Where am I going with my many blogs on drug treatments for depression?
If you’ve been reading my previous posts, this is a question you may be asking yourself. In fact, that is a question I’m also asking myself. My answer is…….I’m not entirely sure.
Although I had originally envisioned writing only 3 or 4 posts on depression, I’m now up to 8. My initial posts were largely a rehash of old lecture information that I had assembled for classes I taught. However, as the posts progressed and I began examining issues on which I had not lectured, I had to rely more on recent publications (both scientific journal articles and news reports). Fortunately, or unfortunately, the more I read, the more issues I find to be nerdy about.
A science fiction writer I like described himself as a “pantser” when designing his stories. He describes two general writing strategies. Some writers plot the story line in advance and then fill in the details as they write. The other approach he describes as “flying by the seat of your pants” (i.e. “pantser” approach) in which the writer doesn’t think too far ahead and lets the story line go in whatever direction seems appropriate and interesting. I definitely fall in the pantser category of blog writing. Eventually I will get somewhere, but I’m not exactly sure where that “somewhere” will be, or how I will get there. My approach is also influenced by the random stops and starts by which the leading edge of science normally proceeds.
Although psilocybin has already been approved for therapeutic use in Oregon, and can be used on a limited experimental basis elsewhere in the U.S., psilocybin has not been officially approved by the federal government. Psilocybin remains in the DEA Schedule 1 category, supposedly making it illegal for any purpose. Psilocybin’s status appears similar to marijuana which is approved for therapeutic and recreational use by many states, although considered illegal by the federal government.
In this post I present some of the issues relevant to the DEA and FDA granting federal approval for psilocybin as a therapy for depression (although it may be therapeutic for other purposes as well). I also issue the disclaimer that I am not an “insider” in the psychedelic treatment of depression and much of what I present here comes from my general knowledge of pharmacology as well as from reading some of the relevant literature. Although much of what I present is pretty straightforward, you should take my opinions at the end “with a grain of salt.”
As discussed in the previous post, the three classical, serotonin-like, psychedelics that have been used most often in treating depression are LSD, psilocybin, and ayahuasca. However much of this work, mainly with LSD, was performed in the 1950’s and 1960’s before these drugs became illegal. While this early evidence supported therapeutic effectiveness, the research designs employed did not use modern research methods, allowing for alternative explanations.
Since 2018, when psilocybin received FDA breakthrough status, scientists have been reinvestigating psychedelics using randomized clinical trials, the linchpin of modern drug research (more about this later). In this regard, Reiff et al. (2020) identified 14 well-designed studies that investigated the effectiveness of psychedelic drugs for treatment-resistant depression, anxiety, end-of-life issues, and PTSD. This post will draw on this work, with an emphasis on psilocybin, since it is currently the only serotonin-like psychedelic FDA-approved for limited experimental use. Reiff et al.’s (2020) review supports psilocybin’s antidepressive effects being both quicker and longer lasting than traditional monoamine antidepressants for many patients.
(While not covered in this post, the FDA has also provided break-through status for a catecholamine-like psychedelic, MDMA, for the experimental treatment of PTSD, putting its status in a similar state of bureaucratic limbo.)
While the FDA has not yet reached a decision on whether to legalize psilocybin for general therapeutic use, the state of Oregon already finds the evidence convincing. In November 2020, Oregon approved the use of psilocybin for state-wide therapeutic use by licensed professionals! I had not been following these developments at the time and when I read about Oregon’s decision in the New York Times , I was a bit surprised by how quickly Oregon made their decision.
History and Pharmacology of Psilocybin use.
First a bit of background. A more detailed account is found in the previous post.
There is evidence that indigenous peoples began using psilocybin for religious and therapeutic purposes before recorded history. For example, cave paintings depicting a dancing Shaman with a bee-like head and mushrooms sprouting from his body date human use to as early as 3500 BC. However an awareness of psilocybin by Western Culture didn’t really begin until Thomas Wasson wrote an article in Life Magazine in 1957 and coined the term “magic mushroom.” In the 1960’s, Timothy Leary became one of the early pioneers in both the scientific and recreational use of psychedelics although his advocacy of unregulated recreational use clearly contributed to the banning of these drugs by the government. Nonetheless, following this banning, some psychiatrists and scientists continued to strongly advocate for therapeutic use.
