Dose-dependent effects of LSD in double-blind placebo-controlled study (2020)
25 comments
·February 12, 2025monkburger
nabla9
There was 96 experiments total. 16 participants, each going trough 6 sessions separated by at least 10 days.
indiantinker
Agreed. I mean n=16 and its on nature.
cypherpunks01
> Sixteen healthy subjects
> Six participants had previously used LSD
> The sessions were conducted in a calm hospital room.
> Standardized lunches and dinners were served at 1:30 p.m. and 6:00 p.m
> The subjects were never alone during the first 16 h after drug administration
> The study included a screening visit, six 25 h test sessions (each separated by at least 10 days)
I understand the concept of informed consent, but the study design sounds bad to me, to be honest. According to S1, seven of the subjects had never taken any psychedelic (LSD/psilocybin/MDMA). The study confined them for their first LSD experience, and likely multiple followups, in a hospital room, with a stranger who was not on LSD. And six sessions? LSD should not be used multiple times within 1 year, in my opinion, let alone 2 weeks apart, I think multiple rapid use unnecessarily increases the low-ish risk of psychosis. No matter how nice the room, this seems unethical to me for a few reasons. People shouldn't be experiencing their first psychedelics in a hospital room unless they can't physically leave a hospital bed. I just don't think the basic dose-response curve gains us much new science, this is exactly what most people would draw who have experimented with LSD doses between 25-200ug (though the BDNF effects are interesting as another commenter mentioned).
I guess this is a general problem for all psychedelic studies, though. There's no way to place all the necessary controls around the subject, without keeping them indoors and making them feel like a trapped mouse. The inability to change your own setting during a significant psychedelic trip can definitely induce or prolong major anxiety, much more for someone experiencing novel effects for the first time.
hx8
> I think multiple rapid use unnecessarily increases the low-ish risk of psychosis.
Not that I disagree, but the 200ug dose is generally considered safe in a clinical setting, and most doses administered were smaller. Assuming individuals were screened for mental health risks before entering the study I don't think the risk was significantly elevated because of the dosing rate.
edm0nd
>LSD should not be used multiple times within 1 year, in my opinion, let alone 2 weeks apart, I think multiple rapid use unnecessarily increases the low-ish risk of psychosis.
People regularly dose LSD dozens of times a year or even month without any issues.
6 times is no big deal imo.
pessimizer
This all sounds like warmed-over hippie-lore. I would have loved for my first time to take LSD to have been in a completely safe, clean environment filled with treats, doctors, and other people who were attending to me. The worst parts of the first experience for most people are fear of police, fear that one is having a medical problem, and fear that one is being a problem for the people they're with. This experience has precisely none of that.
It's good that they got data from first time users. It would be even better to get data from people who hadn't been set up with psychedelic culture expectations, but that jury pool is hopelessly tainted.
> I think multiple rapid use unnecessarily increases the low-ish risk of psychosis.
I don't think there's any good evidence that LSD affects the rate of psychosis, just the entirely expected outcome that people who have psychosis may be triggered to express that psychosis by LSD use, combined with the statistical fact that people try psychedelics at the same period of life as schizophrenics start showing their first symptoms (late teens to early 30s.)
lm28469
> doctors, and other people who were attending to me
I did my fair share and this sounds like absolute hell on earth. But then again my first trip was alone deep in the middle of the woods, still my best drug related experience so far, and that was more than a decade ago
neom
Very interesting to me that the BDNF effects were present with 5-HT2A blocked. Also interesting to see how much deeper they were at 200ug. Would be interesting to see a much longer temporal profile of the BDNF response. If this is also interesting to you, you might enjoy: https://pubmed.ncbi.nlm.nih.gov/29898390/
TeaBrain
One of the hypothesis I've seen thrown around is that the therapeutic effects, including the increased neuroplasticity, may be largely due to TrkB, and may have little with 5-HT2A alone. Apparently, the effects on TrkB are shared by some prescription antidepressants, including SSRIs. One of the studies listed under the study linked by you is related to this idea:
"Psychedelics promote plasticity by directly binding to BDNF receptor TrkB" https://pmc.ncbi.nlm.nih.gov/articles/PMC10244169/
corry
Thanks for sharing, although I'm curious what prompted this to be posted in 2025?
