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Are psychoactive drugs with lower lethal doses more neurotoxic (more damaging to the brain)? For example, tetrahydrocannabinol (one of the active components of cannabis) has a much higher lethal dose than benzoylmethylecgonine (cocaine), so could we deduce that cocaine is more damaging to the brain? Moreover, is a mathematical relationship between neurotoxicity and lethal doses known?

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    $\begingroup$ I think this is the wrong way of looking at the question. Neurotoxins are more lethal (have a lower LD50) because less of it is required to kill the organism due to their specific action. $\endgroup$ – March Ho May 22 '15 at 21:33
  • $\begingroup$ @March Ho I figured it wasn't that simple. My chemistry/biology knowledge is very limited $\endgroup$ – St Vincent May 22 '15 at 21:58
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Short answer
The causes of death after heroin, cocain or cannabis overdose are mainly due to cardiac and respiratory arrest, and not to neurotoxic effects.

Background
The cause of death after a lethal overdose of your mentioned drugs are the following :

  • Cocaine (lethal dose: 30 mg - 5 g via mucus membrane (EMCDDA)): Cocaine-related deaths are often a result of cardiac arrest followed by an arrest of breathing (NIH). Cardiac effects are mediated via increased sympathetic output and a local anesthetic effect (Schwartz et al., 2010);
  • THC: (lethal dose: ~1000mg/kg i.v. in primates (Drug library)): No known cases of human fatalities. Toxicity appears as achypnea (rapid breathing), tachycardia (fast heart rate), ataxia, hyperexcitability, and seizures (Fitzgerald et al., 2013), but death seems mostly associated with respiratory arrest and cardiac failure (Drug library);
  • Heroin: (lethal dose 200 - 2000 mg i.v.(EMCDDA)): overdose often due to respiratory arrest (Anoro et al. 2004) caused by mu-opiate receptor activation in the brainstem (Karch, 2006).

Hence, heroin, THC and cocain are lethal mainly due to peripheral causes (i.e., cardiac and respiratory arrest). Although these effects are mediated, at least partly, through central mechanisms (i.e., occurring in the central nervous system and specifically the brain), the drugs themselves do not cause death because of neurotoxicity.

And a closing comment, with credits to @MarchHo - In general, neurotoxins do not cause death due to neural toxicity per se. Most notably even botulotoxin, being one of the most potent neurotoxins known, causes death due to respiratory failure (CDC).

References
- Anorro et al., Rev Esp Salud Publica (2004); 78(5): 601-8
- Fitzgerald et al., Top Companion Anim Med (2013); 28(1):8-12
- Karch, Drug Abuse Handbook (2006) - Schwartz et al., Circulation (2010); 122:2558-69

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  • $\begingroup$ I think that this answer is only partially correct, since almost all (I can't think of one which does not) neurotoxins cause death indirectly via paralysis of nerves or muscles. $\endgroup$ – March Ho May 23 '15 at 13:34
  • $\begingroup$ @MarchHo - the question is on drugs of abuse. $\endgroup$ – AliceD May 23 '15 at 13:36
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    $\begingroup$ What I mean is that in general, neurotoxic drugs cannot cause death solely by their neurotoxicity. $\endgroup$ – March Ho May 23 '15 at 13:37
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    $\begingroup$ Hm, I would say that botulotoxin does indeed cause death because of neurotoxicity; it is simply a peripheral neurotoxin, and since the vagus nerve is paralyzed, death ensues. But if it were not neurotoxic, respiratory arrest would not occur. Things are a bit muddled here. There are lots of neurotoxins; I'd still say their mechanism of action and the cause of death is due to neurotoxicity. I might have to consult a toxicology text. :-/ $\endgroup$ – anongoodnurse Jan 23 '16 at 3:05
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    $\begingroup$ @anongoodnurse Ah! I read the title again... It is asking for effects on the brain. Christiaan's answer is placing it in that perspective. $\endgroup$ – AMR Jan 23 '16 at 3:37

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