harmine and its similarity to serotonin

[red22]

Is there any significance in the fact that harmine, the MAOI traditionally used for DMT preparations,* is highly similar to serotonin? I have this idea that this fact conveys that harmine would be much more compatible with the brain than other MAOIs and inhibitor-type antidepressants, none of which are nearly as similar in structure to an endogenous chemical, as far as I know. I would imagine that the more dissimilar a chemical is from the brain's molecular foundations, the more it bangs things around when it enters the brain (in contrast to interacting smoothly with the brain); and inhibitor-type antidepressants including Nardil and Parnate,** two of the oldest MAOIs, definitely feel toxic in my experience.

For comparison purposes I'm listing other MAOIs below, including pictures of their structures, if it's useful. Maybe someone can say something about the comparison between their structures and harmine's structure.

*Harmine is the predominant MAOI in Banisteropsis caapi vine.

Banisteriopsis caapi, a unique combination of MAO inhibitory and antioxidative constituents for the activities relevant to neurodegenerative disorders and Parkinson's disease. Samoylenko, V.; Rahman, M.; Tekwani, B. L.; Tripathi, L. M.; Wang, Y.; Khan, S. I.; Khan, I. A.; Miller, L. S.; Joshi, V. C.; Muhammad, I. Journal of ethnopharmacology. 10/2009; 127(2):357-67. DOI: 10.1016/j.jep.2009.10.030 DOWNLOAD


**Generic names: phenelzine and tranylcypromine.


Chemical Name: brofaremine
Molecular Formula: C14H16BrNO2
C AS No.: 63638-91-5

Chemical Name: caroxazone
Molecular Formula: C10H10N2O3
CAS No.: 18464-39-6

Chemical Name: eprobemide
Molecular Formula: C14H19ClN2O2
Formula Weight: 282.769
CAS No.: 87940-60-1

Chermical Name: amiflamina
Formula Weight: C12H20N2
CAS No.: 77697-37-1

Chemical Name: metralindole
Molecular Formula: C15H17N3O
CAS No.: 54188-38-4

Chemical Name: minaprine
Molecular Formula: C17H24Cl2N4O
Formula Weight: 371.3
CAS No.: 25905-77-5

Chemical Name: pirlindole
Molecular Formula: C16H22N2O3S
Formula Weight: 322.42
CAS No.: 60762-57-4

Chemical Name: toloxatone
Molecular Formula: C11H13NO3
Formula Weight: 207.23
CAS No.: 29218-27-7

Chemical Name: moclobemide
Molecular Formula: C13H17ClN2O2
Formula Weight: 268.74
CAS No.: 71320-77-9

Chemical Name: befloxatone
Molecular Formula: C15H18F3NO5
Formula Weight: 349.303
CAS No.: 134564-82-2

Chemical Name: cimoxatone
Molecular Formula: C19H18N2O4
CAS No.: 73815-11-9

Chemical Name: esuprone
Molecular Formula: C13H14O5S
Formula Weight: 282.315
CAS No.: 91406-11-0

Chemical Name: methylene blue
Molecular Formula: C16H18ClN3S
Formula Weight: 319.85
CAS No.: 61-73-4

Chemical Name: sercloremine
Molecular Formula: C14H16ClNO
Formula Weight: 249.739
CAS No.: 54403-19-9

Chemical Name: tetrindole
Molecular Formula: C21H30N2O3S
Formula Weight: 390.54
CAS No.: 135991-95-6

Chemical Name: phenelzine
Molecular Formula: C8H12N2
Formula Weight: 136.19
CAS No.: 51-71-8

Chemical Name: tranylcypromine
Molecular Formula: C9H11N
Formula Weight: 133.19
CAS No.: 95-62-5

 

[endotropic]

Honestly I don't see much similarity between serotonin and harmine, none of the herteroatoms are in the correct positions relative to each other. In my eyes minaprine looks most "serotonin-like" but I'm not sure that holds any significance to its action.

It's an interesting theory that chemicals more dissimilar to neurotransmitters would have more off target side effects, but I'm not sure if there's any evidence to support that (or how you would test it exactly).

 

[sekio]

Harmine is biosynthesized via a tryptamine intermediate... other than that the two molecules only "look" the same when we draw them as line formulas. In reality going from a 2-aminoethyl to a pyridine ring is a pretty major change. By making that change not only do you remove an axis of rotation, you also alter the basicity of the nitrogen by adding substituents, and introduce an aromatic ring which can participate in pi-stacking where there wasn't one before. So the molecules actually "look" much different to an enzyme.

