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MBDB toxicity

D_DOOD

D_DOOD

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Nov 15, 2004
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How much is known nowadays about MBDB neurotoxicity? serotonin depletion?

Its a new thing over here, sold in headshops and 7/11s(israel).
 
Neurotoxic effects of the alpha-ethyl homologue of MDMA following subacute administration.

The possible neurotoxic effects of the alpha-ethyl homologue of MDMA, N-methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine (MBDB), were examined following a regimen of twice daily dosing for four days. The levels of norepinephrine, serotonin and its metabolite 5-HIAA were quantitated by standard HPLC-EC techniques. In addition, the number of 5-HT uptake sites was estimated by examining the binding of [3H]-paroxetine to rat cortex homogenate. With 20 mg/kg (IP) subacute dosing of MDMA, a nearly 60% reduction in 5-HT, 5-HIAA, and 5-HT uptake sites was found, with no change in NE, two weeks posttreatment. A behaviorally equipotent dose of MBDB (25 mg/kg, IP) also produced a significant decrease in the serotonergic markers; 5-HT, 5-HIAA and [3H]-paroxetine binding sites. However, a comparison of the relative toxic effects of MDMA and MBDB indicates that MBDB may be slightly less neurotoxic. It was also found that MDMA but not MBDB caused a significant increase in dopamine levels at 3 hours following a single IP injection. The results are discussed in relation to the therapeutic index of MBDB and the relative importance of dopamine release in the neurotoxicity of MDMA.

Johnson MP, Nichols DE. Department of Medicinal Chemistry and Pharmacognosy, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, IN 47907. Pharmacol Biochem Behav. 1989 May;33(1):105-8.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2476831&dopt=Citation

N-methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine (MBDB): its properties and possible risks

Abstract:

MBDB (N-methyl-1-(1,3-benzodioxol-5-yl)-2-aminobutane) is the f-ethyl homologue of MDMA (3,4-methylenedioxy-N-methylamphetamine). MBDB is metabolized and excreted similarly to MDMA: presumably, the majority of oral MBDB is excreted in urine unmetabolized.The main metabolic routes in man are thought to be O-dealkylation and subsequent methylation, sulphation and glucuronidation of the newly formed hydroxy groups. The major acute neuropharmacological effects of MBDB in the rat are an increase in serotonin release in the brain and an inhibition of serotonin and noradrenaline re-uptake. These effects compare well with those of MDMA, although the latter is more potent. MBDB may also slightly increase dopamine release and inhibit dopamine re-uptake, but to a lesser extent than MDMA. This is important, as dopamine release has been implicated in the reinforcing qualities of substances such as cocaine and amphetamine. The neuroendocrine effects of MBDB resemble those of MDMA. Both substances increase plasma ACTH, corticosterone, prolactin and renin. The neurophysiological effects of MBDB are characterized by a decrease in electrical activity throughout the brain, most notably in the alpha2 and delta frequency bands. In contrast, hallucinogens increase the activity in the alpha1 band, especially in the corpus striatum. In drug discrimination tests in the rat, MBDB, like MDMA, can be distinguished clearly from both stimulants and hallucinogens.The class of substances to which MBDB belongs may be named entactogens. MBDB dose-dependently increases locomotor activity and decreases exploratory behaviour in the rat and causes distress vocalization and wing extension in the newly hatched chicken. The rewarding properties of MBDB appear to be smaller than those of MDMA, as suggested by a 2.5 times weaker potency in the conditioned place preference test in rats. The main subjective effects of MBDB in man are a pleasant state of introspection, with greatly facilitated interpersonal communication and a pronounced sense of empathy and compassion between subjects. In this respect, MBDB again resembles MDMA. However, there are also differences. MBDB has a slower and more gentle onset of action than MDMA, produces less euphoria and has less stimulant properties. The few toxicological data available suggest that MBDB may cause serotonergic deficits in the brain, although the potency of MBDB to cause this neurotoxic effect is smaller than that of MDMA. Severe acute reactions in man as have been reported for MDMA have not been published for MBDB. The dependence potential of MBDB appears to be small, probably even smaller than that of MDMA. MBDB has been available at least since 1994 but its position on the synthetic drugs market is marginal. Subjective reports indicate that MBDB is less popular among users than MDMA. The reason may be that MBDB produces less euphoria than MDMA. Another possible explanation is that MBDB largely lacks the stimulant properties of MDMA.We calculated a margin of safety with a method similar to one used in the risk assessment of pharmaceuticals. The results suggest that MBDB is three times less likely to cause serotonergic brain deficits than MDMA. However, it should be noted that for both substances the margin of safety is less than one, indicating that the risk of neurotoxicity is not negligible. In animals, serotonergic brain deficits after exposure to MDMA have been linked to the degeneration of serotonergic nerve terminals.

