• Neuroscience & Pharmacology Discussion Welcome Guest
    Posting Rules Bluelight Rules
    Recent Journal Articles Chemistry Mega-Thread
    FREE Chemistry Databases! Self-Education Guide

  • N&PD Moderators: Skorpio

Candy/hippy/etc. Flipping dangers understated?

Skorpio

Skorpio

Administrator
Staff member
Joined
May 11, 2011
Messages
4,932
Location
The zone
This might be a PD thread, but I want mechanistic discussion rather than people talking about hangovers from candy flipping.

https://www.reddit.com/r/DrugNerds/...elic_combinations_an_underrated_risk/.compact

This thread on drugnerds has a study demonstrating a heavily increased serotonin load when psychadelics are combined with mdma. I would like to learn the following:

Are these risks significant enough so that a 4 times a year roller who enjoys candy flipping should alter use patterns?

Are there ways of mediating the specific increase in toxicity?

What is the mechanism of increased toxicity?

How does it compare to toxicity from say mdma and amphetamine or methamphetamine?

These are all pretty far fetched questions, but this is one of the better places for getting real answers.
 
that's probably a pretty OK regimen... you're not gonna get retarded doing MDMA in that frequency. practice safe rolling measures like don't push the dose with the MDMA and supplement with antioxidants and you'll probably be good. i don't know if there's much else one can do to reduce damage from rolling.

hard to compare with MDMA + stimulants, it's not as straight-forward as that, dosing and frequency matter too... MDMA + any stim is probably more neurotoxic than MDMA alone though, as the increased DA release supposedly contributes for neurotoxicity (there's that study where after subacute dosing of an MDAI + amph combo they found reduced paroxetine binding sites on mice, something that didn't happened with either drug alone, but the dosing regimen used was pretty hardcore IMO)
 
I would go lower dose on the MDMA and a solid preload is a given. Alexander Shulgin suggested 4 times a year maximum for just MDMA alone so I wouldn't keep up the candyflipping 4 times a year forever. Some of the damage of MDMA is from dopamine auto-oxidative damage but make no mistake there can definitely be damage to the serotonin nerve terminals especially on a higher dose MDMA. I believe that shrooms/whatever would increase the damage to the serotonergic axons because that is so much activity at the serotonin neurons and so much serotonin in the synaptic cleft, but not necessarily dopamine damage as much with something like shrooms. Whatever you candyflip with let it not be a longer trip like acid etc. IMO

Concerning MDMA combined w/ stimulants the biggest factor besides the increased excitotoxicity/production of ROS from cells/dopamine oxidative stress would be the missing sleep. Sleep is essential! It has recently been shown the missing a night even without drug use involved kills brain cells, and you make your new brain cells during sleep. Your brain clears out all the gunk from your brain cells firing during deep sleep and it will help save your brain from alzheimers/neurodegenerative disease down the road which I believe a lot of frequent rollers are at greatly increased risk of. Allowing yourself some decent time to sleep with meds if necessary (benzo sleep > no sleep) will help your brain through the candyflipping longterm, but missing sleep would be one of the biggest contributors to neurotoxicity when using any stims with psychedelics or without.
Cardio increases neurogenesis throughout he brain but in the Dentate Gyrus specifically a very important place for serotonin. Seeing as candyflipping probably involves mostly serotonergic damage I believe cardio a couple times a week would be very beneficial for staving off long term deficits.
 
Thanks for the replies.
Cotcha: you said that some of the increased damage would be due to excess serotonin in the terminals from the activity of psychs, but don't traditional psychs only agonize 2a (gross oversimplification, but main thread that binds them together)? Are you referring to displacement of serotonin by the psychadelic ligand increasing concentrations competitively?

Anyway, I guess I'd like to strike all of the questions in my post except for the specific mechanism of toxicity, because that is what I think is the least clear for me, and I would be able to at least make an educated guess regarding the rest of the queries knowing more about how this combo is toxic.
 
Hi skorpio! between a serotonin releasing agent like MDMA and an agonist like psilocybin that is a lot of serotonin binding post-synaptically you are correct sir mainly to 2A (we've known for a long time 2A antagonists block the perceivable psycho effects) also we know now its interestingly a 5-HT2A-glutamate heterodimer that is mediating most of the psychedelics that are classically considered 2A. Excitotoxicity is classicaly glutamate mediated and these psychedelics activate glutamate through serotonin :) Although I must say the 2A's interactions between other brain cells is very complex, but I would be concerned about increased excitotoxicity and damage to nerve terminals with all that post-synaptic binding. Serotonin is inhibitory in some places but excitatory in others, 2A is the main excitatory kind! but outside of the 2A's themselves they interact with most other brain cells, they increase dopamine the prefrontal cortex as well. Psilocybin increases dopamine in the basal ganglia too from serotonin interactions, but LSD is much more dopaminergic and a lot of the toxicity from candyflipping would in my theory by dopamine related. At any rate I would want you to dodge LSD etc. and shoot for something like shrooms if candyflipping, I should mention even psilocin increases dopamine because of the 2A mostly but 1A affinity as well, and a lot of MDMA's magic is through 1A but anyways psychedelics aren't strictly serotonergics just to be clear because the serotonin connects to other cells on down the road and could increase damage to other cells and not just serotonin axons when combined with something more stimulant-like and associated with neurotoxicity, where as shrooms by themselves are likely very harmless and wouldn't really reach a level of toxic dopamine/glutamate activity alone.

