A Depressed Shrink Tries Shrooms

I’ve been suffering from treatment-resistant depression for over a decade now. Sometimes, out of curiosity, I’ve subjected myself to the same depression scoring questionnaires as I’ve done to my patients, with the expected results: this mf down bad very sad. Or perhaps that’s me being rather interpretative, what they actually labeled me with was “moderate-severe depression”.

If we’re being precise about it, treatment-resistant depression affects roughly 10-30% of people with major depressive disorder, depending on how you define “treatment-resistant” (usually failure to respond to at least two adequate trials of different antidepressants). That puts me squarely in a club of approximately 3-4 million Americans, and maybe a hundred million globally, assuming the conservative estimates are correct. Not exactly an exclusive membership.

To a large extent, this can be attributed to what we in the business call “Shit Life Syndrome”. Yet my life is far from objectively shit, and in the grand scheme of things, most of the hurdles I’ve run into are of minimal importance in the long-run. That doesn’t change the fact that I was depressed. Often badly so. Never actively suicidal, but often wondering what the point of waking up and getting out of bed was. Things seemed grey, my body and mind had immense resistance to the idea of doing anything at all.

Heard joke once:

Man goes to doctor. Says he’s depressed. Says life seems harsh and cruel. Says he feels all alone in a threatening world where what lies ahead is vague and uncertain.

Doctor nods, hollow-eyed. "Treatment is simple. Great clown Pagliacci is in town tonight. Go see him. That should pick you up."

Man bursts into tears. "But doctor... I am Pagliacci."

Doctor stares. Then his face crumples. He lets out a wet, shuddering laugh.

"Oh, fuck me," he says. "I’m a fucking 🤡 for trying to cure you when I’m depressed myself."

A long silence.

"...You wanna grab a drink?" Pagliacci asks.

Doctor exhales. "God, yes."

They go to a dive bar, swap stories of failed marriages and existential dread, and get just drunk enough to laugh at the cosmic joke of it all. It doesn’t fix anything, but for a few hours, they don’t feel so alone.

Best therapy session the doctor’s ever had.

This phenotype, incidentally, maps quite well onto what researchers call anhedonia, the technical term for that specific flavor of depression where nothing feels rewarding anymore. The mesolimbic dopamine system, responsible for motivation and reward processing, appears to be particularly dysfunctional in treatment-resistant cases. Traditional SSRIs work primarily on serotonin reuptake, but if your problem is downstream in the reward circuitry, flooding your synapses with more 5-HT might be like trying to fix a broken car by adding more gasoline.

It’s not like I was uniformly sad, it had its ups and downs. The few months right after I found out that I’d matched into psychiatry were likely the happiest I had ever been. Unfortunately, like most good things, it didn’t seem to last. And living alone in Scotland? That absolutely didn’t help. There’s the ever elusive “Glasgow Effect”, with that particular city underperforming on health-indexes to a degree not explained by socio-economic factors, but I don’t even live in Glasgow! Even so, some of the environmental factors are common. No sun for most of the year, a populace allergic to the idea of color, be it in their clothing or architecture.

The latitude effect on depression is real, by the way. Scotland sits at roughly 56-60°N, putting it well into the territory where seasonal affective disorder becomes a genuine population-level concern. The phototherapy literature suggests that even modest reductions in light exposure can dysregulate circadian rhythms and melatonin production, which cascade into mood disturbances. Add the cultural tendency toward what might charitably be called “emotional restraint” and you’ve got yourself a perfect storm for persistent depressive symptoms.

I realized I was at a nadir, and willing to consider alternative options. I’d heard good, or at least interesting things about psilocybin and ketamine, but before I decided to look up seedy nightclubs, an opportunity made itself apparent.

The research landscape for psilocybin has exploded in recent years. Initial phase 2 clinical trials of psilocybin given alongside psychological support for major depression and treatment-resistant depression (TRD) demonstrated encouraging signs of basic safety, with effect sizes that would make any pharmaceutical executive weep with joy. We’re talking Cohen’s d values in the 2.0-2.5 range for some studies, which, if you’re not statistically inclined, is roughly equivalent to the difference between a professional athlete and your average couch potato. Most antidepressants struggle to achieve effect sizes above 0.3.