L. A. G. J. M. Van Aerts, M. Mallaret, H. Rigter. A1 Trimbos Institute, Netherlands Institute of Mental Health and Addiction, Utrecht, The Netherlands. A2 Centre Hospitalier Universitaire de Grenoble, Laboratoire de Pharmacologie, Grenoble, France.

http://taylorandfrancis.metapress.c...al,19,37;linkingpublicationresults,1:100644,1
 
So it looks like it's less neurotoxic because it releases less dopamine, but it probably wont be as fun, because it doesn't release as much dopamine.
 
I honestly don't see the connection between dopamine and neurotoxicity. All of the reports I have read about mdma and neurotoxicity suggest that damage done to serotonin axions occurs because of oxidative stress. MDMA could also cause damage to dopamine axions, as amphetamines do. MBDB would do less damage to the dopamine centers, because it is not a stimulant. That f-ethyl substitution pretty much abolishes any amphetamine like stimulation (dopamine and noradrenaline release and reuptake inhibition). Hence the lack of dopamine release as compared with mdma in that first abstract. Exactly how is dopamine supposed to cause damage to serotonin axions?
 
Dopamine ---> MAO-B ---> ROS.

What are these "reports" you have read? The dopamine theory AKA "the intergrative hypothesis" is one of the most common theories of MDMA-mediated neurotoxicity.
 
This study raises questions on the dopamine theory:

The mechanism by which 3,4-methylenedioxymethamphetamine (MDMA) produces serotonin (5-HT) neurotoxicity is unknown but considerable evidence suggests that endogenous brain dopamine (DA) is involved. However, it has recently become apparent that some of the data implicating brain DA in MDMA neurotoxicity may be confounded by drug effects on thermoregulation. The purpose of the present studies was to examine the role of DA in MDMA neurotoxicity, while controlling for possible confounding effects of drug- induced changes in core temperature. Rats were treated with reserpine, alone and in combination with alpha-methyl-p -tyrosine (AMPT), to deplete vesicular and cytoplasmic stores of DA. When drug-induced hypothermia was averted (by raising ambient temperature), the 5-HT neuroprotective effects of reserpine and AMPT were no longer apparent. The lack of neuroprotection by AMPT and reserpine, alone and in combination, in studies that control for the effects of these drugs on core temperature, suggests that DA per se is not essential for the expression of MDMA-induced 5-HT neurotoxicity.

Yuan J, Cord BJ, McCann UD, Callahan BT, Ricaurte GA "Effect of depleting vesicular and cytoplasmic dopamine on MDMA neurotoxicity", J Neurochem, 2002; 80(6):960-9
Click to expand...

This commentary on that study, from thedea.org, is pretty convincing:

In 2002, an important new piece of research was done: Animals who had been given drugs that removed virtually all of the serotonin and dopamine in their brains were given what should have been a neurotoxic dose of MDMA. And nothing happened. There was no damage.[3] At first, it seemed as though the 'dopamine' camp had been right. However, the scientists noticed that something else was different in these dopamine depleted animals: When they gave them the overdose of MDMA, they didn't overheat as expected.

That was significant, because past research had shown that overheating was the key to MDMA neurotoxicity. It wasn't enough to give an animal a massive dose of MDMA; if the body's protective mechanisms weren't impaired by overheating, the animal could usually cope and did not suffer damage. Knowing this, the researchers took another group of dopamine depleted animals, gave them another overdose of MDMA, and warmed them with heating pads so that their temperature reached the same levels as normal (control) animals did when given the same ammount of MDMA. The results were striking: The animals with essentially no dopamine in their brains suffered the same level of neurotoxic damage as the control animals did when their body temperatures were kept as high. Something else was at work; dopamine was not the toxic chemical in question. (Ironically, dopamine and norepinephrine release appears to still be important in MDMA neurotoxicity because it promotes activity/heat production, increasing the risk of overheating (which in turn seems to greatly increase the risk of neurotoxicity.))
Click to expand...
 
Yes, indeed, the dopamine/intergrated hypothesis theory is probably exclusively bullshit... but if there was going to be neurotoxicity, increased dopamine would lead to increased core temperature, and hence, worse neurotoxicity.
 
Agreed, but your raising it up as an example spurred me to play devil's advocate.

I've found pre-loading with DLPA increases (subjectively, in some ways, anyway) the high of and definitely decreases memory of an MDMA trip. I decided that, health issues aside, the trade-off wasn't worth it. Any correlation with neurotoxicity here? Hrm.

I noticed my local corner store now sells pot-pipes. No MBDB yet, though. Israel must be an interesting place!
 