I would imagine that the more dissimilar a chemical is from the brain's molecular foundations, the more it bangs things around when it enters the brain (in contrast to interacting smoothly with the brain);

This doesn't actually hold true and is a subset of the 'naturalist's fallacy' in chemistry. You can have things that are closely related to neurochemicals that are super toxic (6-hydroxydopamine, 5,7-dihydroxytryptamine) and also chemicals that appear "unnatural" and look nothing like any known neurotransmitters that are of comparably low toxicity (THC) or even sought out and abused (like morphine @ opioid receptors... even though it occurs in traces endogenously, B-endorphin is the native ligand).

Another head scratcher: if being close to neurotransmitters structurally is important, 5-MeO-AMT should be pretty close to serotonin. But unfortunately it's regarded as one of the roughest, nastiest compounds out there. In fact, I wouldn't be surprised if direct infusion of stuff like serotonin or dopamine isn't actually any fun. Dopamine and norepinephrine are used IV as cardiac emergency drugs, but I don't see the docs sneaking off to IV any for a rush!

In fact, if you asked me, I would say the further away from a "natural" ligand for a receptor you get (and the more complex you go), the more likely it will be selective for one receptor over many. Generally bigger, more complex molecules have fewer favored interactions. There is certainly no easy predictable correlation between molecular structure and "toxic feeling".

 

[red22]

Thanks for the responses!


In Hofmann's Potion (2002), Albert Hofmann emphasized that brain monoamines are very similar in structure to psychedelic drugs; and indeed harmine shares a property of psychedelic drugs that the other MAOIs don't (as far as I know).


The harmala alkaloids also possess some activity as agonists in their own right. In Pelletier's Alkaloids: Chemical and Biological Perspectives, the affinity of harmine, harmaline, and six other β-carbolines was assessed in rats. They were found to have moderate affinity for μ- and δ- opioid receptors (IC₅₀ 5-13 μM), and minor affinity for the principally hallucinogenic 5-HT_2A receptor (IC₅₀ = 58 ± 6.8 μM), and others of this subtype. For perspective, the classical psychedelic drugs exhibit dissociation constants measured in nanometres (nM, 1×10⁻⁹ M), while the activity of β-carbolines at the same sites is measured in micrometers (μM, 1×10⁻⁶ M), which is an order of magnitude less. This explains why the harmala alkaloids are only weakly psychoactive as compared to the psychedelic tryptamines they loosely resemble.

Ped, via private message. Dec. 18, 2014.

 

[sekio]

For perspective, the classical psychedelic drugs exhibit dissociation constants measured in nanometres (nM, 1×10−9 M)

nM in med chemistry generally means nanomoles - a measure of concentration, not nanometres - measure of difference.

 

[red22]

Which one of those MAOIs looks the most promising from a structural standpoint (as far as lowest toxicity and effectiveness)?

 

[sekio]

You can't really predict something like that based upon structure alone.

 

[red22]

Which of those would be easiest to synthesize?

 

[sekio]

It depends on what you have on hand and what you consider "easy".

Phenelzine is by far the simplest (lowest molecular weight). Moclobemide and eprobemide look pretty simple too. All the others... you'd need to chase down literature synthesis protocols.

 

[red22]

Is there any structural justification for the idea that moclobemide is dirty? I bought the powder and I ended up overdosing on it and I experienced a horrible discoordination of body awareness. I felt like I was on the verge of going crazy.

¼ tsp. that was a bit above level.


Also, requesting a copy of this:

Monoamine Oxidase Inhibitors Extracted from Tobacco Smoke as Neuroprotective Factors for Potential Treatment of Parkinson’s Disease
DOI: 10.2174/1871527314666150325235608

 

[serotonin2A]

Is there any structural justification for the idea that moclobemide is dirty? I bought the powder and I ended up overdosing on it and I experienced a horrible discoordination of body awareness. I felt like I was on the verge of going crazy.

¼ tsp. that was a bit above level.


Also, requesting a copy of this:

Monoamine Oxidase Inhibitors Extracted from Tobacco Smoke as Neuroprotective Factors for Potential Treatment of Parkinson’s Disease
DOI: 10.2174/1871527314666150325235608

You probably used more than 1 gram. Why would you think that using a teaspoon to measure doses of a drug would be a good idea. Please don't do that.

All drugs, if the dose is high enough, are dirty. That's one reason why overdoses are bad.

 

[red22]

Lower doses felt like a milder version of what I experienced... And friend of mine said the same thing. After hearing about my overdose he was very conservative and started with a tiny dose to test for an allergic reaction and then when he raised the dose for DMT, as he was waiting for the dosing of the DMT he said the moclobemide made him feel an agitation that he had previously experienced with other antidepressants. And you're wrong, not all drugs are dirty when you overdose. I can think of a few that aren't. Cannabis and LSD. Those drugs won't produce an unbelievably toxic body stimulation that makes you feel like you need an EMT to rush in with a needle full of some sort of tranquilizer. Opiates are another example. I remember a Bluelighter who had seriously overdosed on heroin reported, 'there's no pain.'

