Human beings are great experimenters. We are always looking for something to ease the endless suffering of our lives. Very few mind-altering substances have broken into the mainstream. Mainly due to the fact that history has shown that their repeated use leads to significant devastation upon the mind they are altering. Alcohol is common place in modern human society. THC is gaining acceptance. On deck is psilocybin (Si-lo-Sib-in).
Psilocybin is the molecule responsible for the mind-altering effects of hallucinogenic mushrooms. This chemical is rapidly absorbed into your blood stream, readily crosses your blood brain barrier, and binds strongly to serotonin and dopamine receptors in your brain.
Serotonin and dopamine are two neuro-transmitters heavily involved in mood and reward. Psilocybin’s strong affinity to these receptors leads to the hallucinogenic and euphoric effect from shrooms. As you can imagine, dopamine and serotonin can be both the angel and the devil on your shoulder depending on the behavior that leads to their release.
Despite the widespread use of SSRIs (selective serotonin re-uptake inhibitors), the world has not made much headway in reducing the incidence of depression. Also, many patients are non-responders to SSRIs. In theory, psilocybin should aid in treating this condition.
This was a Phase 2, double blind, randomized controlled trial comparing psilocybin to escitalopram (SSRI). Patients were included in the study if they were 18-80 and suffered from long standing moderate-severe depression.
Phase 2 studies are mainly focused on safety. They do not try to prove efficacy. However, researchers do collect data to get an idea if their theory is sound.
Participants were excluded if they had used escitalopram previously, they or an immediate family member had a history of psychosis, pregnancy, previous suicide attempts, unable to have an MRI of their brain, or other “serious” diseases that would make them unsuitable for study (as assessed by a physician).
Participants were recruited via social media. All participation was voluntary. Psychiatric medication was discontinued 2 weeks prior to the start of the study. Psychotherapy was stopped 3 weeks before the trial.
The primary endpoint was the change in a pre-validated depression questionnaire known as the QIDS-SR-16 self-report survey. Besides simple comparison they looked at response rates (> 50% reduction), and remission rates (score of 0-5 on the scale).
The experimental group was given 25 mg of psilocybin 4 weeks apart. The control group was given 1 mg of psilocybin and 10 mg of escitalopram at the beginning of the study. The purpose of the 1 mg of psilocybin was to reduce expectency bias (when a researcher has a cognitive bias towards a treatment, can easily observe the effects, then influence the participant). The researchers informed all of the participants that they would be receiving some amount of psilocybin. One group would receive a therapeutic dose (25mg), while the other an ineffective dose.
However, they did not address confirmation bias. This occurs when a previously held beliefs influence the response to new information. More on this in the discussion.
Adverse events were monitored via phone interview. Participants were simply asked how they were feeling each week.
Here’s what they found
1000 patients were screened for the trial. After a significant portion were excluded or refused, 59 were left for participation.
Participants were mostly white males around the age of 40 with a 20-year history of depression.
The mean difference in depression score was (-8.0 +/- 1.0) vs. (-6.0 +/- 1.0) [CI -5.0 – 0.9] in the psilocybin and control groups respectively. This was not statistically significant.
70% vs. 48% achieved response ( > 50% reduction in depression score) in the psilocybin and control groups respectively.
57% vs. 28% achieved remission ( score of 0-5) in the psilocybin and control groups respectively.
(They did not calculate p-values or confidence intervals for the secondary outcomes)
87% vs. 83% reported adverse events in the respective groups. Most of the adverse events in the psilocybin group occurred with 24 hours of dosing.
I’ll summarize the findings form the authors: 1) There was no difference between Psilocybin and Escitalopram, 2) Secondary outcomes favored psilocybin, 3) Larger and longer trials are need to compare psilocybin with established anti-depressants. 4) The safety profiles were similar.
Now this is a phase II study. The goal isn’t to prove a clear distinction between the new therapy and the incumbent. Ideally you establish some efficacy with a favorable safety profile. There will be no approval for the usage of psychedelic mushrooms as an adjunct for the treatment of depression based on this study. I question whether this is worth investigating further. My thesis is below.
There was a lot of opportunity for bias here. First, the participants were recruited for a medical research trial through social media knowing it was a study investigating psilocybin. This is going to attract a certain type of individual. Particularly a risk taking individual. Possibly one that has tried mushrooms in the past, or other illicit substances. You may judge me for stereotyping the participants, but it’s likely true.
