough. If the advice is "we don't have data on psychedelics, they have an unknown risk factor. But we do have data on this pill with a known factor, so you should take it instead".. well. We're all adults.

jrapdx3 5y ago
Yup, you're an adult, you make up your own mind. If you're in my office and I recommend a medication that you decide not to accept I'm not going to twist your arm to take it. I might take calculated risks and do things myself, but when there are unknown risks due to utter lack of knowledge, you're right I wouldn't advise it for others. In my role trustworthiness is everything, it simply is wrong to do things that violate patients' trust. So true I won't take unnecessary chances with their health and well-being. Not my job to defend conduct of others of decades ago. I could argue with your comment about "overprescribing", but really I see no point debating non-issues. Discussion only means something when based on facts, IOW it always comes down to specifics, not squishy generalities.
- recuter 5y ago
  I don't know how one can reasonably weigh between a medicine with known risks (and plausibly unknown risks!) and the unknown risks of something like psychedelics, which are not yet understood at all but anecdotatlly appear to potentially have a very high reward/risk ratio. Shrooms is not cocaine, you can't OD on the stuff. That is not to say it can't cause other types of damage. Not prescribing anything at all might be the safest course of action. And here you also say that unlike the advice you give your patients you might decide differently when it comes to yourself. > Not my job to defend conduct of others of decades ago. I'm not saying this judgmentally, there doesn't seem to be an obvious way to reconcile all these things. Your predecessors clearly also meant the best and gave the most prudent advice they could at the time. This is something to factor into the risk profile. The most trust worthy thing to do is admit that there are limits to our knowledge. But I understand why you would hesitate to provide this asterisk with your advice as a lot of people will take it poorly and rush to webmd and homeopaths as a result.

alecst 5y ago

> It's showing promising results, however, the details re: dosing and adverse effects are still being worked out. I'm gonna let out a galaxy-level eye roll when the FDA comes out with a "prescription" psilocybin x mg/kg or whatever. People have been taking mushrooms since the stone ages. The standard that these drugs have to meet is just so freaking high compared to say, Ambien, or Xanax, or Zoloft, or Prozac, which are given to at-risk populations by default.