Neurotoxicity of drugs

ungelesene_bettlek

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I'm writing this in some kind of confession. My alma mater Rudolphina rewarded me with a Mag. rer. nat. degree (more or less an equivalent to a MSc) in mathematical physics, but denied me my Dr. rer. nat. / PhD. So please explain to me in scientific terms to a more-or-less pharmacology newbie in what drugs are neurotoxic. As far as I know, you can say that for scientfic certainty for alcohol, antipsychotics, MDMA and probabl most (all?) entactogens and unfortunately dissociatives. I mention this because I went trough a shitload of methoxethamine (probably 0.4-0.5 kg, mostly smoked), and I fear that I permanently damaged my brain trough this process.

Fun facts: my Dr. med. univ. Kurt Blaas is the the leading expert in cannabis-as-a-medicine movement in Austria (he just published a German-speaking book on that topic, with the legal part written by my lawyer and dedicated to his wife, who was a former psychotherapist of mine), he is also the one who sent me to the clinical psychologist that diagnosed my Asperger's syndrome, my aforementined alma mater Rudolphina has a delta-9-THC molecule drawn on a whiteboard on its German frontpage entitled "Gemeinsam forschen" (roughly translated: doing science together), and I just listened to the song "Sagan" by Nightwish.
 

ungelesene_bettlek

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More fun facts: Ernst Späth, the first guy who synthetized mescaline was also on my alma mater Rudolphina, my PhD adviser kicked me off the second time after I confessed to him that I had bought a Trichocereus (Echinopsis) cactus after he gave me the opportunity to call him "Du" (in German, roughly translatable to the english "thou", which means we would be more or less close friends after knowin each other for 10 years, this is my 888 post and one the same university was discovered that "666" from the revelation of John is probably equivalent to the emperor Trajan according to Ao. Univ.-Prof. Dr. Hans Taeuber and his computer science student Diana Altmann - also a career dream of mine that vanished trough the loss of my brain.
 

Cotcha Yankinov

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I wouldn't limit the concern to neurotoxicity.

The adverse effects of drug abuse can include changes to brain cells, brain circuitry and structure that may not be classified as actual neurotoxicity, but are still undesirable.

For example, the dissociative ketamine has been shown to be able to cause a reduction of the expression of something called Parvalbumin in certain inhibitory interneurons. This may not necessarily be viewed as neurotoxicity, but its still undesirable and could possibly contribute to psychosis after dissociative abuse.

Dissociatives can also cause increase the expression of genes such as DeltaFosB - this could also be another undesirable change that occurs with drugs of abuse but it isn't necessarily neurotoxic in nature
 
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ungelesene_bettlek

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Thank you a lot for your input, Cotcha Yankinov! I need to read more about DeltaFosB tomorrow.


My background is pretty bad, I'm over 36 years old and I never had an real, continuous job. The next best thing was a junior software developer at the Vienna University of Economics and Business that Specialisterne got me into (an organisation that tries to implement people in the autistic spectrum in the first job market). Unfortunately, I got split up with them due to Methoxetamine induxed mania. My boss there was a great guy, someone I really look up to (he managed to do the complete computer system with a handful of people - this job was failed before by a mayor company). Obviously, he was a physicist as well (From the TU Vienna), who did not finish his PhD to follow his greater passion (coding). Unfortuntely, in my mania I published his marijuana smoking habit, something I deeply regret.

The ony real input was a paper on general relativity I posted 6 year ago on https://arxiv.org/ (not even printed in a magazine), and the worst thing is, I just found a typo in it.

Some think I posted in march in another forum is probably worth repeating here:

me said:
I only use benzodiazepines and thienodiazepines to get me to sleep, and this is why I prefer the short-acting ones (namely, etizolam (which I got from the grey-market) and triazolam (which I get prescribed to from my general practitioner as halcion (R) in 250 microgram portions)). Undfortunately, I got a bad habit of taking them recently, which I now try to dampen off. Last night I had no sleep (I'm writing this shortly after 12:00 central European time), but the following night I will try with 375 micrograms of triazolam.

Very, very bad idea: approx. 1.5 years ago I swallowed an unknown quantity of LSD after an unknown quantity of some benzo-/thenodiazepines. This led me to me locking myself out of my flat, wondering trough my city, sleeping somewhere far away from my home. Then I was brought to my hospital in the morning, washing me off, and I precisely remeber that I got an epileptic seizure while talking on the phone with to my sister. I vividly recall that the sound of my voice was fading away, and I was kept in a narcotig state for approximately two weeks. Six weeks later (after the epileptic seizure) I left the hospital, and only one week later I had a stroke. I left the hospital at christmas 2015 and got a part of my skull replaced by a 3D printer output in early 2016. This left me with some bad nazi-like parting in my hair - fortunately, I could not even grow a hitler beard because I have almost no beard growth there.

