Psychedelics for depression

[sTeamTraen]

There is quite an academic spat developing over a recent paper claiming that psychedelics (e.g., MDMA) can reduce depression. Regular readers of the forum may recognise the name of Professor David Nutt as one of the authors. There's a good summary here.

I'm not sure where this movement has come from, but it seems to have been growing for a while. About 6 months ago I was invited to help debunk some claims about psilocybin, but after looking at it, it didn't match my particular set of skills™. Some people are claiming that there is something large and nefarious about it, but it's not clear why that might be. Maybe people who spent their student time dropping E's or eating shrooms are reaching the age where they're getting the big grant bucks.

[bob sterman]

This whole "psychedelics for depression" area is a bit different to "the vitamins/foods to prevent/cure disease" area.

We know that psilocybin, LSD and MDMA - in sufficient doses - can have huge effects on the brain and produce extremely pleasurable euphoric experiences. That's not controversial.

The key research question is - can they relieve depression when administered in doses sufficiently low that they don't also cause people to dance all night and claim to be the Messiah? And ideally low enough that people are left able to go about their normal daily lives.

So instead of messing around with one-tailed tests - Nutt et al should try upping the dose! Or getting a different dealer.

[Grumble]

This whole "psychedelics for depression" area is a bit different to "the vitamins/foods to prevent/cure disease" area.

We know that psilocybin, LSD and MDMA - in sufficient doses - can have huge effects on the brain and produce extremely pleasurable euphoric experiences. That's not controversial.

The key research question is - can they relieve depression when administered in doses sufficiently low that they don't also cause people to dance all night and claim to be the Messiah? And ideally low enough that people are left able to go about their normal daily lives.

So instead of messing around with one-tailed tests - Nutt et al should try upping the dose! Or getting a different dealer.

Nutt stated in an interview I heard that the dose he uses in trials is the same as a recreational dose, because that’s the amount required to produce a trip.

[discovolante]

This whole "psychedelics for depression" area is a bit different to "the vitamins/foods to prevent/cure disease" area.

We know that psilocybin, LSD and MDMA - in sufficient doses - can have huge effects on the brain and produce extremely pleasurable euphoric experiences. That's not controversial.

The key research question is - can they relieve depression when administered in doses sufficiently low that they don't also cause people to dance all night and claim to be the Messiah? And ideally low enough that people are left able to go about their normal daily lives.

So instead of messing around with one-tailed tests - Nutt et al should try upping the dose! Or getting a different dealer.

Nutt stated in an interview I heard that the dose he uses in trials is the same as a recreational dose, because that’s the amount required to produce a trip.

Was that psilocybin in particular?

[Grumble]

This whole "psychedelics for depression" area is a bit different to "the vitamins/foods to prevent/cure disease" area.

We know that psilocybin, LSD and MDMA - in sufficient doses - can have huge effects on the brain and produce extremely pleasurable euphoric experiences. That's not controversial.

The key research question is - can they relieve depression when administered in doses sufficiently low that they don't also cause people to dance all night and claim to be the Messiah? And ideally low enough that people are left able to go about their normal daily lives.

So instead of messing around with one-tailed tests - Nutt et al should try upping the dose! Or getting a different dealer.

Nutt stated in an interview I heard that the dose he uses in trials is the same as a recreational dose, because that’s the amount required to produce a trip.

Was that psilocybin in particular?

Yes

https://www.bbc.co.uk/sounds/play/m00168m9

[Bird on a Fire]

Nutt stated in an interview I heard that the dose he uses in trials is the same as a recreational dose, because that’s the amount required to produce a trip.

Was that psilocybin in particular?

Yes

https://www.bbc.co.uk/sounds/play/m00168m9

Yes, my understanding is that psychedelic therapy - be it LSD, psilocybin, ketamine etc - often/usually involves administering doses powerful enough to induce a trip, but in a controlled clinical setting. The benefits are then felt in the weeks or months following.

Disorders like depression often involve a lot of repetitive thought patterns, dwelling on the same ideas or feelings. A few hours communing with the machine elves jolts the brain out of those patterns, at least temporarily.

