Psilocybin Bests SSRI for Major Depression in First Long-Term Comparison

The methodology is also kind of strange, the psilocybin group got a total of 20 hours of in-person therapy during their 'treatment' and 6 follow-up skype calls, whereas the SSRI didn't get anything other than the 6 month questionaire. Those 20 hours of personalized therapy while they were dosing had no effect on their psychology? Any change was all a result of the psilocybin and not the 20 hours of therapy?

They also measured results by a self-administered 16 question "quick inventory" depression survey. To enter the study they had to be officially diagnosed with major depression by a doctor, but the results of the study were based completely around a self-reported 16 question questionaire?

An ironclad rule for medically approved drugs is that no fun is allowed - approved drugs must not have any positive effects on mood or well-being or must come with such heavy side effects that no sane healthy person would willingly take them.

For some reason, the medical profession considers the enhancement of one's quality of life beyond some arbitrarily chosen 'healthy' baseline to be forbidden, and is in cahoots with the executive branch to gatekeep it at all costs.

> Normally the journey is quite inward, so patients do not require active support during the psychedelic experience [around 6 hours]. Sometimes they do require some hand-holding, or helping them to 'let go', or breathing exercises. The important part is the integration work that comes afterwards," Barba added. [...]

> However, [Rucker] noted, it is also possible that the results reflect biased reporting between groups. This is more likely here because studies involving psilocybin tend to attract those with positive preconceptions about psilocybin and negative preconceptions about conventional antidepressants

The issue is that what people generally say, like, “oh sometimes you need to encounter your demons,” maybe that will be temporarily traumatizing—in general people recover from that. The real issues are…more complex. More complex than any diagnoses in the DSM can cover. The brain is very complicated, and everyone’s brain is a bit different, and we do not know, really, what goes on in there when you take a drug like Psilocybin. Sometimes something gets a little knocked out of place, and the system doesn’t fully recover.

The last time I took a very high dose of psychedelics I couldn’t think straight for a few weeks after. Thoughts came out of nowhere, I had no control over them; often the constant, unceasing flow of thought was distressing and uncomfortable. Thankfully I could still talk to people—talking made me better. I got plenty of sleep, cut out all drugs, even caffiene, got regular exercise and ate a very healthy diet: about a year and a half later I was back to my old habits. But it wasn’t an easy recovery, and certainly not one any psychiatrist could’ve treated adaquetely. But, now I know to be more careful in the future.

People worry about various side-effects: I work extremely hard and know others who have done psychedelics and continue with b2b saas and similar.

That said, it’s serious stuff. I think it permanently increased the amount that I like music; other studies show longtitudinal changes to big-five personality traits. Proceed with caution.

My chronic depression is mostly gone, but I have noticed an uptick in physiological signs of anxiety (though no mental signs).

But more importantly, my gut health is better than it has been in 12 years. I am eating more and losing weight. My energy levels have skyrocketed. My impulsiveness has catered so hard that I was worried my libido was impacted. My executive function issues and ADHD are greatly minimized.

All from a supplement. Utterly life changing.

A more wholistic approach to health care would be beneficial. For folks looking for more depth or purpose, Psilocybin seems to help reconnect people with a part of themselves they only dimly remember.

I often hear people talk about the risks of psychedelics, which are to be considered, but what’s the risk of doing nothing or withholding the best treatment?

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4172306/

I guess maybe it doesn’t even matter in the end as long as people feel better.

That being said, there are a number of studies that suggest this is an effective treatment, so I hope this can become more available to those who need it. However, for treatment resistant depression (especially with a catatonia component), intranasal ketamine is very hard to beat. Only topped by ECT in my experience.

https://www.mayoclinic.org/diseases-conditions/depression/in...

>Post-SSRI sexual dysfunction (PSSD)[62][63] refers to a set of symptoms reported by some people who have taken SSRIs or other serotonin reuptake-inhibiting (SRI) drugs, in which sexual dysfunction symptoms persist for at least three months[64][65][66] after ceasing to take the drug. The status of PSSD as a legitimate and distinct pathology is contentious; several researchers have proposed that it should be recognized as a separate phenomenon from more common SSRI side effects.[67]

>The reported symptoms of PSSD include reduced sexual desire or arousal, erectile dysfunction in males or loss of vaginal lubrication in females, difficulty having an orgasm or loss of pleasurable sensation associated with orgasm, and a reduction or loss of sensitivity in the genitals or other erogenous zones. Additional non-sexual symptoms are also commonly described, including emotional numbing, anhedonia, depersonalization or derealization, and cognitive impairment.[64][68] The duration of PSSD symptoms appears to vary among patients, with some cases resolving in months and others in years or decades;

https://www.pssdnetwork.org/

At least, the mushroom didn't steal my mojo

Also, SSRI can definitely kill your sex life - and by extension your relationship(s) as well. And not just short-term (physiological changes have been observed). SSRIs have never been the best option (except for pharmaceutical companies).