There is also a difference between straight up neurotoxicity and a change in brain chemistry after use, there is a very interesting process called astrogliosis that few people seem to be aware of. We don't yet know exactly how much drugs can kick it off in a brain area but I suspect a great deal in response to say cell death/ROS/inflammation concerning stimulant toxicity. I mention brain area because this does not necessarily mean "Oh shit you've lost 5-HT2A's" but that when glial cells scar up the area they will effect everything probably for worse.

Ultimately most of the damage is from excitotoxicity/ROS from mitochondrial permeability transition pore where mitochondrial swelling kills the cells through Apoptosis aka programmed cell death. https://en.wikipedia.org/wiki/Mitochondrial_permeability_transition_pore probably mostly with dopamine/glutamate cells. but the change in brain chemistry doesn't just stop at the lost cells if Astrogliosis is kicked up. Any questions fire away, careful with yo brain! peace
 
Thr glutamate link is very cool, putting it on my list of things to pub med binge about, as I am pretty in the dark about glutamate.

Increased dopamine activity makes sense; isn't there a pathway for ros generation that is the go to dopamine breakdown pathway that is rather reactive, and the whole mdma specter involves uptake of dopamine by serotonin neurons (because post loading with ssris really attenuates toxicity). If psychs increase dopamine action, more free dopamine will cause worse effects.

Also if that is true, wouldn't lsd not be much worse than psilocybin because the dopamine release comes from serotonin disinhibition, and lsd only agonizes dopamine, rather than causing extra release? Or is the mechanism for dopamine toxicity excitotoxicity, because if that is the case then any dopamine would be bad.

If excitotoxicity is the case would an nmda antagonist reduce toxicity or would the (pretty much built in) dopamine reuptake inhibition make the toxicity worse?

Thanks for being a good sounding board, this is giving me a nice transition from full time lurker.

Edit: just saw this about mematine and mdma, I know that mematine is super fucking promiscuous and probably not = ketamine, but do you think this neuroprotective effect would transfer? R drugnerds musings (which I take with more than a grain of salt) seem to think that it occurs due to a7 nach antagonism, and ketamine does negatively modulate acetylcholine so there may be a link. What do you think?
http://www.sciencedirect.com/science/article/pii/S0161813X07001842
 
Last edited:
Let's just look at one paper for a minute. Paper attached; I decree that these are indeed educational purposes and the doctrine of fair use shall apply. Sue me, Elsevier.

http://onlinelibrary.wiley.com/doi/10.1002/nrc.20023/abstract
http://www.pdf-archive.com/2015/09/26/lsdmdmatransporterloss/ (full paper)

The argument is based on differences in optical density of the stained hippocampus under different drug treatments: control vs. MDMA vs. MDMA + LSD vs. MDMA + Glemanserin (MDL). The averaged optical density can be seen in Table 3. The first thing that sticks out at me is that MDMA + 2.5mg/kg MDL and MDMA + 5 mg/kg MDL show increasing optical density but MDMA + 7.5 mg/kg MDL shows a decrease resp. MDMA + 5 mg/kg MDL. As the other correlations are rather smooth, this outlier is particularly interesting.

The other datapoint of note is that LSD alone causes an apparent decrease in the optical density of the stained hippocampus. Paired with other results about the apparent lack of long-term LSD neurotoxicity we may come away questioning the metric. But the real reason for this is in Fig 1 and Fig 2: there is a noticeable difference between Fig 1B (LSD only) and Fig 1A (control) as well as between Fig 2B (MDL only) and Fig 2A. In fact both LSD and MDL seem to make the hippocampus significantly darker to the eye, but on the chart this translates to a lower mean optical density.

In Fig. 6 we are left wondering whether MDL really had any effect after all, or if the apparent reduction of neurotoxicity seen with MDL 5 mg/kg was really just a coincidence. There is a sort of "false-positive generation effect" that occurs when multiple regressions are run on the same dataset; it becomes probable that one will return a positive result.

But the correlation in Table 3 occurring between MDMA + 25 µg/kg;50 µg/kg;100 µg/kg LSD is indeed frightening to look at. To get an idea of how these translate to human doses, a 100 µg/kg dose of LSD in a 0.25 kg rat allometrically scales with an exponent of 0.75 (normal stuff) to about 1700 µg LSD in a 70 kg human (if we assume the rat weighs 0.125 kg, the human equivalent is 1400 µg). That is, even the smallest dose of LSD tested appears to be much larger (equivalent to ~425 µg) than a typical human dose, and the dose which produced truly concerning effects is in fact much larger than a typical human dose. It is not entirely unreasonable to suggest that since LSD is already rather unselective that at these dose levels many "side-effects" of LSD become prominent and may in fact be primarily responsible for the observed increase in neurotoxicity.