I've heard from a few underground psychedelic facilitators that LSD is one of the best 'medicines' for therapy of various kinds, but (a) the duration is often uncomfortably long, (b) the social/political stigma hangover from the 60s adds undesirable connotations which can 'prime' the participant in negative ways, and (c) the variability in street doses makes it unpredictable to work with if you don't have a way of measuring potency yourself (which I would argue disqualifies you from being a facilitator to begin with, but that's a separate topic...)
As for duration, this research indicates that lower doses are metabolized much faster (6.7 hours for 50ug vs 11+ hours for 200ug) which could help although the tradeoff is less 'good effect' even if 'bad effect' is minimized as well.
However, with respect to dose potency, a PSA for anyone new to this area -- go to the /r/LSD subreddit and read the pinned post on street dosages -- in short, street doses are on average ~100ug below what they claim.
So when this study says that 50ug produces such and such effects -- and the typical psychonaut on reddit might roll their eyes at such a 'light dose' -- keep in mind that an accurate "50ug" in a lab likely means "150ug" on the street which is a fairly typical dose sold. Of course the data shows an occasional over-dosed tab vs. the reported value, too.
Which leads to the most important PSA of all: please don't put any psychoactive substance into your body without having a lot of confidence in its actual composition and dose.
foobiekr
You forgot (d) which is that the people involved are often terrible people.
The issue of people on mind-altering substances being involved with "facilitators"/therapists who use that power for their own ends showed up even in the recent MAPS trial with alleged professionals.
LSD and other psychedelics like mushrooms of mescaline are best used with someone who actually cares about you in a setting you control for self-exploration and absolutely devoid of the kind of people who become psychedlic-assisted underground therapists.
corry
I hear you, and it's a good warning, but I think the word "often" in your first sentence requires some qualification or maybe nuance.
It's no different from any other potential for abuse from someone with power - the way to mitigate it isn't merely to try pick good people (of course, start there), it's to wrap the vulnerable elements in protective practices and institutional controls to prevent abuse if an individual actor fails to live up to the standard.
For example, in the biggest abuse scandal of our generation (sexual abuse by Catholic priests), it's not just that the priests did great individual evil but also that the institution itself utterly failed to do anything about it or even abetted it.
However, the illicit nature of psychedelics makes those kinds of controls or institutions impossible or very hard to put in place.
Finally, for the abuse in the MAPS MDMA trial (which was 1 patient out of 200 participants) to be used as evidence that psychedelic therapy is more prone to abuse, you'd have to look at the rate of abuse among therapists and psychologists as a whole to know if it's par for the course or something extraordinary.
Bad actors will try to take advantage of the vulnerable -- and these drugs put you in a more vulnerable position than otherwise -- so your warning still stands. I just don't think these issues are unique to this stuff other than the legal status.
foobiekr
I think you’re basically ignoring the history. I cited the MAPS example specifically because it was a highly observed study where the people involved were incredibly aware of what had gone wrong in the past with psychedelic-assisted therapy and even given that still couldn’t keep it out of a single trial.
The history of psychedelic use in therapy is part of how we got here in the first place. The therapists in the 50s and 60s were engaging in inappropriate behavior with their patients with regularity.
I am very pro psychedelics but the 60s provides an almost endless array of examples of how it can go wrong. Psychedelics basically do not belong in a therapist to patient context because the therapists attracted to that approach have a tendency self-select.
A lot of the modern day gurus and shamen have exactly the same problem.
wing-_-nuts
>with someone who actually cares about you in a setting you control for self-exploration
Yeah I've never tried any psychedelic. I once had a girl offer to 'trip sit' me but honestly, I was too worried about old traumas coming up. I liked her and I did not want her to see that.
foobiekr
I hear you. I didn't try any of them until I was in my late forties. I don't drink and we basically tried pot a few times a year in our thirties. I read about set and setting and we decided to try it.
Taking mushrooms with my wife in our forties was probably one of the top ten most important things I've done in my life.
The traumas absolutely come up. That's kind of the point. They take you where you need to go even if you don't want to go there. I had a lot of rage and anger and deep embarrassments and now it feels like that's been scraped out of me, like a boil that needed to be lanced.
It's not for everyone to enjoy but I think it's for everyone, once or twice.
killjoywashere
Skimmed this. Is it just me or does the data look a little too perfect?
