MAPS MDMA as a replacement for SSRIs for treating depression

[ebola?]

MDA (Methylenedioxyamphetamine) would be a way better candidate entirely due to the reason that it would eliminate (or rather decrease the likelihood) of neurotoxicity. However, it would still cause depression in the long-term just like MDMA.

This is mistaken, as MDA is justifiedly hypothesized to be more neurotoxic than MDMA.

ebola

 

[JWills20]

I read once somewhere (can't remember where exactly or find it right now, but it was a reasonably scientific paper) that regular low-dose MDMA could serve to increase neurotrophic growth factors causing serotonin neurogenesis thus helping to reduce depression. I don't think it's quite as simple as the held view of 'MDMA is neurotoxic' which it certainly is in higher doses. I'm rather certain that doses between 40-80mg are not neurotoxic (this is actually modest to my actual view, I don't believe MDMA is particularly neurotoxic until doses over 250mg), nor are doses between this range potent enough to cause serotonin depletion. Perhaps I'm biased (well, I certainly am), but I see no contraindications to at least testing threshold doses of MDMA used in the same sense that SSRI's are (taken daily for weeks). MDMA certainly has a place in psychotherapy, but regular low-dose (0.5mg/kg) rat studies could begin to unravel whether threshold doses may have a long-term therapeutic effect. There is certainly some theory at least.

 

[any major dude]

The toxicity is almost certainly dose dependent. I'm not sure where the threshold for clinically significant toxicity is or if it's even been established. AFAIK frequent low doses haven't been looked at much if at all.

I'm quite skeptical about daily, or even weekly use of any amount of MDMA being clinically useful. It seems with psychedelics, empathogens, & quite possibly dissociatives as well, the clinical benefit is quite directly tied to experiential factors as opposed to being more purely pharmacological. Tolerance to experiential factors builds quite quickly & thus seems to preclude any utility for frequent dosing schedules. This also has the benefit of requiring less drugs overall, which is generally a good thing.

 

[ebola?]

We need to be careful about how we operationalize toxicity though. While receptor downregulation, changes in transporter density, changes in intercellular monoamine levels, etc. are reversible, sometimes they are moderately enduring and responsible for unwanted changes.

ebola

 

[JWills20]

We need to be careful about how we operationalize toxicity though. While receptor downregulation, changes in transporter density, changes in intercellular monoamine levels, etc. are reversible, sometimes they are moderately enduring and responsible for unwanted changes.

ebola

But are low (40-60mg), but regular, doses of MDMA really likely to induce the negative effects you talk of...?

Personally, I'm not convinced it would. I think initial animal studies could help answer these questions anyway, not that it's ever going to happen.

 

[ebola?]

But are low (40-60mg), but regular, doses of MDMA really likely to induce the negative effects you talk of...?

Honestly, I don't think that we yet have relevant evidence, though some sort of serotonergic depletion would be likely, just because the endogenous synthesis is so slow.

ebola

 

[JWills20]

Honestly, I don't think that we yet have relevant evidence

Agreed. Hence why I said some initial animal studies would be useful. There's at least some theory to warrant a study.

though some sort of serotonergic depletion would be likely, just because the endogenous synthesis is so slow.

Perhaps. I'd imagine you could offset such an issue by adding 5-HTP to the dosing regime though.

 

[any major dude]

5-HTP supplement would almost certainly not be sufficient in this case. Also a fair bit of this discussion seems predicated on the serotonin model of depression, which has been dropped by everyone except TV ads for SSRIs. Serotonin≠happy juice.

 

[JWills20]

5-HTP supplement would almost certainly not be sufficient in this case.

Why so? Release from threshold doses is likely to be pretty small, I'd imagine similar to SSRI release but that's just speculation. The only problem I see is the inhibition of Tryptophan Hydroxylase, eventually causing 5-HT depletion, so 5-HTP would offset that. If partial serotonin release caused long-term depletion, SSRI's would also cause depletion.

Also a fair bit of this discussion seems predicated on the serotonin model of depression, which has been dropped by everyone except TV ads for SSRIs. Serotonin≠happy juice.

Yeah, the serotonin hypothesis is not exactly convincing. But there's no doubt that serotonin plays at least a partial role in depression. Unlike SSRI's, MDMA is able to cause the complete opposite of depression. So in reality it also offers an insight into actually understanding depression more. If it's not just serotonin release, what is MDMA doing exactly that is causing such a profound state of self-content? Obviously MDMA doesn't just release serotonin, and has some DA/NE release, but if we absolutely understood how MDMA causes the state it does, surely that would provide a solid direction for the development of new treatments, even if those treatments did not involve MDMA itself. I've read in a lot of places that if you could essentially remove MDMA's toxic metabolites, prevent serotonin depletion and remove the stimulant effects (which is controversial considering they probably contribute to the overall state MDMA puts you in) you'd have the ultimate anti-depressant safe for daily use.