[discovolante]

Yes I think the stated idea (not commenting on whether it works or not) is that psilocybin etc encourages neuroplasticity so a 'full' dose is needed to achieve that. I don't think giving a depressed person a massive dose of MDMA is likely to help much in the long run!

[Bird on a Fire]

MDMA is also tricky because it can interact with SSRIs and other meds to cause serotonin syndrome, which can be very nasty.

But the paper is about psilocybin. And the controversial stuff seems to be about their hypothesis for how it works, rather than whether it does.

I don't really think of MDMA as a psychedelic - am I wrong on that? Certainly not in the same ballpark as shrooms and acid and forgetamine.

[discovolante]

MDMA is also tricky because it can interact with SSRIs and other meds to cause serotonin syndrome, which can be very nasty.

But the paper is about psilocybin. And the controversial stuff seems to be about their hypothesis for how it works, rather than whether it does.

I don't really think of MDMA as a psychedelic - am I wrong on that? Certainly not in the same ballpark as shrooms and acid and forgetamine.

I guess the definition might vary but id also instinctively make a distinction between psychedelic and psychoactive substances for eg...the reason I asked in the first place was because the OP referred to MDMA. Which is a bit confusing because it's a pretty different drug.

[bob sterman]

MDMA is also tricky because it can interact with SSRIs and other meds to cause serotonin syndrome, which can be very nasty.

But the paper is about psilocybin. And the controversial stuff seems to be about their hypothesis for how it works, rather than whether it does.

I don't really think of MDMA as a psychedelic - am I wrong on that? Certainly not in the same ballpark as shrooms and acid and forgetamine.

In terms of mechanism - you're not wrong. MDMA arguably has more in common with SSRIs and even amphetamine than it does with full-on psychedelics.

[Bird on a Fire]

MDMA is also tricky because it can interact with SSRIs and other meds to cause serotonin syndrome, which can be very nasty.

But the paper is about psilocybin. And the controversial stuff seems to be about their hypothesis for how it works, rather than whether it does.

I don't really think of MDMA as a psychedelic - am I wrong on that? Certainly not in the same ballpark as shrooms and acid and forgetamine.

In terms of mechanism - you're not wrong. MDMA arguably has more in common with SSRIs and even amphetamine than it does with full-on psychedelics.

Indeed, with the MA standing for methamphetamine*. I'd always thought of it as basically a stimulant that also makes you a bit huggy, which is presumably what wiki means by calling it a " empathogen–entactogen stimulant". But apparently it does also classify as a psychedelic, so I've learned something.

*as in the line from MF DOOM on All Outta Ale: "One for the money, two for the better green / 3,4-Methylenedioxymethamphetamine". But I digress.

[jdc]

Yes I think the stated idea (not commenting on whether it works or not) is that psilocybin etc encourages neuroplasticity

Sounds interesting. First thing I've found is this review looking at ayahuasca, DMT, psilocybin, and LSD: https://www.frontiersin.org/articles/10 ... 24606/full

Findings from the current review demonstrate that psychedelics induce molecular and cellular adaptations related to neuroplasticity and suggest those run parallel to the clinical effects of psychedelics, potentially underlying them.

Lots of caveats re there being limited evidence, small sample sizes, etc etc.

[Woodchopper]

And the controversial stuff seems to be about their hypothesis for how it works, rather than whether it does.

As far as I know we are still in the territory of there being several small scale studies. But we know that in general within that territory most positive findings turn out to be wrong. So we should probably wait for a few large (eg involving thousands of people), long term, double blinded, placebo controlled RCTs before concluding that it does work. For example, after decades of positive results it was shown that SSRIs have no more effect than a placebo for mild and moderate depression.

[Cardinal Fang]

Isn't the other aspect of using psychedelics to do with their dissociative properties, that allow people to, metaphorically, look in from the outside and thus be able to look at their illness from a different perspective?

CF

[Grumble]

Isn't the other aspect of using psychedelics to do with their dissociative properties, that allow people to, metaphorically, look in from the outside and thus be able to look at their illness from a different perspective?