Well, there's evidence that LSD has some hazardous effects when it's overdosed, but my moclobemide overdose was only slightly above regular doses, perhaps double. The LSD thing I'm referring to is a massive dose: http://www.bluelight.org/vb/threads/719348-So-how-much-LSD-did-these-guys-take

I think the fcat that I got such bad effects from only a slight overdose of mocloebmide is basically the true colors of moclobemide. Same thing happened when I ignorantly tried to gt high on Cymbalta, reasoning that it had the same mechanism of action as cocaine. Simply a few extra pills gave me a toxic body load. This isn't normal as compared to e.g. going to a party and smoking 3-4 times a much weed as you usually do or taking 3 or 4 extra benzo pills or going to a festival and eating shrooms and acid in doses well above your normal ones. You try to take an inch with things like Cymbalata and moclobemide and you might require medical attention. This stuff is plastic and it's incompatible with the body

 

[serotonin2A]

And you're wrong, not all drugs are dirty when you overdose. I can think of a few that aren't. Cannabis and LSD. Those drugs won't produce an unbelievably toxic body stimulation that makes you feel like you need an EMT to rush in with a needle full of some sort of tranquilizer. Opiates are another example. I remember a Bluelighter who had seriously overdosed on heroin reported, 'there's no pain.'

You are misunderstanding me here. The term "dirty" in pharmacology refers to off-target effects. All drugs loose their selectivity if the dose is raised too high. As you mentioned, if you take enough LSD you will go into a coma, experience respiratory arrest, and your blood will stop clotting.

I think the fcat that I got such bad effects from only a slight overdose of mocloebmide is basically the true colors of moclobemide. Same thing happened when I ignorantly tried to gt high on Cymbalta, reasoning that it had the same mechanism of action as cocaine. Simply a few extra pills gave me a toxic body load. This isn't normal as compared to e.g. going to a party and smoking 3-4 times a much weed as you usually do or taking 3 or 4 extra benzo pills or going to a festival and eating shrooms and acid in doses well above your normal ones. You try to take an inch with things like Cymbalata and moclobemide and you might require medical attention. This stuff is plastic and it's incompatible with the body

It is a principle of pharmacology that all drugs have safety margins (the therapeutic index). Moclobemide and duloxetine may not have wide safety margins. I'm not really sure why you are blaming the drugs for what happened to you, that is the risk you take when you exceed the recommended dose of a medicine. They weren't necessarily designed to be taken at the doses you were using.

 

[red22]

Yeah, and what am I saying!? I'm saying that the low safety margins are probably indicative that they're inherently effed up, meaning toxic or at least nowhere near as effective as alternatives.

 

[serotonin2A]

Yeah, and what am I saying!? I'm saying that the low safety margins are probably indicative that they're inherently effed up, meaning toxic or at least nowhere near as effective as alternatives.

I think you are under the mistaken impression that it is generally OK to exceed the recommended dose range of pharmaceutical substances. Although that might not be a problem with some substances, if you do that with many medications you will potentially experience unpleasant side-effects. It doesn't necessarily mean they are inherently toxic or there is something wrong with them -- the most likely cause is that they aren't selective at high doses, or maximally effective doses of the drug may disrupt physiological processes (eg, high doses of morphine suppress respiration). That is why there is a recommended dose range for most drugs.

For example: Diphenhydramine is a very effective antihistamine, and not very toxic, but if you take a few hundred mg you will experience anticholinergic effects. Tramadol and buproprion cause seizures if you exceed the recommended dose range. Acetaminophen is very effective but a even relatively small overdose can be fatal. Even caffeine, which is generally considered to be safe, has a pretty narrow therapeutic index. People have died from 1 gram of caffeine.

 

[red22]

OK, I took 2x the maximum starting dose of moclobemide and I incurred agitation/lessening of body awareness and a drop in body temperature. What I'm saying is maybe some of those other MAOis wouldn't come anywhere near such toxic effects even when administered in high doses.

 

[serotonin2A]

OK, I took 2x the maximum starting dose of moclobemide and I incurred agitation/lessening of body awareness and a drop in body temperature. What I'm saying is maybe some of those other MAOis wouldn't come anywhere near such toxic effects even when administered in high doses.

600 mg is considered a high dose of moclobemide. 300 mg is the highest recommended starting dose. You took 1-2 grams, so 4-5x higher.