MDMA is such a fantastic tool for studying depression simply because no other drug can produce entactogenic effects quite like it. Similar RC's like methylone come close, but most users at least subjectively vouch for MDMA being in a league of it's own. If it wasn't illegal and taboo, I'd imagine researchers would be all over all the serotonin-releasing agents, looking at the causes of their effects and ways to chemically engineer them into a sustainable medicine.

 

[any major dude]

IIRC the increase of the amount of 5-HT in the CNS consequent to 5-HTP administration is pretty modest. & due to 5-HT's peripheral effects, especially in the GI tract, one can only increase the dose so much before running into diminishing returns. The side effects aren't terribly severe, but unpleasant enough to certainly discourage use at a certain level.

SSRIs don't cause depletion per se, but they do cause serotonergic downregulation which is a problem. As reuptake inhibitors they don't cause release, just an accumulation as 5-HT isn't cleared from the synaptic cleft as readily. Mdma causes both depletion & downregulation, which is why it generally doesn't work very well taken multiple days in a row or even within a couple weeks. It's pharmacology just isn't sustainable IMO. However taken just a few times a year it might be able to improve some people's quality of life considerably.

While it isn't inaccurate to say 5-HT is involved in depression, being that it's among the most abundant neurotransmitters in humans, that's a really non specific claim. It's involved in seriously everything from hunger & peristalsis to sleep & anxiety to blood pressure & body temp regulation.

I definitely agree with you on research into its effects on human behavior. I've seen some interesting research on it's effects on oxytocin release & pro social behavior recently. And there was a fair bit of self experimentation here on BL a few years ago during the selective serotonin releasing agent craze of 2009-10. Unfortunately MDAI & it's ilk proved to be less than impressive on their own. However combined with DA/NE releasers/reuptake inhibitors the experience was all but indistinguishable from MDMA.

Unfortunately in psychopharmacology there's almost never a free lunch ('racetams may be an exception). If you remove the aspects that make MDMA somewhat toxic, you largely negate it's unique effects. We saw this with the aminoindanes & tetralins a few years ago. AFAIK the 5-HT releasers never led to any significant pharmaceutical advancements either, just obscure novelties for the intrepid psychonaut.

Also, I think the idea that medication need be taken every day is a pretty modern western idea. The most promising research into depression treatments currently is glutamatergic modulation. I even have it on good authority that Johnson & Johnson is developing an intranasal ketamine product to that end. & the dosage schedule for that type thing ranges from once every two weeks to 3x per week. IMO the less frequently one can take drugs the better. Usually ;-)

 

[JWills20]

IIRC the increase of the amount of 5-HT in the CNS consequent to 5-HTP administration is pretty modest. & due to 5-HT's peripheral effects, especially in the GI tract, one can only increase the dose so much before running into diminishing returns. The side effects aren't terribly severe, but unpleasant enough to certainly discourage use at a certain level.

I know that 5-HTP has reasonably poor efficacy, but in the presence of TPH inhibition, it would appear to be the best option for replenishing 5-HT if MDMA was a hypothetical treatment. The synthesis of the monoamines are linked together, so if 5-HT was deprived I'd imagine 5-HTP would be more efficient than in a normal person. Just like some MDMA users find it beneficial for the MDMA comedown, when serotonin is depleted and dietary sources are not replenishing stores.

SSRIs don't cause depletion per se, but they do cause serotonergic downregulation which is a problem. As reuptake inhibitors they don't cause release, just an accumulation as 5-HT isn't cleared from the synaptic cleft as readily.

Yeah I know how SSRI's work, I just use release as an easy way to talk about things. If anything increases synaptic serotonin it is, effectively, a releaser despite not directly releasing. Serotonin increaser is probably a better phrase to encompass any mechanism.

Mdma causes both depletion & downregulation, which is why it generally doesn't work very well taken multiple days in a row or even within a couple weeks. It's pharmacology just isn't sustainable IMO. However taken just a few times a year it might be able to improve some people's quality of life considerably.

I'd agree with you if we're talking about recreational doses (100+mg), but I'm not sure this is the case for lower doses. Would threshold doses of MDMA (and I'm talking literally 0.5mg/kg) really cause depletion and downregulation? It's known that MDMA has a steep dose-response curve, with higher doses causing exponentially increased amounts of 5-HT, so threshold doses would be unlikely to cause depletion if you asked me. Long-term downregulation, I'm less sure.

While it isn't inaccurate to say 5-HT is involved in depression, being that it's among the most abundant neurotransmitters in humans, that's a really non specific claim. It's involved in seriously everything from hunger & peristalsis to sleep & anxiety to blood pressure & body temp regulation.