I saw that someone on a private group chat for psychiatry trainees had circulated a pamphlet aiming to recruit for a trial called COMP006. Seen any patients with treatment resistant depression? They might be interested in a trial of psilocybin.

Well. As a matter of fact, I did know somebody who might be keen.

COMP006 is part of COMPASS Pathways’ broader development program for their synthetic psilocybin formulation, COMP360. This isn’t your garden-variety magic mushroom extract, it’s a precisely manufactured crystalline form of psilocybin designed to eliminate the variability inherent in natural fungal products. The trial design follows the now-standard protocol: two sessions separated by at least three weeks, with extensive psychological support before, during, and after administration.

I fired off an email, which met with a quick response. I met the eligibility criteria, signed the forms, and after a lot of headache wrangling leave, arrived at the study center in England for the first of two doses.

Of course, like any respectable double-blinded study, they concealed the details of administration, neither I nor the treating physicians were supposed to know whether or not I was actually being given psilocybin.

This is a laudable theoretical ideal, which, like any trial of strongly psychoactive substances, was easier said than done. You can’t just give some of the cohort an inert placebo, because no amount of sugar pill will fake the effects of a psychedelic. I believe this trial attempted to somewhat mitigate this by including a 1mg dose in one of the arms, which is usually sub-threshold, approaching a micro-dose.

The blinding problem in psychedelic research is genuinely thorny. Some trials have tried using niacin (which causes mild flushing) or low-dose stimulants as “active placebos,” but these approaches have their own issues. The 1mg dose they used in COMP006 is clever because it’s pharmacologically active but typically below the threshold for obvious psychoactive effects. Based on the dose-response curves from earlier studies, 1mg produces measurable 5-HT2A receptor occupancy (roughly 10-20%) but rarely produces the characteristic perceptual changes that would unblind participants.

I have little doubt about what I’d been lucky enough to receive, because, brother, I was tripping balls not long after after the dose was administered.

It started as ringing in my ears. I found myself moving my jaw in the vain hopes of opening up my eustachian tubes, much like you’d do on a plane. It felt like my ears were stuffed.

This was quickly followed by shooting and tingling sensations in my jaw. I’ve got mild sensitivity to cold, so imagine biting into an ice-cube. My teeth also ache when I see beautiful women (don’t ask), so perhaps this bit was idiosyncratic. Fortunately, these symptoms abated, but they were highly uncomfortable while they lasted.

These early somatic effects are consistent with psilocybin’s broader serotonergic activity. Psilocybin modulates temperature by central 5HT2AR and 5HT1AR dependent mechanisms, and the jaw tension I experienced likely reflects activity at 5-HT2C receptors, which are involved in muscle tone regulation. The auditory changes make sense too: psilocin (psilocybin’s active metabolite) has significant affinity for 5-HT2A receptors in auditory cortex, and even modest receptor occupancy can alter auditory processing.

40 minutes in: I began to feel nauseous. I didn’t hurl, but it was close, I wasn’t inclined to leave the comfort of a recliner. This abated by the hour’s mark. I believe that if it got too bad, the staff would have hit me up with a dose of an anti-emetic.

The nausea is predictable and well-documented. Psilocybin activates 5-HT3 receptors in the chemoreceptor trigger zone, the brain region responsible for detecting toxins and initiating vomiting. From an evolutionary perspective, this makes perfect sense: most naturally occurring psychoactive compounds are produced by plants or fungi as defense mechanisms, so having a robust “spit this out immediately” response probably kept our ancestors alive. The temporal pattern I experienced (onset around 40 minutes, resolution by 60 minutes) matches the known pharmacokinetics of oral psilocybin perfectly.