MAO inhibitors are notorious for producing side-effects. Moclobemide actually has very few side-effects for a MAO inhibitor, but that doesn't mean you can take as much as you want.

It is possible that you are sensitive to moclobemide, or intolerant of it. That is why people recomend "allergy testing" when someone tries a new drug. You took the opposite approach, measuring your dose using a teaspoon. Why would you think it would be a good idea to take more than the maximal starting dose (300 mg), let alone the maximum dose they normally give to patients (600 mg)? The reason they don't normally give patients higher doses is because they produce side-effects, as you discovered.

 

[red22]

I had the powder. To this day I don't know how much I used. And it was a ¼ teaspoon that was a bit above level. I based my dose on some sort of amateurish deduction from spoon conversions given for powdered sugar. One of my last lessons that taight me to bee more responsible with my drug use. And MAO inhibitors are not notorious for producing side effects.* They're notorious for possibly killing you if you co-ingest protein-rich foods that have undergone aging. There's a difference! And moclobemide is much less likely to produce that hazard (same with most of the MAOIs listed in the first post).** This doesn't mean that moclobemide doesn't possess less side effects in general and it may even produce more side effects than the potentially fatal MAOIs.


*Jay Amsterdam at the University of Pennsylvania goes up as high as 120 mg of Parnate(tranylcypramine) and claims fewer side effects at higher doses.

This Month’s Expert: Jonathan Cole, M.D. Reflections on the Use of MAOIs. Psych Central Professional.


**http://www.bluelight.org/vb/entries/7609-moclobemide-(MAOI)-diet-info

 

[serotonin2A]

I had the powder. To this day I don't know how much I used. And it was a ¼ teaspoon that was a bit above level. I based my dose on some sort of amateurish deduction from spoon conversions given for powdered sugar. One of my last lessons that taight me to bee more responsible with my drug use. And MAO inhibitors are not notorious for producing side effects.* They're notorious for possibly killing you if you co-ingest protein-rich foods that have undergone aging. There's a difference! And moclobemide is much less likely to produce that hazard (same with most of the MAOIs listed in the first post).** This doesn't mean that moclobemide doesn't possess less side effects in general and it may even produce more side effects than the potentially fatal MAOIs. *Jay Amsterdam at the University of Pennsylvania goes up as high as 120 mg of Parnate(tranylcypramine) and claims fewer side effects at higher doses. This Month’s Expert: Jonathan Cole, M.D. Reflections on the Use of MAOIs. Psych Central Professional. **http://www.bluelight.org/vb/entries/7609-moclobemide-(MAOI)-diet-info

I wasn't referring to interactions with dietary amines. Moclobemide is regarded as being well tolerated by patients, and has less side-effects then tricyclic antidepressants: http://www.ncbi.nlm.nih.gov/pubmed/1394027

The link you cited didn't say that tranylcypramine produces few side-effects. It said that high doses produce less side-effects compared to lower doses. The patients still might be experiencing a lot of side-effects compared to moclobemide.

But FYI, interactions with dietary amines ARE considered side-effects of irreversible MAO inhibitors. Look at the side-effects section of the labeling/prescribing info and you will see it listed there.

 

[atara]

There's no reason to synthesize harmine; syrian rue is easy to buy and there's every indication that the nausea is a result of harmine itself, because it also happens when you use B. caapi. Also probably why harmine was passed over in favor of moclobemide for development; the latter was dropped after being insufficiently efficacious but it wasn't very potent which does suggest that harmine (which is in fact much more potent than moclobemide) might look better.

Selective RIMAs like harmine are the most well-tolerated class of antidepressants if the small amount of data available is anything to go on. There however remains the possibility of "unexpected" interactions with food or drugs due to inhibition of hepatic MAO-A. Consult with a doctor before taking harmine regularly, if that's what you're thinking.

Anywho, the fact that harmine looks formally like the cyclization/oxidation product of melatonin has no bearing on its safety or efficacy, and really isn't usually a good sign. MDMA looks like dopamine and that's bad, modified neurotransmitters are often used to break things (oxidopamine e.g.) because they can be metabolically toxic by "tricking" the brain's enzymes. In this case harmine's pyridine ring means it will follow a very different metabolic course than melatonin.

OK, I took 2x the maximum starting dose of moclobemide and I incurred agitation/lessening of body awareness and a drop in body temperature. What I'm saying is maybe some of those other MAOis wouldn't come anywhere near such toxic effects even when administered in high doses.

Who cares? That could easily be placebo. However as noted moclobemide is a rather weak MAOI so it makes sense to me why someone would want to use harmine (which is active at 30 mg as opposed to 300 mg for moclobemide). As an overbroad generalization more potent -> more selective, but counterexamples are everywhere (LSD, e.g.).