This is NOT a trial that was designed to assess the safety of psilocybin. This was a trial meant to show that a particular dosage of psilocybin is /safe enough/ to pursue further research in that dose range.
This was a /phase one/ clinical trial.
Phase One: administer small doses under very close supervision in a tiny number of people to determine whether it's immediately dangerous, or safe enough /for further study/. They used 89 - initial randomization of 30 each to placebo, 10mg, and 25mg. That's a good number for a phase one trial. But when we look at the sort of things that start hurting people when released to market, they're the sort of adverse effects that go undetected in trials with thousands of participants, and would need an infeasible large trial (>10k patients) to detect.
This trial does not prove safety. This trial is meant to establish a dosing range that is /safe enough/ to participants to allow for further study. They found no "serious" adverse effects, in healthy volunteers - that is, not depressed patients. Can drugs like this have different effects in people w and without depression? Yes they most certainly can, in particular if those people are on concurrent medications (which they will be, since this is being developed for treatment-resistant depression).
“We wanted to look at the safety and tolerability profile of our psilocybin, and to look at the feasibility of a model where up to six one-to-one sessions are held at the same time." No they didn't /want/ to - they /had/ to. This is article is just a press release.
Phase 2 is generally a range of doses, within the range established in phase one, wherein we attempt to determine, to a rough level of accuracy, which doses show toxicity, which show therapeutic benefit, and at roughly what proportions. This phase is meant to determine what dose will be used in a phase 3 trial, if any dose exists with an appropriate proportion of therapeutic benefit to side effect.
Phase 3 - a dose (or couple of doses) of a drug in a regimen meant to reflect real-world proposed usage is distributed and compared against either a currently used drug or a placebo. Depending on how big an effect is expected, how common the disease, etc. we'd look at trials of hundreds to thousands of patients. This is the trial where we get a real sense of safety, side effect profiles, efficacy, etc. This is the make-or-break line for getting your drug to market.
Phase 4 "trial" - aftermarket surveillance. Goes on for years after a drug hits market, because there's no trial that comes to close to capturing the rare side effects that may be visible when applied to the general population.
This was, also, presented to a neuropsychopharm conference, not published data. Which is to say, they're ready to brag about it, but they're not ready to submit themselves to close scrutiny.
Defines Toxicity level 4 as ~ 2000 to < 5000 mg/kg
The most potent strain of "magic mushrooms" are at most ~2% by weight(Psilocybe azurescens)[0]. So according to all the de facto standard literature, a potentially fatal dose of magic mushrooms is over 3 ounces of dried mushroom per kilogram of body weight. At 68 kg I would need to ingest over 5 kg to come up to the lower bound of the LD50.
No one without an axe to grind could realistically argue toxicity is a real valid concern.
Acute toxicity and LD50/fatal dosages are fine when you're worried about acute overdoses or unintentional ingestions.
Those are not the measures we are concerned with when we're talking about uncommon or rare effects (which, like the Vioxx deaths, had an incidence of one in /thousands/ at standard dosages), or effects that manifest with /chronic/ usage (e.g., over years of use, as is common with anti-depressant therapy).
It's worth noting that they were testing with 10mg and 25mg, which is equivalent to about 2g and 4.5g of dried mushrooms which are significant doses (e.g. far from microdosing). They reported no significant negative effects on cognitive and emotional functioning which is surprisingly positive for such an experience. Instead it is just the expected psychedelic experience.
As to safety, the LD50 of psilocybin is pretty well established at very high levels, with physical effects being unreported below that.
The press release noted no negative effects. The poster they presented to the neuropsychopharm folk the other night noted a few hundred, but none life-threatening.
Still big news that anyone is even doing phase 1 trials, since you wouldn't tend to bother if you didn't intend to follow up with further phases. I.e. "X is safe in a phase 1 trial" is never a useful terminal fact that you set out to prove and then, having proven it, do nothing more.
The vast majority of drugs don't make it through phase 3. Most will fail by the end of phase 2. If we trumpeted every time a prospective intervention underwent the earliest phases of study... well, I guess we'd have what we have had for years. Constant claims of miracle drugs on the way, with almost no subsequent impact on human lives.
If you find the endless hype a source of optimism and hope, then ... well, I guess I /am/ glad you have another source of optimism and hope. I don't share it, though.
Oh, to be clear, I'm not excited by the prospect of psilocybin making it all the way to FDA approval. What excites me is that this is more evidence of a pattern of change in what medical research is being conducted. There were many drugs that we were "leaving on the table" before, that we're actually bothering to look into now. Whether or not they turn out to work for anything, at least we'll know, instead of pretending they don't exist!
Thanks for this breakdown. Any thoughts on how this process might unfold for psilocybin as opposed to a drug that's subject to a chemical patent? Funding, timing, etc.