Yeah you're right. But unlike SSRI's which just increase serotonin, MDMA's acute effects of central serotonin, and the direct receptor sub sites it influences, do serve to directly eradicate depression. Even if it's not just the serotonin, could modest doses act to subtly stimulate these central sites, promoting long-term entactogenesis?

I definitely agree with you on research into its effects on human behavior. I've seen some interesting research on it's effects on oxytocin release & pro social behavior recently. And there was a fair bit of self experimentation here on BL a few years ago during the selective serotonin releasing agent craze of 2009-10. Unfortunately MDAI & it's ilk proved to be less than impressive on their own. However combined with DA/NE releasers/reuptake inhibitors the experience was all but indistinguishable from MDMA.

I'm not really talking about re-creating the MDMA experience for day-to-day life, I'm talking about causing some long-term changes to brain function which ultimately cause an underlying increase in entactogenesis.

Unfortunately in psychopharmacology there's almost never a free lunch ('racetams may be an exception). If you remove the aspects that make MDMA somewhat toxic, you largely negate it's unique effects. We saw this with the aminoindanes & tetralins a few years ago. AFAIK the 5-HT releasers never led to any significant pharmaceutical advancements either, just obscure novelties for the intrepid psychonaut.

Yeah I get you. The whole concept of chemically engineering is obviously something that would go way beyond my capacities, but it was an analogy for the potential MDMA may have as an anti-depressant. It could be done though, I mean look at Prof Nutt trying to create a non-toxic version of alcohol to stop the UK from drinking themselves to death... You might lose some of the subjective effects, but if that trade-off is a much safer and sustainable drug then it's worth it.

Also, I think the idea that medication need be taken every day is a pretty modern western idea. The most promising research into depression treatments currently is glutamatergic modulation. I even have it on good authority that Johnson & Johnson is developing an intranasal ketamine product to that end. & the dosage schedule for that type thing ranges from once every two weeks to 3x per week. IMO the less frequently one can take drugs the better. Usually ;-)

That's pretty awesome! It's tough to talk about what dosing regime would be the rest when they're isn't even any research on the idea. Perhaps taking threshold doses of MDMA 3 days a week might yield an enctactogenic benefit without significant side-effects? Or perhaps it require everyday use? Perhaps it doesn't work at all? Perhaps it would cause long-term downregulation? Only way we would know is to study it. Only way to study it is to have a solid hypothesis and way of testing it. There is a hypothesis (I've read it somewhere), so a study could be warranted. Just nobody has done it yet.

 

[ebola?]

I'd agree with you if we're talking about recreational doses (100+mg), but I'm not sure this is the case for lower doses. Would threshold doses of MDMA (and I'm talking literally 0.5mg/kg) really cause depletion and downregulation?

My guess is probably. In relation to other monoamines, since there is less overall serotonergic activity, changes to serotonergic release have a more dramatic impact on the system, and it takes way longer to recuperate from 'overactivity'. Just through casual observation, ritalin is a lot more similar to dexedrine than mdma is to prozac.

Also, downregulation isn't our enemy here. It is likely that downregulation at 5ht sites in response to chronic dosing of SSRIs underlies the set of downstream changes responsible for their utility for depression. It's unlikely that we tend to treat some sort of organic 'deficit' in synaptic 5ht. If this were the case, we'd have difficulty explaining the delay in SSRIs' efficacy or their continued effectiveness over long periods.

ebola

 

[JWills20]

My guess is probably.

Why so? Is this just your intuition? Mine is just speculative intuition so if you have any better reason I'd probably change my mind.

Also, downregulation isn't our enemy here. It is likely that downregulation at 5ht sites in response to chronic dosing of SSRIs underlies the set of downstream changes responsible for their utility for depression. It's unlikely that we tend to treat some sort of organic 'deficit' in synaptic 5ht. If this were the case, we'd have difficulty explaining the delay in SSRIs' efficacy or their continued effectiveness over long periods.

Not going to lie, reading some of this stuff becomes ambigious and confusing (perhaps because there is a lot of misinformation spread around). Some places suggest that receptor downregulation is negative, whereas other sources suggest that it can be positive. There's an underlying notion, in MED, that downregulation is bad. Do you reckon you could clear some of that up? I know we're not trying to treat serotonin deficiency, and if small-dose MDMA did cause partial depletion couldn't this follow a similar mechanism to what you suggested for SSRI's: depleted 5-HT --> downregulation --> downstream changes --> improved cognitive symptoms.

Thoughts?

