AMA Wed 4/29/20: psychedelic medicine expert from Stanford

Happy to! The psychedelic that is closest to being FDA-approved is MDMA in the context of MDMA-assisted psychotherapy for PTSD. The phase II clinical trial results were promising with larger effect sizes (a measure of efficacy) than are typical seen in psychiatry. However, it is important to keep in mind that these trials tested a relatively small number of people. Testing is now in larger phase III trials sponsored by the Multidisciplinary Association for Psychedelic Studies (MAPS), so it will be interesting to see if these large effect sizes are maintained. Pending the results of those trials, MAPS is hopeful that MDMA-assisted psychotherapy for PTSD could be FDA-approved as early as 2021, although this may be delayed due to the pandemic. Once it is approved, there will be great interest in using it given that approximately 30% of people with PTSD are resistant to treatment. One limiting factor will be what the FDA decides in terms of what training is needed to be qualified to administer MDMA-assisted psychotherapy. The current evidence does suggest that MDMA-assisted psychotherapy is beneficial for certain PTSD patients, but it is important to keep in mind selecting the right patients. One issue that doctors in this field are particularly mindful of is the abuse potential of these substances along with health effects of long term use.

Ketamine is considered by some to be a psychedelic and esketamine, which was FDA approved in March 2019, is covered by some insurance companies under particular conditions (e.g. BCBS will provide coverage if someone meets criteria for MDD and has failed at least two oral antidepressants, among other criteria). Given that the other psychedelics, including MDMA and psilocybin, are currently schedule I substances, they will need to be FDA-approved before insurance companies consider reimbursing for these treatments. It’s hard to say when they will start covering these treatments after they are FDA-approved, but it does seem like a good idea from an economic perspective given that while these treatments will be very expensive upfront, there is evidence that a course of MDMA-assisted psychotherapy can have long lasting benefits up to years after.

Stigma is unfortunately all too common with mental illness and it’s even worse in this case given these drugs have a sordid history in the United States. I find that comparing mental illness to other medical illnesses can help put things in perspective. I would explain to your significant other or family member that having an illness like depression can be thought of like having high blood pressure, for example. Some people will respond to the standard therapies but others will have treatment-resistant hypertension and alternative or experimental therapies will need to be tried in order to reduce the blood pressure and the risk of stroke and heart attack. Untreated treatment resistant depression, like untreated high blood pressure, can also be fatal due to the higher risk of suicide.

My pleasure! I’m not aware that there will be any psilocybin trials that will allow the medication to be taken at home. A trial is taking place at Stanford (currently on hold due to the pandemic) along with 22 other sites (https://clinicaltrials.gov/ct2/show/record/NCT03775200) in which patients in one of the arms will be receiving low dose psilocybin (1mg) while the other groups with receive moderate (10mg) and high dose (25mg). There are multiple studies ongoing with psychedelics. This site has comprehensive listing as of March 2020: https://psychedelic.support/resources/how-to-join-psychedelic-clinical-trial/#psilocybin. The Multidisciplinary Association for Psychedelic Studies (MAPS) is currently sponsoring phase III trials and, depending on the outcome of these trials, hopes to have FDA approval as early as 2021.

Certainly :slight_smile: I have not prescribed troches previously, so I unfortunately cannot comment from personal anecdotal experience about which I have observed to be more effective. I am not aware of any head-to-head studies of IV ketamine vs. oral ketamine for depression, so it is also difficult to say based on rigorous scientific evidence which is more effective. Part of the controversy comes from the fact that the bioavailability for troches is much lower than IV ketamine, which is 100%. It’s also easier to manage side effects, such as nausea and elevated blood pressure, in an office setting as opposed to One concern about the use of ketamine at home is the possibility of using more than is prescribed. While fortunately ketamine does not suppress respiratory drive, there are known health effects in studies of people who have used ketamine recreationally, so it’s definitely important to not take more than the dose prescribed by your physician. That said, it does seem reasonable to take an alternative form of ketamine under the guidance of a physician if a person finds it effective in situations when IV ketamine is not available in order to maintain the benefit.

My pleasure! As noted above, I’m not aware of any research that has compared oral to IV ketamine for depression.

  1. In chronic ketamine abusers, researchers have noted deficits in spatial memory. However, other work has found that acute administration of subanesthetic doses of ketamine in the range used for depression has procognitive effects, including improvement in visual and working memory. For review, see here. As part of the Williams PanLab at Stanford, I am involved in an ongoing trial in which one of the questions we are asking about is the effect of acute IV ketamine on cognition in healthy volunteers.
  2. There is good evidence and reason to think based on what is known about how brain circuits and neurotransmitters contribute to particular symptoms that different depressive symptoms will respond to different treatments. In terms of your example of anhedonia, that’s interesting what you say about psychiatrists you have spoken to about this. There is good evidence from the literature that anhedonia does not respond well to conventional serotonergic antidepressants (Uher et al., 2012) and that medications that affect reward circuitry and dopaminergic pathways may be more effective for anhedonia (Dunlop et al., 2007). For example, the Williams PanLab conducted a small, open-label pilot study of pramipexole, a dopamine agonist, in patients with prominent anhedonia (described here). Dr. Andrew Krystal from USCF recently published an exciting study showing an experimental drug affected reward neurocircuitry and improved anhedonia in patients with prominent anhedonia: article here and commentary by my PI Dr. Williams and myself here.
  3. It will definitely be interesting to pursue more work in this area, but I can’t say currently which form of ketamine is more effective. We’ll need a head-to-head trial to make this determination. The ketamine clinic where I trained at Emory uses racemic IV ketamine.
  4. Currently, of course, it is the standard of care to first start with an SSRI and proceed to other therapies that are considered more risky, such as ketamine and psychedelics, due to their abuse potential and health effects from long term use. However, one of the goals of precision psychiatry is to be able to match people better with the treatment that will work for them from the start. Our lab is actively working on this and I do hope in the future we are able to bypass SSRIs in those we identify a priori as being non-responders.
  5. I haven’t read that book, but I do think the evolutionary origins of disease are important to understand for clinical practice. As an example, about ⅓ of people with major depression have elevated chronic levels of inflammation and there is evidence that the inflammation contributes to their symptoms. From an evolutionary perspective, the effect of acute inflammation to make someone feel anhedonic makes sense so they will rest and recover from their presumed acute infection, but this may become anhedonic depression if chronic.