RIMR
Can you elaborate on this? If you see something suspicious about this, maybe actually explain what you saw...
neom
Not op but: dose response curves shown in their figures are quite smooth, and ceiling effect at exactly 100ug for positive effects with anxiety &ego dissolution continuing to increase linearly above that, some might read that as narratively convenient? I think it's a byproduct of it being 8:8 subjects in a well controlled setting, it's Liechti lab after all, they know what they are doing.
killjoywashere
Am op, sorry haven't had my coffee yet. Yeah, agree with noem. These curves would be smooth for a 3000-subject phase 3 trial. For 16 people? The error bars are even weirdly tight. One general truism: all the normals are the same, but abnormals are increasingly different in different ways. That gets more true as people get older, they just accumulate more varied life experience. Just looking at the participants section,
> "eight men and eight women; mean age ± SD: 29 ± 6.4 years; range: 25–52 years"
> "The participants were asked to consume no more than 10 standard alcoholic drinks/week and have no more than one drink on the day before the test sessions."
> "Drug administration timing did not consider the menstrual cycle in females for practical reasons. Four women used a hormonal contraceptive and one was menopausal."
> "Six participants had previously used LSD (1–3 times), eight participants had used methylenedioxymethamphetamine (MDMA) (1–5 times), ten participants had previously used a stimulant, including methylphenidate (four participants, 1–2 times), amphetamine (six participants, 1–3 times), and cocaine (two participants, 1–2 times), and one participant had smoked opium (once)."
These are not your standard young, male athletes you'd typically desire for a tightly controlled result.
zelon88
As someone who's done most of the substances listed in the article; none of this matters.
First of all, you can't take 16 people with the drug-taking profiles listed and reliably account for their drug and alcohol intake. 100% of their sample came into the lab as drug seeking individuals. Expecting them to only take drugs under your supervision is a fairy tale. Expecting them to tell the truth about their alcohol intake is also a fairy tale. I'm not trying to be incendiary, I am speaking from experience as a recovering alcoholic with 5 years sobriety.
Second of all, 10 day spacing between doses is insane, and dangerous. Having done this particular drug many times, I can tell you that it takes at least 2 days to feel "normal". And by that, I mean "as normal as you're ever going to feel." You see, LSD changes you... forever. Each time I took LSD I only ever "came down" 99.5%. That other 0.5% stays with you for years, if not forever. You never fully "come down" all the way. You're always just a little "less" than you were before.
Thirdly; this particular drug is not just mind altering, it is life altering. It unlocks things in your mind that permanently change your perception. I don't know anyone who's taken this drug who disagrees with this statement. This permanent altering of your consciousness is literally the thing you pay for and hope to receive.
Honestly science will probably never get LSD right. In order to do so the scientists would need to experience LSD first hand, several times before they could reasonably ever begin planning such an experiment. "You just don't know what you don't know."
null
cess11
"Thirdly; this particular drug is not just mind altering, it is life altering."
Why do you think that? In my experience most people that have used LSD changed little in their lives because of it. Looking back at the sixties, a lot of the people who dosed heavily then went on to work for the man or otherwise become very ordinary citizens.
pessimizer
> this particular drug is not just mind altering, it is life altering. It unlocks things in your mind that permanently change your perception.
I agree, but to 100x less of a degree than learning French, or becoming very good at chess.
One thing we need to pay attention to is the degree to which this chemical, and this class of chemicals, have been romanticized by the culture. Especially because these drugs make you more suggestible, expectations picked up from social lore can dominate one's subjective experience, and the memory of it.
luckydata
I just disagree with the "little less" statement. Your experience of dependence maybe colors your language, I would use different but not less, as my psychedelics experiences have taught me so much about myself I don't feel diminished in any way after having them.
The most egregious limitation is the absurdly small sample size (n=16), which utterly cripples its statistical power. The authors throw around p-values without any serious correction for multiple comparisons.. Their confidence intervals (CIs) are embarrassingly wide in several places, making many of their so called significant findings borderline meaningless. For example, their pharmacokinetic (PK) values show ranges so broad (eg: Tmax varying from 0.25–5.0h, CL/F spanning 1.6–22 L/h) that any attempt at a reliable dose-response relationship collapses under basic scrutiny; their p-values dance precariously around the threshold of significance. (There are many more)
If this is what’s guiding psychedelic research, we’re in serious trouble.