Psilocybin (and its derivative, psilocin) are plant alkaloids made by a number of different mushroom species (in multiple genera). The mushrooms can be eaten raw, brewed as a tea, or cooked. The chemical structure of psilocybin was identified in 1958, and now can be readily synthesized in pharmaceutical laboratories eliminating the need for mushroom cultivation. Synthetic psilocybin allows for more precise dosage control and virtually all recent FDA-approved clinical studies have used synthetic psilocybin.
Once in the body, psilocybin is enzymatically converted into psilocin, the active form of the molecule. Although less potent than LSD (i.e. requires a higher dosage for effectiveness), psilocybin’s psychedelic efficacy is almost identical. In other words you can produce the same psychedelic effects with psilocybin as LSD, you just need a larger dosage. Psilocybin’s side effects of dizziness, nausea, and vomiting are also similar to LSD. However these side effects are transitory and generally well tolerated in both therapeutic and recreational settings.
Why psilocybin rather than LSD or ayahuasca?
LSD, ayahuasca, and psilocybin all appear therapeutic in treating depression with many more published studies examining LSD than the other two. So why is psilocybin turning out to be the preferred psychedelic? It turns out that psilocybin has advantages over both LSD and ayahuasca.
An advantage over ayahuasca is because psilocybin can be synthesized allowing for precise dosage control. Ayahuasca, on the other hand, is a plant-based preparation containing a host of other ingredients which may vary a bit from preparation to preparation, and which is administered as a tea, making dosage control more difficult. In addition, once the active molecule in ayahuasca, dimethyltriptamine (DMT), enters the blood it is readily destroyed by an enzyme (monoamine oxidase) before it can enter the brain to exert its effects. However, in ayahuasca, DMT’s destruction is blocked by monoamine oxidase inhibitors also present in the ayahuasca. Like psilocybin, DMT can be synthesized in a pharmaceutical laboratory, however, pure DMT presents the complication of possibly needing additional drugs to reliably obtain desired effectiveness. More research is necessary to clarify this point.
When comparing LSD and psilocybin, the important considerations are potency, efficacy, and therapeutic index. Potency refers to the dosage necessary produce the effect. Efficacy refers to the magnitude of the effect that a drug can achieve. The therapeutic index is calculated from a knowledge of potency and efficacy and reflects the drug’s safety margin. LSD and psilocybin appear approximately equally effective as psychedelics. However, LSD is much more potent and exerts its effects at a much lower dosage. In fact, LSD is the most potent of ALL known synthetic drugs!
Although it may seem counterintuitive, drugs that combine low potency with high efficacy have a high therapeutic index. The reason is that the dosage difference between when first showing effectiveness and when maximally effective is always greater for low-potency drugs. Consequently low-potency drugs have a larger safety margin when you don’t get the dosage exactly right. (This relationship also explains why fentanyl, with its very high potency , is now the leading cause of preventable death in the the current U.S. opiate epidemic. Although other opiates can also kill you, fentanyl’s low therapeutic index makes it much easier to accidentally overdose.)
Procedures For Legalizing Psilocybin (and MDMA) For Nationwide Therapeutic Use.
Two federal agencies are tasked with approving and regulating drugs. Although their goals are different, they typically work together in reaching final judgements. The Drug Enforcement Agency (DEA), part of the Department of Justice, is concerned with categorizing and enforcing the legality of drugs according to their perceived harm/therapeutic value. After reviewing the evidence, the DEA places a new drug into one of five Schedules ranging from Schedule 1 (no accepted use) to Schedule 5 (over-the-counter and relatively safe prescription drugs). The DEA is also the lead agency for policing the proper use of drugs domestically as well as coordinating and pursuing U.S. drug investigations abroad.
The Food and Drug Administration, on the other hand, is part of the Department of Health and Human Services, and is concerned with insuring that new therapeutic drugs are both effective and safe. To that end, any new drug must first be tested with animals for general pharmacology and toxicity as well effectiveness in animal models of the human disorder. If the animal testing looks good, the drug can then be approved for experimental human testing in 3 successive phases. Phase 1 is a preliminary test of safety in which 20 to 80 healthy volunteers are given the drug and toxicity/metabolism/side effects are measured. If Phase 1 looks good, researchers can then move to Phase 2 which preliminarily tests between 20 and 300 patients for effectiveness in treating the disease condition. If Phase 2 looks good, Phase 3 is a much more extensive test of both effectiveness and safety, typically using many more patients (200 – 3000+) as well as looking at different dosages and drug combinations as well as comparisons with other approved drugs.