(I was left largely alone, and was taking notes on my phone, which is why I have reasonably reliable timestamps handy)

I was browsing on said phone, when the first perceptual changes became noticeable. 2D images seemed to pop and gain depth, or at least that’s the best way I can describe it. I was in a rather drab and windowless room on a rainy day, so there wasn’t much to look at outside. We weren’t allowed to leave either.

The visual effects I describe align with what we know about psilocybin’s action on visual cortex. Hallucinogens, which include naturally occurring chemicals such as mescaline and psilocybin, as well as synthetic compounds, such as lysergic acid diethylamide (LSD), induce profound alterations of human consciousness, emotion, and cognition primarily through 5-HT2A receptor activation in cortical areas. The “depth” effect I noticed likely reflects altered processing in areas V4 and V5, which handle visual motion and depth perception. Neuroimaging studies show that psilocybin increases connectivity between normally segregated visual processing networks, potentially explaining why 2D images might suddenly seem three-dimensional.

I’d brought along headphones, and was, in fact, looking forward to listening to music. I wasn’t disappointed, it hit different. It felt like my auditory equivalent of “stereopsis” (visual depth discrimination) was off the charts. Every song decomposed into layers, and it felt like I’d splurged for the best headphones money could buy instead of a cheap but cheerful Chinese Bluetooth headset. It was sublime. Music reliably induced frisson, and I’d come prepared with a playlist of both music and video.

The music enhancement is one of the most reliably reported effects of psilocybin, and it’s not just subjective hyperbole. fMRI studies show that psilocybin dramatically increases connectivity between auditory cortex and limbic structures like the amygdala and hippocampus. Under normal circumstances, music processing is fairly compartmentalized: rhythm goes to one area, melody to another, emotional valence to limbic structures. Psilocybin seems to break down these barriers, creating a more integrated, emotionally rich auditory experience. The “frisson” I mention is mediated by dopamine release in the nucleus accumbens, which is likely enhanced by psilocybin’s indirect effects on dopaminergic signaling.

I will shamefully admit that, out of boredom, I’d recently been watching Instagram reels. The majority of them are slop, but this time, they seemed positively riveting. I wouldn’t say they were spiritually compelling in the least, but I could barely drag my eyes away. For some reason, high-on-shrooms-SMH has the same taste is reels as an incredibly basic Valley Girl, leaving his sober counterpart the uphill task of unfucking the algorithm.

Consider this a fascinating window into psilocybin’s effects on attention and salience processing. The ventromedial prefrontal cortex, which normally acts as a kind of “relevance filter” for incoming information, shows dramatically reduced activity under psilocybin. Simultaneously, there’s increased activity in areas associated with sensory processing and pattern recognition. The result is that normally mundane stimuli (like algorithmically optimized social media content) can suddenly seem fascinating and worthy of sustained attention. It’s the same mechanism that makes people spend hours staring at wood grain patterns or carpet fibers on psychedelics.

Things got a lot funnier. Just about anything had me guffawing with laughter. Watching Map Men was a blast, British humor is an understandable evolutionary response to living there.

The enhanced humor appreciation has a neurobiological basis too. Psilocybin increases activity in the anterior cingulate cortex and temporoparietal junction, brain areas crucial for detecting incongruity and resolving cognitive conflicts. These same regions are activated when we “get” jokes, particularly ones that involve unexpected twists or absurd juxtapositions. The net effect is that your brain becomes hypersensitive to incongruity and finds resolution of that incongruity extremely rewarding. Hence, everything becomes hilarious.

I’d been hoping for visuals, but if there were any, they were incredibly subtle. I think there was some color fringing, especially around the edges of large patches of uniform, saturated colors, but nothing glaring. The walls seemed very content holding their breath. No fractals or smearing in motion. (This is based off notes taken during the time, I didn’t want to leave it to fallible memory).

The relatively mild visual effects suggest I likely received the 10mg dose rather than 25mg. Visual hallucinations on psilocybin follow a fairly predictable dose-response relationship: geometric patterns and color enhancement typically emerge around 15-20mg, while full-blown hallucinations (the classic “breathing walls” and fractal patterns) usually require doses above 20mg. The “color fringing” I noticed is consistent with altered processing in area V4, which handles color perception and can become hyperactive even at moderate doses.