From my personal experience, SSRI (zoloft) felt like a temporary coffee-like stimulant. Psilocybin (or easier to handle synthetic analog 4-aco-dmt) provided short-acting relief from depression and some new perspectives. But ketamine is truly a magic pill if done right. After glow is about a month, and the trip takes 2-3 hrs max. FDA-approved, see Spravato. I feel like at some point ketamine therapy at scale would make SSRIs obsolete, it's just better and faster.

https://www.thelancet.com/action/showPdf?pii=S2589-5370%2824...

Study design and methods:

> "All the patients provided written informed consent and after discontinuing any pre-trial antidepressants, enrollees received two oral doses of psilocybin (1 mg or 25 mg) with accompaniment from two experienced therapists for ∼6–8 h, separated by 3 weeks, as well as daily pills (escitalopram 10–20 mg or placebo capsules). Thirty patients were randomised to PT and 29 to ET."

> 'The PT condition consisted of two high-dose (25 mg) treatment sessions with the serotonergic psychedelic psilocybin, administered with support from two study therapists...and daily placebo capsules. The ET condition consisted of daily doses of the selective serotonin reuptake inhibitor (SSRI) escitalopram - 10 mg for three weeks followed by 20 mg for a further three weeks—as well as equivalent psychological support including dosing sessions with placebo-like doses of psilocybin (1 mg)."

This is an interesting way to address the placebo issue, giving a noticeable microdose of psilocybin (1 mg) versus the active dose (25 mg) for the non-control group.

Fundamentally I think psilocybin's main overall psychological effect is to push subconscious issues up into the mind's conscious processing space. Large doses can generate visual hallucinations related to those subconscious issues which can be unpleasant, even terrifying, for many people, so that's why caution is warranted. Extremely large doses cause complete dissociation from external sensory input, which is of course very dangerous for the unprepared individual in an uncontrolled situation - an experience unlikely for any herbivore to want to repeat, hence the evolutionary selection pressure for biosynthesis of such compounds by plants and fungi.

Great idea to compare a new trendy treatment with promise of potential financial windfalls to another treatment that barely works. If you kept feeding them cocaine under medical supervision, they'd probably report feeling slightly better, too. They're recreational drugs. People take them because they feel good. The most common symptom of depression is to take refuge in drug consumption.

Shrooms sadly do not agree with my digestive system.

Bio:

- Late 30s.

- Long history of depression my entire life. "Melancholic" child. Bad drunk teenager. Suicidal in college (failed attempt).

- No drugs except alcohol until I was in my mid 20s.

I've been prone to major bouts of depression my entire life. I went to therapy multiple times a week for years and got on SSRI's towards the end of university as a response to a failed (but serious) suicide attempt.

SSRI's never did anything for me except make me feel like shit (and not be able to take one). Eventually I went off them and sort of got by, and I managed to stay safe by drinking no alcohol. Therapy twice a week was an utter waste of time and money.

Then, sort of on a whim, I grew some mushrooms at home with my then fiancée and we took them together. I was mid 20s and had no prior experience with any drug but alcohol. Not knowing what I was doing, we took a BIG dose. I had a trip that was fun at first and then became quite unenjoyable.

For the next twelve months I felt like myself again. The change was subtle but, over a long term, quite obvious.

After about 18 to 24 months, my depression came back. We took mushrooms again and the same thing happened. A year of well being in exhcange for 2 fun hours and 6 tough ones.

So about every two years I'll take a big (2-4g dry) dose of mushrooms and...it's like magic. I feel like myself again. I'm "back." Life is not happy, none of my problems go away, but I feel like I'm an agent in my own life as opposed to a spectator.

The well being lasts about a year or 18 months (less if I've been drinking alcohol). It's almost never as bad as when I was suicidal, but it still sucks. For me depression is like being a professional chef and one day your taste buds make everything taste like ash. Or a painter and one day you see colors less and less.

Last year I went into a VERY deep depression, so deep that I refused to take mushrooms until my wife basically forced me to. Same thing. The very next day I felt like "I was back."

Those things changed my life.

I've since had fun with other drugs maybe 5 times. Acid a couple times, molly a couple times. Cheap (wtf) fun for a half a day, but nothing like the impact mushrooms have on my mind.

I've had one bad trip while taking mushrooms recreationally. I don't understand who would take those things for fun, at night.

Strictly during the day, well-rested, with loved ones, and in nature!

I'm also convinced that the impact they have on me is purely chemical. It has nothing to do with "facing my demons" or "connecting with a higher spirit" or anything like that. I just get off my stupid rut.

"Neurons that fire together wire together" as they say, and when I'm depressed it's the stupid neurons that fire together. Mushrooms makes a whole different set fire, and fire hard, and that seems to be enough.

The deepeest lesson I've gotten while on shrooms is:

"I'm trying my best. Everything is actually fine."

Pretty good lesson.