Psilocybin is currently in FDA Phase-3 human trials. The results so far appear highly promising. Ongoing and future studies are presumably to address a variety of issues the FDA sees as important. Eventually, a panel of “experts” at the FDA will review all the evidence and evaluate whether psilocybin’s therapeutic use is acceptable, whether it should be prescription, its addictiveness, its potential for illegal use, and how psilocybin compares to other approved drugs for the same condition. The FDA must also approve and any site where psilocybin will be manufactured. Should the FDA decide to approve psilocybin, the DEA must also reschedule psilocybin to a category that allows for its legal use. Psilocybin is currently a DEA schedule-1 drug (no accepted use) and would have to be rescheduled to at least Schedule 2 (accepted clinical use with restrictions).
Randomized Clinical Trials.
In order to meet the FDA’s requirements for Clinical Trials with humans, experimenters must use modern research methods. While some details can vary from trial to trial, all share a number of features to minimize various types of bias. These features unfortunately were not present to the same degree in research performed in the 1950’s and 1960’s and thus the earlier studies of psychedelic effectiveness are often amenable to alternative explanations.
Selection of Subjects. The subjects of FDA clinical trials are volunteers. However the volunteers are screened for a number of issues before being accepted. With respect to psilocybin treatment of depression, the subjects must be moderately to severely depressed. This is because therapy effectiveness is more easily evaluated in more severe cases. The volunteers should not be taking any other medications for their depression and time must have elapsed for any previous medications to be cleared from their systems. Also volunteers should not have any other psychiatric condition that might predispose to a bad outcome.
Random Assignment to Conditions. Trials have 2 or more treatment conditions. The different treatment conditions might vary by dosage or some other aspect of the treatment protocol. Ideally you want all extraneous variables that might influence the outcome (i.e. level of depression, anxiety level, age, sex, etc) equally represented in all treatment conditions. Random assignment to treatment conditions statistically accomplishes this goal, particularly with the large sample sizes used in most clinical trials. With small sample sizes (under 12 per treatment condition) it may be necessary to match subjects into conditions as best you can.
Crossover Designs. Most clinical trials now allow all subjects to receive the psilocybin treatment, but at different times. Advance knowledge that they will eventually receive treatment has the added advantage of increasing subject participation.
Subjects are randomly assigned to treatment and non-treatment conditions for the first phase of the trial. Differences in this phase provide the main data for analyzing the therapeutic effects of the psychedelic. However, after this first phase is complete, subjects previously in non-treatment conditions are then given the psychedelic. This procedure provides additional before-and-after assessments to provide a secondary evaluation of therapeutic effects.
“Blinding” of both subjects and experimenters. Knowledge of treatment condition by either the subject, or by the “hands-on” experimenters can potentially bias the outcome of the study. To attempt to remove this bias, both subjects and experimenters must be “kept in the dark” while the experiment is underway. Only after the experiment is completed are the subjects and experimenters allowed to know which subjects were treated and which were not. Unfortunately, as explained below, it is impossible to do a totally “blind” study using psychedelics.
Use of a placebo. Drugs are notorious for producing “placebo effects” (i.e. effects determined not by the drug but by a subject’s expectations). Consequently it is usually necessary to have a placebo control condition which ideally differs from the drug treatment only in possessing no therapeutic value. If subjects don’t know whether they are receiving the drug or the placebo, random assignment should insure that the two groups have comparable expectations. The effects of the drug can then be contrasted with that of the placebo to determine the drug’s “true” therapeutic value.
As mentioned above, it is impossible to have a completely valid placebo for psilocybin (or any psychedelic). Some clinical trials use niacin as the placebo since it has no psychedelic effects but can mimic some of psilocybin’s side effects such as dizziness, nausea and vomiting. This may fool some in the placebo condition into thinking they have received psilocybin. However, because of psilocybin’s unmistakable psychedelic effects, everyone in the psilocybin condition, as well as the experimenters administering the psilocybin, will know who has received psilocybin. Thus subject and experimenter bias can not be entirely eliminated. These biases do present an issue for interpreting results.