 

[any major dude]

My guess is probably. In relation to other monoamines, since there is less overall serotonergic activity, changes to serotonergic release have a more dramatic impact on the system, and it takes way longer to recuperate from 'overactivity'. Just through casual observation, ritalin is a lot more similar to dexedrine than mdma is to prozac.

Agreed, & ritalin is more similar to cocaine than to dexedrine, just to further demonstrate how far SSRIs are from entactogens.

Also, downregulation isn't our enemy here. It is likely that downregulation at 5ht sites in response to chronic dosing of SSRIs underlies the set of downstream changes responsible for their utility for depression. It's unlikely that we tend to treat some sort of organic 'deficit' in synaptic 5ht. If this were the case, we'd have difficulty explaining the delay in SSRIs' efficacy or their continued effectiveness over long periods.

ebola

Yes & no, SSRIs are somewhat effective for patients with severe MDD (& moreso in women than men IIRC), but for mild to moderate depression they're more or less an active placebo. But even in the less severe cases they can cause a discontinuation syndrome (brain zaps, mood swings, etc etc) that is quite unpleasant. While that downregulation almost certainly plays a role in their antidepressant effects, it seems equally likely that it also plays a role in the discontinuation syndrome. I guess we could call it a frenemy It's also possible that the garden variety mild to moderate depression/anxiety/NOS they're prescribed for may stem from a separate physiology hence the lack of effect at that acuity level. I'm straining not to go into a diatribe on the limits of the symptom cluster based diagnostics we have to use in psych, ha.

Why so? Is this just your intuition? Mine is just speculative intuition so if you have any better reason I'd probably change my mind.



Not going to lie, reading some of this stuff becomes ambigious and confusing (perhaps because there is a lot of misinformation spread around). Some places suggest that receptor downregulation is negative, whereas other sources suggest that it can be positive. There's an underlying notion, in MED, that downregulation is bad. Do you reckon you could clear some of that up? I know we're not trying to treat serotonin deficiency, and if small-dose MDMA did cause partial depletion couldn't this follow a similar mechanism to what you suggested for SSRI's: depleted 5-HT --> downregulation --> downstream changes --> improved cognitive symptoms.

Thoughts?

while that *might* be possible, the mechanism itself is, seemingly, of very little utility. & you'd be using a pharmacologically messier substance to achieve similar ends.

And in regards to downregulation, from a recreational perspective it's a negative because it plays a large role in tolerance, but that's also positive in that it makes compulsive use impractical at best. While i suppose it's possible to term any long term changes to structures in the brain "damage" i don't know if that term necessarily applies here.... It may well be a question of degree, or just semantics. Ebola might be able to speak to that issue in a more informed manner than I.

 

[ebola?]

it seems equally likely that it also plays a role in the discontinuation syndrome.

I consider this nearly certain, actually.

It's also possible that the garden variety mild to moderate depression/anxiety/NOS they're prescribed for may stem from a separate physiology hence the lack of effect at that acuity level.

Good point: this could easily be true. At the same time, it could be that the mechanisms underlying any given treatment's efficacy inhere at a level of analysis different from those mechanisms which cause the disorder. For analogous reasons, cognitive behavioral therapy can plausibly ameliorate psychopathology 'physiological' in origin.

Why so? Is this just your intuition?

Yup.

downregulation is bad. Do you reckon you could clear some of that up?

Well, downregulation tends to be undesirable in the absence of other mediating effects. Following use of an SRA, there is downregulation AND depletion of presynaptic vesicular stores of 5ht. In the case of SSRI therapy, the downregulation is accompanied by continued high levels of synaptic 5ht.

ebola
ebola

 

[JWills20]

Well, downregulation tends to be undesirable in the absence of other mediating effects. Following use of an SRA, there is downregulation AND depletion of presynaptic vesicular stores of 5ht. In the case of SSRI therapy, the downregulation is accompanied by continued high levels of synaptic 5ht.

Got it. But then on the other hand, can depressive cognitive symptoms be a result of excessive 5-HT receptors & density? I know it's more complex than that, but just try and keep things basic, is that plausible?

At the same time, it could be that the mechanisms underlying any given treatment's efficacy inhere at a level of analysis different from those mechanisms which cause the disorder. For analogous reasons, cognitive behavioral therapy can plausibly ameliorate psychopathology 'physiological' in origin.

Indeed. Unfortunately in the psychology domain, research is usually just from one paradigm. For instance, cognitive research shows little acknowledgement of neuroscience, whereas neuroscience shows little acknowledgement of cognitive. Hypothetically, cognitive neuroscience should ameliorate that, but from my experiences there's a lot of individual cognitive, neuropsychology and neuroscience being labelled as cog neuro. And tbh, despite the fact I like the cognitive neuroscience techniques (EEG, TMS, fMRI), they're really overrated and expensive for what they actually provide to brain research.