"How to Change Your Mind" by Michael Pollan

There's also a Netflix doc series based on the book.

https://michaelpollan.com/books/how-to-change-your-mind/

https://news.ycombinator.com/item?id=41283493

one time much later i was in the hospital because i had a bad fever. maybe i was being kind of paranoid for going in. but as i was laying in the hospital bed my fever suddenly broke. and a wave of intense depression, unmistakable, washed over me. i thought this might be turning into an emergency but soon enough it passed as if nothing had happened. it was very useful to know about the connection between inflammation and depression during that little journey.

why is the connection between inflammation and various psychiatric diseases not taken seriously by the medical establishment? because its too complicated of a subsystem for a statistical study to tease it out. even if it were the sole cause of depression it still wouldnt lend itself to any study that is not exploring directly the biochemical mechanism. expect some breakthroughs in this area.

The primary outcome of depression symptoms (QIDS-SR-16) was not significantly different between the groups. The sample size is small and unrepresentative of the real-world population of depression patients - the trial participants are very disproportionately male and university-educated. There are obvious and much-discussed issues with blinding in psychedelic trials.

These results point to a treatment that may be superior to treatment-as-usual for a minority of patients, but the results certainly aren't revolutionary. There is still the potential for significant risk in wider clinical populations who may have psychiatric comorbidities that would exclude them from trials like this, and in delivering psychedelic treatments in more normal clinical settings that are likely to be far less carefully controlled than a clinical trial.

Not even getting into the side-effects of SSRIs including PSSD, brain zaps, lethargy, and a whole lot more.

I just don't understand people who do this shit recreationally, as it was quite possibly the worst experience I had in my life.

2021: https://jamanetwork.com/journals/jamapsychiatry/fullarticle/...

2022: https://www.jwatch.org/na55225/2022/08/16/antidepressants-wo...

2023: https://www.nature.com/articles/s41380-022-01661-0

In any case, I believe that ADHD, Depression and many other “umbrella” psychiatric diagnoses are being overdiagnosed, much like “hysteria” was for hundreds of years (eg 1 in 4 middle-aged women is on antidepressants now, and the opioid epidemic in men was largely exacerbated by the pharma industry, as has the overdiagnosis of ADHD prescribing amphetamines to kids).

To be fair, the actual incidence of phychiatric conditions from ADHD to autism to depression has increased, as well as autoimmune disorders, diabetes etc. although not as much as the pharma industry wants us to believe. It could very well be the result of upstream changes in nutrition (eg wild increases in sugars like fructose across the board, antibiotic overuse on factory farms, buildup of microplastics everywhere etc.), and to a large degree society (including loneliness, dating, relationships, work, etc) and medicating them downstream (eg with amphetamines or opioids) is just a bandaid.

Late stage capitalism has had a direct role in exacerbating this. For example, the tech industry (which many on HN are involved in) has redefined dating, relationships, job searches, political discourse, and much more. All of these affect how people interact. A seminal book even back in 2001 was “Bowling Alone” by Robert Putnam, who noticed Americans aren’t attending communal activities like they used to. Corporations have co-opted many movements (like women’s lib) to make people work harder, neglect their kids, eat unhealthy food, become obese, develop diabetes, lose sleep, and now be part of the gig economy etc.

I like to show this Cadillac commercial from 2014 as a great example of the corporate brainwashing: https://www.youtube.com/watch?v=xNzXze5Yza8

Working as a clinical psychologist, who also reads a lot of research, this study is just another brick in the wall that I am banging my head against when it comes to doing actual evidence-based therapy. I actually read the entire paper and the pre-registration. The title on Medscape and the article are, to me, completely reading the research wrong, and just another example of the actual research design and findings living in a different universe than the press release and subsequent discussion.

Let me try to communicate why I feel this way by summarizing the research in my way, as opposed to the title: "Psilocybin Bests SSRI for Major Depression in First Long-Term Comparison."

Hers my take: Research finds no significant difference between psilocybin and SSRI in the primary outcome from pre-registration (self-reported depression on an emailed form), even when only administering SSRI for 6 weeks, where the maximum effect of SSRI is expected at 12 weeks. As such, this does not even qualify as standard treatment with SSRI. This is after excluding 90% of the applicants for the study. The effectiveness is primary supported by p-hacking, as seen by reporting additional measures not in the registered, where some of them favor psilocybin. And SSRI actually scores BETTER in the main outcome.

Now, someone might come along and call me cynical, mistaken, or worse. But having been through this with biofeedback, metacognitive therapy, light therapy, mindfulness therapy, and ketamine treatment already, I can clearly see the same pattern: lying by omission, p-hacking, not taking into account the "decline effect," borderline acceptable results. It all culminates in a big nothingburger, and any progress for my field remains stagnant. Based on the quality of this study, I am certain that if we just aggressively started treating depression with psilocybin, I just know that it wouldn't make much difference, because I have been through it before with the exact same numbers and effect sizes, just different treatment modalities.

Here is the best indication I found for SSRI: Resistant phobic anxiety (panic attacks that don't stop even after long exposure), and burnout-related depression (person worked normally their whole life but is suddenly just empty of energy and does not look forward to anything with joy). These are examples that very often make a big difference with SSRI, in conjunction with therapy.

Psilocybin seems to work best for existential depression and anxiety that is driven by pathological self-focus (not egotism, but inability to stop focusing on one's own inner states).

But these personal theories are just that, and the studies that keep getting funding are very seldom useful, at least for me, as I genuinely am trying my best to help my patients.