At the same time, contrary to what many nonscientists believe, scientific research can never “prove” anything! All research can do is gather evidence to either support or reject a hypothesis. When the supporting evidence is sufficiently convincing to other scientists, the hypothesis becomes “accepted.” Even with psilocybin’s built-in bias, many experts are finding the evidence convincing.
Measuring Depression and Other Relevant Dependent Variables. Experimenters must also have objective, reliable, and valid tests to quantify depression, the dependent variable of interest. Depression can be measured by a number of validated paper and pencil tests. These include the Quick Inventory of Depressive Symptomology (QUIDS), the Beck Depression Inventory (BDI), the Hamilton Depression Rating Scale (HAM-D) and the Hospital Anxiety and Depression Scale (HADS). Most experimenters utilize more than one test to assess the degree of depression. The tests are typically administered before, during, immediately after, and often weeks-to-months after treatment, to assess immediate, short-term, and long-term effects.
The effects of psilocybin treatment on other dependent variables are often measured as well. Since many depressed individuals also suffer from anxiety, anxiety also is typically measured by well-validated tests.
Evidence exists that the antidepressant effect of psychedelics also correlates with the magnitude of a “mystical” or “peak” experience. Consequently, the degree to which the person has such an experience is often assessed as well.
Set and Setting. The response to a psychedelic experience can vary widely. At one extreme, some people have what they consider one of the best experiences of their lives. At the other extreme, some people find the experience terrifying and, in rare cases, particularly in predisposed individuals, experience a psychotic breakdown. Whether the psychedelic experience is positive or negative is strongly influenced by “set and setting”. “Set” refers to the mindset of the person taking the psychedelic and “setting” to the environment in which the psychedelic is taken.
The willingness of a depressed person to volunteer for a clinical trial likely reflects a predisposition towards a positive mindset. However, prior to the psychedelic treatment, a positive mindset is further optimized by carefully preparing and educating the patient for what is likely to happen. The sensory, cognitive, and potential therapeutic effects, as well as possible side effects, are all carefully explained. If the patient can be convinced in advance that psychedelic experience is going to be positive, it almost always is. A positive response is further optimized by a safe and pleasing setting, free from interruption. In addition, an experienced professional is always available to guide the experience and provide needed support. When the proper preparations are taken, a bad experience is very rare.
Dosage. One major purpose of FDA phase-3 drug research is to develop a protocol for drug administration. Since all therapeutic drugs have side effects that increase with increasing dosage, you want to determine the lowest dosage necessary to produce the desired therapeutic effect. However, the ideal dosage can vary by sex, age, body weight, and other variables. Exactly what is done in the treatment before, during, and after drug administration is also potentially important. As you might imagine, determining the best treatment protocol requires lots of research.
From research already performed psilocybin is both quicker acting and longer lasting than traditional antidepressants for many patients. If approved by the FDA, it will likely be used initially primarily for treatment-resistant patients that don’t respond to traditional antidepressants. However, that might change if psilocybin’s effectiveness is as robust and lasting as some studies seem to indicate. The treatment protocol will almost certainly involve medical professionals in an approved setting resulting in expensive “up-front” costs to the patient. However, FDA approval should make treatment eligible for insurance coverage.
I think that federal approval is largely a matter of having enough data exploring dosage, administration protocols, and potential side effects that FDA experts can feel confident about their decision. In this regard, there is likely evidence being used to guide the FDA’s decision that hasn’t been published yet. Given the prevalence of depression, the less than desirable depression treatments currently available, and the changing public attitudes towards cannabis and psychedelics, my guess is that FDA approval will happen relatively soon and that the DEA will reschedule psilocybin to make approval possible. Just sayin’
Reiff, C. M., Richman, E. E., Nemeroff, C. B., Carpenter, L. L., Widge, A. S., Rodriguez, C. I., . . . McDonald, W. M. (2020). Psychedelics and psychedelic-assisted psychotherapy. Ajp, 177(5), 391-410. doi:10.1176/appi.ajp.2019.19010035