Right now I have fully recovered (I will celebrate my 36. birtday soon). 30 minutes of writing and proof-reading this post. Not that bad, I think.
The loss of brain activity came later on, interestingly just came after the drug abuse. do you consider that possible?
 
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Cotcha Yankinov

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Numerous things can lead to brain dysfunction, it certainly doesn't have to be limited to drugs. But drugs + e.g. life stress can be a bad mix.

If you're having the type of problems that I suspect you're having then I would start to practice mindfulness. Try and app called Headspace for starters. There is also "10% Happier", and numerous guided meditations on youtube. Learn about mindfulness and try to get a handle on the basics, and play it by ear from there.

There is also Neurofeedback.

There can certainly be effects that are a bit latent to the inciting event. Gene transcription can take a while to have an effect on the brain for example. The genes are transcribed and then proteins are created which have to be transported around the cells and incorporated in order to start exerting an effect. That can cause a delay.
 

Limpet_Chicken

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I've heard of specialisterne before. Damn shame there doesn't seem to be anything like that in the UK. Never managed to find even manual labor, 3 job interviews in a lifetime of as many decades. One of the bastards turned right round the moment he found out I was autistic (right in front of me, definitely hadn't received any sort of communication and told me they'd just filled the position, as if I was a complete fucking moron. Didn't press it, just told him where to shove it and left, because I wouldn't want to work for a prick like that in the first place.

Could really use something like them here, for that reason. Plenty of skills to offer, no work history just makes it ever more difficult to enter work the longer its been. That, and prejudice (especially when its Kanner's rather than AS) has made it impossible to find work here.

Even the schooling set things against me, going from my results in science exams (100% in two of them, one missed question on the chem paper) I'd have got A-A* had I been doing the higher tier paper. Special school 'didn't do those papers, sorry' and as a result, stuck with 3 Cs in science despite getting the best results in the sciences the school ever had (at least at the point I took my exams in high-school, a spesh-ed boarding school)

Triazolam is a dodgy benzo in the extreme IMO. Ultrashort duration and extremely potent. A long acting benzo is probably safer. With triazolam, you get physically dependent (and i've heard of it causing mild rebound withdrawal from a single one-time dose after it wore off, more than once) and it'll be impossible to maintain plasma levels at a level that won't leave you on a knife-edge between seizure and being well that would be impossible not to withdraw from multiple times a night.

IMO chlormethiazole if its available is a lot safer than the benzos. Whilst I do have nitrazepam at 10mg/d on script I generally only use it in extremis, or for a couple of nights in a row, max 3, if really needed, due to seizure, then 4x weekly, but I use chlormethiazole for my workhorse seizure prophylaxis and whilst taking it at 192mg cap 3x/d (hah speak of the devil, moment I typed that, it decided to 'say hello' in a weird camphoraceous/fermenting apple/etherial belch backwashing up) I've taken it for a few years, and without physical dependency. Barb site agonist (also alcohol dehydrogenase inhibitor so be extremely careful once your used to the drug before drinking any more than a pint/half pint of beer or so if you drink at all, it'll turn a peashooter-strength drink into a close up load of 00 buckshot in the head from a sawnoff 12-ga. Unlike the barbs though it doesn't seem to fuck about with memory much, since it lacks the negative allosteric modulator properties at AMPA type glutamate receptors that the barbs have, and having tried barbs as well (barbital, phenobarb, only the former being any good), the barbiturates cause a LOT of head-fog whilst chlormethiazole is clearer-headed (and tolerance-wise massively less prone in my experience, to causing physical dependency)

Certainly a lot safer than something as iffy as triazolam.
 
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5HT2c

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I would start to practice mindfulness. Try and app called Headspace for starters.

Definetly, instead of reading about DeltaFosB I'd just start with mindfulness. I think you are trying to relate your behavior with your performance in brain terms and this usually doesn't help. Whats there is there and the best you can do is regular exercise, healthy diet and mindfulness.

Also, I don't know much about brain toxicity in other drugs than methamphetamine, but there I can assure you that brain differences between healthy subjects and meth users don't relate to brain changes for meth use and also, brain changes due to meth use don't relate to impairment in cognitive performance tests... which I think is the hard variable to measure...