The subjective effects peaked about an hour from ingestion, plateuing at that level for maybe another hour or two. After that, there was a relatively steady decline, and I think the majority of the effects had worn off 4 hours in.

This timeline matches the known pharmacokinetics of oral psilocybin almost perfectly. Peak plasma concentrations of psilocin (the active metabolite) occur around 60-90 minutes after ingestion, with a half-life of approximately 3 hours. The subjective effects typically lag slightly behind plasma levels, peaking around 90-120 minutes and returning to near-baseline by 4-6 hours.

Eventually, after what felt like ages, and also no time at all, I was allowed to leave.

I won’t bore you with the details about the second day, it was mostly a rinse-and-repeat of the first. I made sure to plan better, and thankfully didn’t waste as much time on Instagram.

The exact dosage given to me wasn’t disclosed, but my best guess is 10mg, as the effects of 25mg are, anecdotally, too strong, and 1 mg too weak.

Based on the published protocols for COMP006, the active arms were indeed 10mg and 25mg, with 1mg serving as the comparator dose. My experience profile strongly suggests the 10mg dose: clear psychoactive effects with relatively mild perceptual distortions, nausea that resolved within an hour, and a duration of approximately 4 hours. The 25mg dose typically produces much more intense visual effects and can last 6-8 hours.

The aftermath:

There was a lot of fussy screening and post-admin monitoring. Not particularly necessary in my case, I’m in good health barring the whole depression thingy, and in general, psilocybin is quite safe. It’s just standard ass-covering therapeutic diligence.

That said, psilocybin’s safety profile is remarkably benign. A large survey of over 12,000 users found serious adverse events in less than 0.2% of cases, and most of those involved psychological distress rather than medical emergencies. The LD50 (lethal dose for 50% of subjects) in animal studies suggests you’d need to consume roughly 1000 times a typical therapeutic dose to risk death from toxicity alone.

Initially, I didn’t feel very different, but within a day or two, I’m quite confident of several changes.

For one. I don’t feel depressed. That’s the big one, I’d spent months down in the dumps, overwhelmed by self-loathing, self-pitying, occasionally suicidal ideation and lots of ruminating and sighing. As far as I can tell, it’s all gone.

This rapid onset distinguishes psilocybin from conventional antidepressants, which typically require 4-6 weeks to show efficacy. The substantial antidepressant effects of psilocybin-assisted therapy, given with supportive psychotherapy, may last at least a year for some patients, with many people reporting improvements within days of their session. The proposed mechanism involves rapid synaptogenesis: new synaptic connections form within hours to days of psilocybin administration, potentially “resetting” dysfunctional neural circuits.

I’m not euphoric, far from it. The best I can describe it is feeling… normal. Yeah, my life isn’t the best it could possibly be, but why feel so sad and hopeless about it?

This “normalization” rather than euphoria is typical of therapeutic psilocybin experiences and represents a key advantage over conventional antidepressants, which can sometimes induce emotional blunting or artificial mood elevation. The sense of cognitive clarity and emotional equilibrium I describe aligns with neuroimaging findings showing that psilocybin reduces hyperactivity in the default mode network, a brain network associated with rumination and self-critical thinking.

Another change I think I’ve noticed:

My head feels quieter. I’ve got ADHD, and it’s usually quite busy in here. I’m used to it, I find myself good company most of the time. And yet, the apparent volume/noise of my inner monologue or that of my cognition is noticeably dampened. I don’t mind, I consider it a neutral change, albeit a significant one.

This “quieting” effect is consistent with psilocybin’s impact on thalamic filtering mechanisms. A single psychedelic dose of psilocybin changes synaptic vesicle protein 2A (SV2A) and 5-HT2AR density in the pig brain, potentially altering the balance between excitatory and inhibitory signaling. The thalamus normally acts as a “gatekeeper” for sensory and cognitive information reaching consciousness. Psilocybin appears to reduce this filtering, which during the acute phase can lead to sensory overwhelm, but in the days and weeks following may result in a more peaceful, less “noisy” mental state.