In summary, there are numerous methodological problems with this study, which may be why it has only been cited once in eleven years since its publication. It makes one yearn for the '80s; they would have had the rats run in a maze and tried to measure cognitive effects, which are much more meaningful (to me) than some pretty pictures. I should say: I have really only scratched the surface in analyzing this; I have a job these days, it sucks but that's life.

But why do we care? Why should we complain about methodological flaws? If there's a potential risk, shouldn't users be cautioned to avoid it?

The law of unintended consequences plays a role. We should of course be aware of why drug users have begun candyflipping in the first place, which is generally to achieve a more potent intoxicating experience than was achieved on the dose of MDMA in the first place. I suspect that when faced with the claim that LSD potentiates MDMA-derived neurotoxicity users may simply consume more MDMA at a time when they would have been candyflipping, and the result may actually be worse. In reality, the effect from LSD appears to be small, requires very large doses of LSD to occur, and is probably much smaller than the risk of a higher dose of MDMA.

Having read the study, it still seems to me that, for example, taking 100 mg MDMA + 100 µg LSD is safer than taking 150 mg MDMA. Your conclusions may vary. Obviously it would be better to caution people against seeking strong drug experiences, especially those involving MDMA, entirely. Unfortunately, this is rather hard to do.
 
I think there would end up being more and more dopamine and glutamate as the 5-HT2 activity goes up, theres a lot of brain cells downstream from 5-HT2 and dopamine auto-oxidative damage could be responsible for a lot of the fallout as well as more excitotoxicity from the glutamate. NMDA is kinda weird and confusing to me, can't say I'm overly familiar with it. Ketamine does have its own neurotoxicity Olney's lesions and such but I did remember an interesting study - "Serotonergic agents that activate 5HT2A receptors prevent NMDA antagonist neurotoxicity." https://www.ncbi.nlm.nih.gov/pubmed/9408919 However it says that " It is proposed that 5HT2A agonists may also prevent the psychotomimetic effects of NMDA antagonists. Among the 5HT2A agonists examined and found to be neuroprotective are LSD and related hallucinogens." Interesting and confusing :p I can't seem to remember what MDMA does to acetylcholine... I do remember it having some sort of long term effect at A7 NAch though... Idk, once you start mixing more and more stuff there are just more interactions and just BLEH. The one thing I can recommend to try to decrease toxicity is CLONIDINE which I would try combo'd with just LSD/Shrooms whatever first, I don't know if I would mix more and more things if you're already candyflipping I'd wanna see how I reacted to each individual to separate out effects and shit.

From wiki "Many drugs have been found that lessen the risk of neurotoxicity from NMDA receptor antagonists. Centrally acting alpha 2 agonists such as clonidine and guanfacine are thought to most directly target the etiology of NMDA neurotoxicity. Other drugs acting on various neurotransmitter systems known to inhibit NMDA antagonist neurotoxicity include: anticholinergics, diazepam, barbiturates,[24] ethanol,[25] 5-HT2A serotonin receptor agonists,[26] and muscimol.[27].

Potential for treatment of excitotoxicity Since NMDA receptor overactivation is implicated in excitotoxicity, NMDA receptor antagonists have held much promise for the treatment of conditions that involve excitotoxicity, including benzodiazepine withdrawal, traumatic brain injury, stroke, and neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's. This is counterbalanced by the risk of developing Olney's lesions,[28] which have only ever been observed in rodents, and studies have started to find agents that prevent this neurotoxicity.[25][27] Most clinical trials involving NMDA receptor antagonists have failed due to unwanted side effects of the drugs; since the receptors also play an important role in normal glutamatergic neurotransmission, blocking them causes side-effects."

I remember that glutamate is responsible for some of the psychedelics effects so I don't know how much a glutamate antagonist would block your experience. I think it was mainly a metabotropic glutamate heterodimer with the 5-HT2A though.
So basically an NDMA antagonist might help with excitotoxicity but at risk of whatever the combination brings and on its own standard ketamine neurotoxicity type stuff??? I'm thinking a lot of the damage would be dopamine related though and 95% of it involving the MDMA's contribution so one way to be safe is to just dose ONLY LSD/shrooms and pass on the MDMA o.o

Another option if you're gonna candyflip is probably a little bit of Clonidine and benzo. Both just to reduce the excitability, not involving some complicated ass NDMA/acetylcholine antagonism but I wouldn't be surprised if the latter help with the damage too, its just complicated and I would be more concerned about what the MDMA is doing rather than the other drugs. But if taking clonidine or another adrenaline/beta blocker be sure to take some melatonin with it when trying to sleep, beta blockers suppress the production of melatonin. I wonder what clonidine would do to a trip. Would likely help with anxiety/body load too so could make it more enjoyable... I know that it helps with meth toxicity though.
 
You must log in or register to reply here.
Top