Due to the recruitment strategy, it is unlikely the authors captured a representative sample. This was evidenced by the demographic data the provided in table one. The majority were white males, around 40, with college educations. Around 30% of participants had used psilocybin in the past. I could theorize as to why the study attracted this particular demographic group, but the reason is irrelevant, all that is necessary is to conclude that it is not representative. Participants were surveyed prior to the beginning of the study and the majority preferred to be in the psilocybin group suggesting the participants mind was already made-up (confirmation bias).
Second, all of the participants were told that they would be receiving psilocybin. The experimental group received 25mg while the placebo 1 mg. In the discussion they comment that 5 participants quit the trial because they knew they were not in the psilocybin group. No patients requested to quit the psilocybin group after the first dose. Duh!
This evidence supports the weakness in their blinding strategy. I would imagine most individuals get high after eating a psychedelic mushroom (I’ve never tried them). Therefore, they would have a similar experience after ingesting 25 mg of psilocybin. It was clear that some of the participants knew which group they were in based on their response on treatment days. If you are depressed and you have a favorable attitude towards psychedelic mushrooms, and you know that someone has just given you a psychedelic mushroom, how would respond on the depression survey? Probably pretty good. (Confirmation bias)
Third, the authors stated they did not assess the effectiveness of their blinding strategy, and expectancy bias may have influenced the results. How could this happen? A researcher could easily observe which participants were high. You could engage them in conversation, be more attentive to specific participants and ignore others, which could significantly influence someone.
Finally, the evaluation of adverse events was pretty weak. All they did was ask participants, “How have you been feeling since your last visit?” (That’s a rigorous investigation there). Safety is a big deal in phase II studies. To me this is the equivalent of asking an opioid user (not addict) if they think they are addicted to opiates, as you give them opiates. For those that have not read the research on opiates, this is exactly what happened, which led to wrong conclusion in the 1980’s that opiates are not addicting.
In my opinion, the bias introduced in this study was favorable to psilocybin, yet it still broke even with SSRIs. To transfer these results into reality, the expectation would be that individuals that chose to treat their depression with psilocybin will likely be worse off than taking the escitalopram. So, why do we need it? Will we really be able to trust a larger phase III study, when the phase II has at best a slim margin of benefit? Is it really going to be that much better than the incumbent that we should release another substance on society?
In all honesty, I have not done a deep dive in psilocybin. Maybe I should. Maybe I should have more of an open mind (I’m turning into a bit of a curmudgeon as I age). Medicinal psilocybin is gaining momentum. Quite frankly, it makes me nervous on two fronts.
First is the idea that optionality inherently improves outcomes. I don’t believe this to be true. There are many areas in which multiple options are detrimental. You’re best sticking with what you know works. This is known as The Lindy Effect. Those that have survived continue to survive, while new entrants tend to die. They die particularly fast when it turns out they don’t solve a problem. Second, how could we fully understand psilocybin based on a clinical trial? Even a large clinical trial. Its effects are such a wildcard. The risk is very high on the downside to simply break even on the upside.
In my humble opinion, medicine continues to fall into the cognitive trap of believing that depression is some chemical imbalance in the brain, something physiologic, something spontaneous. Depression is much deeper than that. It’s in the soul. It can’t be seen. The individual has to go down and drag up to the surface to fight against. We’re fixated on what we can measure (serotonin), and ignore what we can’t (resentment, bitterness, rejection, dispossession, loneliness, abuse, etc). These emotions are intrinsically human, and intrinsic to our interactions with one another. We believe that if we simply correct serotonin, we can make the patient happy.
We’re probably wrong. For a problem so complex, we fool ourselves into thinking the solution could be so simple. We also fool ourselves to believing we are looking at serotonin as the cause, and not the effect.
That’s not to say the medicines we have today do not make depressive symptoms more tolerable. They probably do, but they don’t rid your mind of the demons you have to defeat. Only you can do that. No amount of shrooms, ketamine, or cannabis is going to help you in that task. If history is a reliable source, these substances will likely work against you in a serious way. We should stick to what’s safe, roll up our sleeves, and do the hard work to root out the underlying causes that torment so many of us.