What didn’t happen:

I admit that, for a long time, I’d been put off the idea of taking psychedelics by some rather pernicious potential side-effects.

Hallucinogen Persisting Perception Disorder (HPPD) is scary. It can range anywhere from mild visual snow to levels that are debilitating. It might even be life-long. While you can avoid the risks to some degree by not taking heroic doses of brain-altering chemicals, you can never really eliminate it. Fortunately, I’m still safe.

HPPD remains poorly understood, but current estimates suggest it affects somewhere between 0.5-4% of psychedelic users, with higher rates associated with frequent use and high doses. The mechanism likely involves persistent changes in visual cortex excitability, possibly related to altered GABA signaling. Interestingly, single-dose therapeutic use (as in clinical trials) appears to carry minimal risk compared to recreational use patterns. Still, it’s a legitimate concern that deserves mention in any honest risk-benefit analysis.

Catching religion: I’m not a “spiritual” person, and I wouldn’t like to be. My tolerance for woo is non-existent, and I’m quite content in the cycles of samsara, thank you for asking.

I look askance at people who consider the kinds of “insight” produced by psychoactive substances meaningful. I’m well aware of what’s going on, in this case, I wanted to reboot my brain with the intent of clearing up some lingering bugs. It’s a mistake to interpret the equivalent of your brain BSOD’ing as some kind of revelation about the underlying firmware.

This perspective puts me somewhat at odds with much of the psychedelic therapy literature, which often emphasizes “mystical experiences” and “spiritual awakening” as key therapeutic mechanisms. While it’s true that many people report profound spiritual insights during psilocybin sessions, and these experiences do correlate with therapeutic outcomes, I suspect the causation runs in the opposite direction. The therapeutic benefits likely stem from the neuroplastic changes I mentioned earlier, and the spiritual interpretations are simply how many people make sense of these dramatic shifts in consciousness and mood.

I feel no compulsion to namaste at people, no sense of one-ness with the universe. I’m happy keeping it that way. Even during the trip, I was a bog-standard materialist, not at any risk of losing myself.

The “ego dissolution” that’s often described as central to psychedelic experiences was notably absent from my session. This might reflect the moderate dose, my skeptical mindset, or individual variation in drug response. Some research suggests that ego dissolution isn’t necessary for therapeutic benefit, though it does appear to correlate with larger effect sizes in some studies. The fact that I maintained my basic worldview and sense of self throughout suggests that the therapeutic benefits don’t require abandoning one’s fundamental beliefs or experiencing mystical transcendence.

How do I feel about the whole affair? Rather positive. The antidepressant effects of psilocybin, while variable and not necessarily permanent, are relatively long-lasting. This is a good thing, because it wouldn’t make for a very useful antidepressant if you had to get as high as a kite every alternate day.

Current data suggests that single psilocybin sessions can produce antidepressant effects lasting 1-12 months, with a median duration of around 3-6 months. Repeated doses of psilocybin were associated with greater antidepressant effects, though the optimal dosing schedule remains unclear. Compare this to conventional antidepressants, which require daily dosing and often lose efficacy over time due to tolerance, and the therapeutic potential becomes obvious.

The risk profile is quite favorable, the subjective sensations, while occasionally uncomfortable, are well worth it. People take the stuff recreationally, and while I had noble, medicinal™ intent in mind, I won’t lie and claim it wasn’t fun.

More than 5 million Americans (and a few million Brits) would be eligible for psychedelic therapy based on current diagnostic criteria for treatment-resistant depression. If psilocybin therapy achieves FDA approval and a NICE sign-off (which seems increasingly likely given the current trial results), we’re looking at a potential paradigm shift in psychiatric treatment. The economic implications alone are staggering: treating 5 million people with two sessions annually instead of daily medication could save the healthcare system billions while potentially improving outcomes.

Ask your doctor if Shroomvera™© is right for you!