Hart, C. L., Marvin, C. B., Silver, R., & Smith, E. E. (2012). Is cognitive functioning impaired in methamphetamine users? A critical review. Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology, 37(3), 586–608. http://doi.org/10.1038/npp.2011.276
 

ungelesene_bettlek

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Thank you also a lot for your imput, Limpet_Chicken amd 5HT2c! I will definitley spend more thought and reading time on the postings you gave. An especially interesting discussion will turn out with Limpet_Chicken in the favour of chlormethiazole vs. triazolam.

But apart from my special point of view, I am really interested in the fact which psychoactive drugs are neurotoxic and why. Think of the rules 4. and esprecially 2. in the following graph:

 

ungelesene_bettlek

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I saw my psychiatrist today (well, actually yesterday, but tomorrow only becomes today after sleeping). The good news is, we completely agreed on the action of the drugs alcohol, nicotine, caffeine, ketamine, methoxetamine, trazodone, LSD and Psilocybin (well, to be more precise, we agreed to disagree in a way very appropriate to two scientists). What troubled me is that she viewed benzodiazepines (and thienodiazepines, to be fully correct) as neurotoxic and antipsychotics as non-neurotoxic, so please give me more details on these two substance classes. What trobles me a bit is that I didn't ask her on her point of view on Memantine and Amantadine, both nootropics and NDMA recepor antagonists and approved medications, and of course her opinion on sugare (compare my other thread).

Sorry for this short text, but I really need to go to bed.
 

Cotcha Yankinov

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Benzos certainly can cause brain atrophy when given chronically. Some portion of that is thought to be due to disruption of REM sleep, and in that sense the atrophy can be thought of being due to not necessarily neurotoxicity but rather an inhibition of normal neurotrophic effects that would occur during REM sleep.

Antipsychotics can tend to cause hypertrophy on the other hand, and help treat the atrophy that is normally seen in schizophrenia. Older antipsychotics may be cytotoxic on some level but the newer ones are better and treating the disease with such a drug is typically much better than letting the disease go unchecked. But yes, antipsychotics can induce some cell growth.
 

ungelesene_bettlek

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Thank you very much for this incredobly valuable informations to me, Cotcha Yankinov! Yes, I know from my very own experience that Benzodiazepines cause loss of memory of dreams. On the other hand, I dream more vividly when I'm not on benzodiazepines/thienodieazepines. One very fascinating experience of mine was when I was on a cold benzodiazepine withdrawal, which caused me to dream while I was still awake.

Sorry for not having more time to answer this. I'll go back when I have more actual questions (rule 12 of a scientist's live should be to do more actual research and less asking for spoonfeding!), but my primary goal at the moment is to find a true goal in life I can be proud of.
 
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ungelesene_bettlek

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I need to start this thread all over. You need to know that I am Asperger autist, and I hold a Master's degree in mathematical physics. So let's view all drugs on a line. On one end, there are LSD and Psilocybin, which are 100% non-neurotoxic AFAIK, and on the other hand is alcohol, wich is 100% neurotoxic, because it is toxic to every cell in the human body. Where in this line are dissociatives/NMDA-antagonists? Are they neurotoxic in the sense of Olney's lesion, or are they neuropotective, as Amantadine and Memantine suggest? Where are typical neuroleptics (dopamine antagonists)? Where are atypical neuroleptics (serotonin antagonists)?

PS: As far as I know, MDMA is known to be neurotoxic, but is this also the case for 5-MAPB?
 
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Limpet_Chicken

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As for antipsychotics (D2 antagonist type) the neurotoxicity depends on the specific drug.

Haloperidol, one of the butyrophenone APs is known to be particularly nasty, since it forms neurotoxic metabolite with similar effects to MPTP.

And whilst I've never looked for any longterm studies, I'm curious as to longterm toxicity or lack thereof of sulpiride/amisulpiride, as these have upregulating or agonistic effects on GHB receptors, which of course would lead to increase in glutamate release. I've nowhere near data enough to accuse these drugs of neurotoxicity, but the glutamatergic secretagogue effects are enough to make one wonder if it could potentially be the case. (Your not the only one on the spectrum around here :) although I'm autie rather than aspie, but quite definitely insatiably curious about..well..everything=D)
 

ungelesene_bettlek

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Thank you a lot for your input, Limpet_Chicken

although I'm autie rather than aspie, but quite definitely insatiably curious about..well..everything=D)
That will not matter in the future, DSM-5 tends to speak of a broader autistic spectrum, and ICD-11 will follow. Obviously you are lying in atypical autism, because people with Kanner syndrome show heavenyl disabled mental behaviour, as far as I know.
 

clubcard

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Cotcha Yankinov surely knows his work well. I can just imagine him leaning down to pick something off the floor of the lab only for an NMR sample tube dropping out of his top pocket. I bet this happened once. Then there is always someone who is a passion fingers. Is it an apocryphal story of a sub-graduate putting a sample directly into the NMR, not in a tube? I keep hearing it. I forget the name but a guy in NZ selling a tiny NMR setup that used solid-state cooling. I forget the company name but it was the size of a small (European) fridge and was silent in operation. I would have loved one but didn't have the $750,000 on me at the time... or ever.