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So it would appear one could simply say that the catecholamine-induced overheating seems to be at the route of the MDMA and the likes neurotoxicity. Comparable to para-chloroamphetamine's neurotoxicity then perhaps? And since the removal of dopamine/norep. activity in something like para-methylthioamphetamine appears to leave us with a non-neurotoxic serotonin releaser, matching p-chloroamphetamine in drug descrimination for MDMA (I know rats don't have much to say 8) ), but also DOES produce thermal raise, where does this kind of leave us?
 
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I find it interesting that you think DAT/NET activity is repsonsible for causing an increase in core body temperature since these problems dont exist in the case of amphetamine. The overheating associated with MDMA is pretty much down to serotonin syndrome.

It comes as a bit of a shock that p-chloroamphetamine is so neurotoxic. I wonder what would happen to an individual if they consumed a sample of this chemical. Then again I would rather not think about it...
 
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Meth causes hyperthermia... but your right, 5-HT2a receptors seem to play a large roll in rat hyperthermia..
Yeah, maybe I was off the mark when I said more dopamine would lead to more hyperthermia..

A "non-neurotoxic" 5-HT releaser, in my mind, wouldn't be neurotoxic even in a hyperthermic animal... the MDMA or any other neurotoxic amphetamine, or one of its metabolites (though I don't neccasarily buy that it has to be peripherally formed) through MAO-B, is making ROS... that's all I know.
 
If it's the case that hyperthermia is the main culprit in neurotoxicity, and that serotonin has a secondary role, then shouldn't drugs like fenfluramine, which is almost exclusively a seroronogic agent, be neurotoxic in conditions where body temp is raised?

And if not, then doesn't that implicate something else (like dopamine)
 
What it could mean is that dopamine AND serotonin mixed together cause an increase in core body temperature. This isnt scientifically based but I would anticipate that 'tricolor' drugs (SERT, NET & DAT) are more likely to do the damage. You know the feeling when your ears are glowing red and you are feeling confusion, even tramadol does this to me on the come-down.
 
Not neccesarily... theDEA.org proposses a theory, where MDMA is neurotoxic along the same lines as MPP+... i.e. it is a neurotoxic chemicals in its own right, BUT is only neurotoxic during hyperthermia because some biological protective mechanism is overhwhelmed... I kinda like that idea myself... I also think its possible that the neurotoxic metabolite theory is partially right.. but people forget, CYPs are expressed in the brain... I just think you need peripheral serotonin release to get hyperthermia, and you need hyperthermia to get neurotoxicity.
 
But how does MDMA invoke lower core temperatures (hypothermia) at lower ambient temps? Surely this is via the same mechamism that causes hyperthermia? In rats dosed at various ambient temps, hypothermia occured without significant depletion of 5HT, so is core temp regulation (hypothalamus?) governed differently in response to peripheral levels of 5HT?


this plot of core temp vs time in rats dosed at an ambient temp

Malberg: Small Changes in Ambient Temperature Cause Large Changes in 3,4-Methylenedioxymethamphetamine (MDMA)-Induced Serotonin Neurotoxicity and Core Body Temperature in the Rat
 
Same mechanism... I don't really know... I'm under the impression that MDMA-induced hyperthermia is caused majoratively by a decrease in cutaneous vascular-bed blood flow due to 5-HT2A-mediated increases in sympathetic tone... I know theres an HPA part, but I suspect thats just because it messes around with the sympathetic nervous system.

Hypothermia... I've just no idea...
 
If you get hypothermia at lower enviromental temp, then it seems like it's due to vasodilation and either loss of heat (in cold enviroments) or increase in body temp when the animals are on a heated pad.

As I recall, it's serotonin that's responsible for post-orgasmic flushing of skin, and that's a product of vasodilation.

As regards the neurotoxicity at highr body temps, I'm fairly certain that I read something about htperthermia being capable of accelerating the rate of production of prion-like amyloid plaque proteins, as seen in people with Alzheimers disease. I suppose it's possible that MDMA also assists in this transformation with increased body temp.
 
Well the neurotransmitter transporters are very temperature sensitive... if MDMA was the toxic species, then increased transporter action would lead to more intracellular MDMA...

I can't see how serotonin would cause flushing... serotonin is vasoconstrictive... and the idea of the hypothermia being caused by vasodilation makes sense, apart from the whole hypERthermia thing.. and the general vasoconstrictive effects of MDMA...
 
Other than that as a mechanism, I can't see how starting rats in a colder ambient temp results in hypothermia. The colder enviroment either messes with the temp regulation mechanism of the brain to lower core temp (not too likely), or the heat transfer between rat and enviroment is enhanced (vasodilation being the most obvious mechanism).


This is a bit off topic, but what does cause the post-orgasmic flushing; I'm pretty sure oxytocin doesn't, and I can't think of anything else (like histamine) that is a component of the post orgasmic state and would have that effect.
 
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