I'm not familiar with the company running this trial, but I can basically guarantee you they have found a way to patent this. Their intention is to come to market in 5 to 10 years, and there's no way they're bearing the expense of phase 3 trials just to become a generic manufacturer. Psilocybin isn't hard enough to manufacture (as opposed to say, propofol) to provide any sort of moat. They'll probably try to patent either an extended-release form or a particular administration device (e.g., inhaler).
E.g., the company that did the major trials for ketamine actually studied the s-enantiomer of ketamine using a nasal spray, which is quite distinct from the years of data we've accumulated on racemic ketamine with prolonged IV infusion. But this let them get a patentable version of ketamine on the market.
Are controlled experiments necessary for proving safety? Intuitively, there shouldn't be a placebo effect, and you could get twice as powerful a study by giving twice as many people the drug and using statistics for the general population as the control group.
No. For phase 1, it's generally sufficient to show that few or no people had life-threatening adverse effects, that none of the life threatening effects were plausibly related to the drug, and there were no meaningful hiccups in CNS, pulmonary, or cardiac function.
In this case, they went for a placebo set-up because they were also trying to grab a little data to show whether 25 mg was significantly distinct from 10mg. The comparison to placebo was not needed, but is winning them a little extra publicity.
What is general population? I guess the study exclude people with more than 95 year old and people with terminal cancer. Other exclusion factors are not so clear, so you need to know the results of no treatment in the same population. For this, you need to split the group at random.
Note also that the study probably include some regular visits to the hospital. Some people may eat more healthy food a few days before a blood exam so the doctor gets happier. Some people may change other habits, like no binge drinking. So you need to measure the results in a group that follow the same explicit and implicit rules.
Does the report of the symptoms use the same criteria in the study than in general population? What about dizziness? Does this produce dizziness? Does the general population report dizziness to their family doctor? Replace dizziness with chest pain, or constipation, or whatever symptom you are interested.
Also, people lie to their doctor because they try to be nice. It's not a voluntary lie, but if there is a study about curing something, people want to be nice and give optimistic feedback. You must have a double blind control group so you can compensate this.
Why shouldn't there be a placebo effect? It's well documented for basically any drug, even for alcohol. Serve people non-alcoholic drinks but tell them otherwise, and they get drunk.
Because the trial wasn't about finding the expected effect (drunkenness) but the secondary effects. People don't get heart disease or cirrhosis from non-alcoholic drinks, or at least, I'd be interested in reading the study where they do.
No, but they can get short-term secondary effects such as nausea, headaches the next day, etc. Probably this category of things is what they want to control for.
This was a /phase one/ clinical trial.
Phase One: administer small doses under very close supervision in a tiny number of people to determine whether it's immediately dangerous, or safe enough /for further study/. They used 89 - initial randomization of 30 each to placebo, 10mg, and 25mg. That's a good number for a phase one trial. But when we look at the sort of things that start hurting people when released to market, they're the sort of adverse effects that go undetected in trials with thousands of participants, and would need an infeasible large trial (>10k patients) to detect.
This trial does not prove safety. This trial is meant to establish a dosing range that is /safe enough/ to participants to allow for further study. They found no "serious" adverse effects, in healthy volunteers - that is, not depressed patients. Can drugs like this have different effects in people w and without depression? Yes they most certainly can, in particular if those people are on concurrent medications (which they will be, since this is being developed for treatment-resistant depression).
“We wanted to look at the safety and tolerability profile of our psilocybin, and to look at the feasibility of a model where up to six one-to-one sessions are held at the same time." No they didn't /want/ to - they /had/ to. This is article is just a press release.
Phase 2 is generally a range of doses, within the range established in phase one, wherein we attempt to determine, to a rough level of accuracy, which doses show toxicity, which show therapeutic benefit, and at roughly what proportions. This phase is meant to determine what dose will be used in a phase 3 trial, if any dose exists with an appropriate proportion of therapeutic benefit to side effect.
Phase 3 - a dose (or couple of doses) of a drug in a regimen meant to reflect real-world proposed usage is distributed and compared against either a currently used drug or a placebo. Depending on how big an effect is expected, how common the disease, etc. we'd look at trials of hundreds to thousands of patients. This is the trial where we get a real sense of safety, side effect profiles, efficacy, etc. This is the make-or-break line for getting your drug to market.
Phase 4 "trial" - aftermarket surveillance. Goes on for years after a drug hits market, because there's no trial that comes to close to capturing the rare side effects that may be visible when applied to the general population.
This was, also, presented to a neuropsychopharm conference, not published data. Which is to say, they're ready to brag about it, but they're not ready to submit themselves to close scrutiny.