My pleasure! The goal of precision medicine for mental health is to better match people with mental illness with effective therapies from initial presentation instead of having to undergo multiple rounds of ineffective treatments. We are doing this by developing more biologically- based classifications for these highly heterogeneous disorders. We definitely hope for a future in which precision psychiatry is the new normal in mental health!

I’m not familiar with this work but I would say, broadly, it may be that TMS and the psychedelics are producing the same effect by modulating the same neurocircuits. Work is actively being done to study which neural circuits are impacted by TMS and, separately, psychedelics and relating this to their effects.

Several top medical schools are actively studying psychedelics, including Stanford, UCSF, Hopkins, and Emory for mental illness. Considered by some to be psychedelic, esketamine was FDA-approved in March 2019. In terms of classic psychedelics, MDMA-assisted psychotherapy for PTSD could be FDA-approved as early as 2021, depending on the results of phase III studies. Agreed about stigma.

Unfortunately, I’m not familiar with Cervella, so I’m not able to comment on it.

This is definitely a challenge. I can’t comment personally on administering any psychedelics except ketamine. In my experience with administering ketamine, I’ve taken the approach of handling it similarly to any other treatment that I prescribe in psychiatry – that is to explain why I think this treatment may be helpful for this particular patient initially (trying not to oversell it) and if it doesn’t work, discussing the importance of not giving up hope and the fact that there are many effective treatments out there and it’s a matter of finding the right one. Unfortunately, I cannot comment about the availability of treatments in the EU.

Yes, this gets to the idea of setting in “set and setting”. I know a lot of thought has been put into making the environment comfortable in the MAPS-sponsored MDMA-assisted psychotherapy for PTSD trials. It seems that practitioners who do ketamine-assisted psychotherapy are attuned to this as well. Less attention is paid to this when ketamine is delivered via the medical model – IV infusion at 0.5mg/kg for 40 minutes without any psychotherapy. Part of the issue is there is likely not space or resources at academic medical centers, where the medical model of ketamine administration is often found, to have private rooms, couches, etc. I can speak for the IV ketamine clinic at Emory that, while it does take place in a clinic setting, we tried to make the environment as pleasant as possible (lying down in a bed [albeit a hospital bed], dimming the lights, having people listen to music and wear eye covers if they wanted, etc.). Also, because people came regularly, they got to know the nurses well.

I have been getting Ketamine IV treatments and using a nasal spray since January of 2019. Has there been any news of risks or side effects associated with long term use of the dosage a doctor would prescribe?

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Is there any time frame when psilocybin might be able to be used to treat depression?

The length of treatment needed is something that definitely needs more investigation. Very few studies that have done long-term follow-up of patients treated with ketamine for TRD. Anecdotally, some patients remit with a single course of treatment and are able to stay in remission with oral antidepressants, while others require regular (usually biweekly on monthly treatments) for years. Determining what distinguishes these patients is an important and active area of investigation.

It seems reasonable to think there may be a synergistic effect between TMS and ketamine. Anecdotally, I saw good improvement for the one patient I am familiar with who had this combination treatment in the Emory TRD Clinic. To better determine whether the combination is more effective than either alone (and for whom), there would need to be a head-to-head trial. In the literature thus far, I’m only aware of one small study assessing the combination which showed improvement with the combination but there was no comparison group.

Thank you if you happen to come across any other psychedelic studies For depression please let me know… I didn’t qualify for any but one and I wrote them but it’s in a neighbor state.

IV ketamine typically costs between $400-$800 per session, while esketamine is a little higher than that. Some insurance companies do cover it, so I would check with your insurance company to see whether they do and do ask which doctors in their network offer it. The Osmind folks have also put together a helpful resource that includes clinics in our local area. I can’t give you an informed answer on the risk of losing SSI or other benefits for pursuing these therapies, although I don’t see why that would be the case. Please don’t pursue any current schedule I therapies (MDMA, psilocybin) outside a research context though.

Thank you so much @DrLauraHack !!! This is amazing and I just want to give you a huge thank you. I’m sure everyone else appreciates you as much as I do :slightly_smiling_face:

Hi @Morg_Ellon this directory might be helpful:

It includes information on the status of clinics during COVID

You’re welcome! Ketamine was first researched for depression in the early 1990’s at Yale in subanesthetic doses at a time when it was becoming clear that other neurotransmitters were involved in depression besides serotonin, including glutamate, and due to the finding that anesthetic ketamine could increase glutamate in the neuronal synapse. Since then, there has been the most testing with IV racemic ketamine but other forms have been tested somewhat for depression. All use of racemic ketamine (mixture of R-ketamine and S-Ketamine) is off-label. No drug company wanted to pursue the testing required for FDA approval on racemic ketamine because it is off patent and they couldn’t make any money off of it. That’s why Janssen pursued use of esketamine, which is now FDA-approved in nasal form.