CF

That seems like it might be another way of describing neuroplasticity.

[jdc]

Isn't the other aspect of using psychedelics to do with their dissociative properties, that allow people to, metaphorically, look in from the outside and thus be able to look at their illness from a different perspective?

CF

That seems like it might be another way of describing neuroplasticity.

Isn't dissociation a temporary distortion of senses, e.g. by reduced default mode network activity or inhibition of NMDA receptors, while neuroplasticity is a physical rewiring of the brain's neural networks?

[Grumble]

Isn't the other aspect of using psychedelics to do with their dissociative properties, that allow people to, metaphorically, look in from the outside and thus be able to look at their illness from a different perspective?

CF

That seems like it might be another way of describing neuroplasticity.

Isn't dissociation a temporary distortion of senses, e.g. by reduced default mode network activity or inhibition of NMDA receptors, while neuroplasticity is a physical rewiring of the brain's neural networks?

But where does one end and the other begin? If every experience does a little bit of rewiring.

[jdc]

That seems like it might be another way of describing neuroplasticity.

Isn't dissociation a temporary distortion of senses, e.g. by reduced default mode network activity or inhibition of NMDA receptors, while neuroplasticity is a physical rewiring of the brain's neural networks?

But where does one end and the other begin? If every experience does a little bit of rewiring.

Does every experience do a little bit of rewiring? I'd have thought it'd be only new experiences - and only then if the new experience required some adaption?

And it'd be a cause of neuroplasticity rather than an alternative description of it, no?

[Grumble]

Isn't dissociation a temporary distortion of senses, e.g. by reduced default mode network activity or inhibition of NMDA receptors, while neuroplasticity is a physical rewiring of the brain's neural networks?

But where does one end and the other begin? If every experience does a little bit of rewiring.

Does every experience do a little bit of rewiring? I'd have thought it'd be only new experiences - and only then if the new experience required some adaption?

And it'd be a cause of neuroplasticity rather than an alternative description of it, no?

Well I meant new experience, because the point of having the trip is to have a new experience. Does it cause a dissociative trip because it induces neuroplasticity? That seems to be Nutt’s hypothesis, but I may (almost certainly) have misunderstood

[jdc]

But where does one end and the other begin? If every experience does a little bit of rewiring.

Does every experience do a little bit of rewiring? I'd have thought it'd be only new experiences - and only then if the new experience required some adaption?

And it'd be a cause of neuroplasticity rather than an alternative description of it, no?

Well I meant new experience, because the point of having the trip is to have a new experience. Does it cause a dissociative trip because it induces neuroplasticity? That seems to be Nutt’s hypothesis, but I may (almost certainly) have misunderstood

I don't think that's it. I think the dissociation is part of the experience you have at the time and the neuroplasticity comes later. I think the dissociation is caused by e.g. reduced default mode network activity or inhibition of NMDA receptors and the increase in neuroplasticity comes from other effects of the psychedelic in question.

If I remember correctly, LSD's effects include inhibition of default mode network activity which would account for dissociation - and the first quote below shows increases in BDNF levels (BDNF regulates activity-dependent plasticity)

this placebo-controlled within-subject study investigated the effect of single low doses of LSD (5, 10, and 20 μg) on circulating BDNF levels in healthy volunteers. Blood samples were collected every 2 h over 6 h, and BDNF levels were determined afterward in blood plasma using ELISA. The findings demonstrated an increase in BDNF blood plasma levels at 4 h (5 μg) and 6 h (5 and 20 μg) compared to that for the placebo.

https://pubs.acs.org/doi/10.1021/acsptsci.0c00099

To be classified as a psychoplastogen, a compound should produce a measurable change in plasticity (eg, changes in neurite growth, dendritic spine density, synapse number, intrinsic excitability, etc.) within a short period of time (typically 24-72 hours) following a single administration. Because their impact on neural plasticity enables subsequent stimuli to reshape neural circuits, they should produce relatively long-lasting changes in behavior that extend beyond the acute effects of the drug.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6149016/