-Check for gross hazards so standard banks of tests (hERG, Ames, Membrane Potential and so on) carried out by people like Huntingdon Life Sciences. hERG, Ames and other required data.
-Check that the compound fits Lipinski's rule of 5. A low cLogP means a drug won't concentrate in brain tissue. If the pKa at plasma pH means 100% of the material carries a formal charge, it won't cross the BBB. How is it metabolized? What physiological effects do the metabolites display?
-Check for the affinity of the compound. How many classes and subtypes of receptor will it interact with? That known, what action does it have at all of those receptors? We are getting much better, but 'silver bullets' are rare and the low-hanging fruit has been harvested.
-Check existing papers and patents. Reaxys is wonderful but costly. If you can access from an educational establishment then do so, it will save you a lot of pain. TGN1412 almost killed 6. A Previous CD28 ligand had resulted in severe reactions and been reported. Nobody checked!
-Now you need to know what action the material actually has. Phases of clinical research uncover first acute and then chronic side-effects. Gaboxadol is a good example. Failed to reach clinical endpoints so someone bought the rights to try it for other medicinal action.

Many CNS agents exhibit neurotoxicity. It seems more like the rule than the exception. It is the level of toxicity and the bodies ability to restore the damage that defines how toxic it is. Sometimes, CNS compounds damage other organs. I won't detail alcohol but both aminorex and fenfluramine exhibited 5HT2b affinity which causes cardiac valvular fibrosis. Bupropion causes seizures. From the gray market, the ortho substituted n-methylaryl PEA class 5HT2a agonists (commonly referred to as NBOMes) exhibit toxic symptoms often enough for a lot of papers. Clin Toxicol (Phila). 2013 Mar; 51(3): 174–177. Clin Toxicol (Phila). 2015 Feb;53(2):85-92. Journal of Analytical Toxicology 2015;39:602 –606. There are many more but the cardinal symptoms are aggression, agitation, hallucinations, hypertension, seizure and tachycardia. Apparently seizure and Serotonin Syndrome (leading to malignant hyperthermia and Long-QT, itself becoming Torsades de Pointes).

What I do find a little worrying is that some medicinal chemists are a little too gung ho for my liking. If people are interested in the life of a stage 1 subject, there is even a jobzine for the work. https://www.guineapigzero.com Now is it just me that feels that this model is unethical? If nothing else, the subjects have have other novel drugs in their system when they do a trial. Sooner or later the tailings of a statin will interact with the next novel compound? While thalidomide, Amobarbital & Propoxyphene are famous examples, rofecoxib, valdecoxib & trovafloxacin have destroyed many more lives. Even pronethalol, the first beta-blocker on the market was withdrawn because of it's carcinogenicity. That is why drug designers look at fused aromatic rings askance. That drug showed the risks of epoxides. Even that Chinese guy who named his product 'Eric 1' was selling a napthalene analogue of pyrovalerone! This even after a second benzene ring was shown to be a bioisostere of a propyl moiety (at least in SNDRI designs based on pyrovalerone).

Sorry.... just rambling.... sorry for wasting everyone's time.
 

Limpet_Chicken

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Why would I be lying?

I did actually go to a Kanner's school (went to two spesh schools, one an aspie boarder, can't say as I was close to the aspie type, although certainly closer to it than to NT [god what a thought..*shudders*], and having dated quite a few girls on both the aspie and the Kanner's side of the spectrum, I'm definitely a lot more like them, and both understand them better and get on better with Kanner's girls.

Yeah, I'm pretty spazzy, but hey, Kanner's spazz and damn proud of it. I wouldn't want things any other way. I've been the way I am all my life, and I love the weird way I'm wired up. Sure I'm different and run some pretty nonstandard wetware, but it works for me. And the kanner's girls...now that, is the kind of direction to point oneself in, if one is looking to meet a REALLY hot girl=D
 
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