[curious_fella1]

> Several classes of opioids have been shown to cause neuronal degeneration

Question for you - is this "brain damage" that I often hear results from taking a particular drug the result of intentful downregulation of certain neuronal receptors (e.g., meth -> too much dopamine in synapse -> downregulate dopamine receptors), or is the drug actually killing brain cells/neurotoxic?

[wittyreference]

That's an excellent question, and an area of active research. It differs a lot by drug, though, because of their affect on different signaling systems, different neurons, and due to indirect damage to the brain from effects elsewhere in the body:

1. E.g., cocaine as a strong vasoconstrictor can directly cause cerebral ischemia, causing hypoxic damage to the brain. Acute hypoxic damage is relatively uncommon, but atrophy due to chronic hypoxia is more common. Because the bulk of atrophy in chronic coke users is in some of the most hypoxia-sensitive areas of the brain, it might be the primary mechanism of damage.

2. Opioids can do the same via respiratory depression, even though blood flow to the brain is not impaired. Chronic opioid abusers tend to dose themselves into respiratory depression - and post-mortems show their brains to have ischemic neural damage.

3. Seizures are intrinsically neurotoxic. Damage from other sources (such as above) predisposes to seizure, which can have effects on the remainder of the brain.

4. We generally suspect there is more cell death than downregulation of neuronal receptors. When we look at the basal ganglia of chronic drug users (the dopaminergic neurons involved in the 'reward' circuit), we find atrophy, suggesting actual neuronal loss.

4b. What type of regulatory (e.g., down regulation) change occurs depends on the drug. Some drugs imitate an existing signal (e.g., opioids), so downregulation would be the homeostatic response. Coke and ecstasy stimulate dopamine release and serotonin release respectively, so we can expect a downregulation in receptors, but we may also see an upregulation in the transmitting cell in response to increased "release this signal" demands. Even that depends on the drug in question - amphetamine prompts dopamine release, so the releasing cell runs low and may increase storage levels. Coke prevents reuptake of dopamine, so active concentrations are up but the releasing cell doesn't see a change in its internal dopamine storage levels. Alcohol, on the other hand, is a glutamate blocker, which increases sensitivity to glutamate signals.

5. Opioids have been shown to be directly neurotoxic. It's unclear on whether this is a significant contributor above and beyond the respiratory depression in real life settings. In the lab, though, heroin, heroin metabolites (6-mono-acetyl morphine and morphine), fentanyl, have all been shown to be directly neurotoxic, though not all equivalently so.

6. MDMA is also shown to be directly neurotoxic, and (at least in a rat model) MDMA metabolites are more neurotoxic than MDMA itself.

7. Adulterants, through their toxic effects, also directly fuck up tissues. We see increased activation of cell-suicide pathways when heroin is induced, but we also see that the degree of activation is inversely proportional to the purity of the heroin.

I can probably go on for a while. I'm sorry if the above is a bit rambly, I didn't really stop and outline it as an essay. I hope that sheds some light, though.

[owenversteeg]

Wow, that's a really great summary, thank you! If you wouldn't mind, I am very curious about two things:

First, what's your opinion on alpha lipolic acid and MDMA neurotoxicity? Given its popularity and its rising use it'd be great to have a simple way to prevent MDMA-induced neurotoxicity, and ALA is pretty widely available and relatively cheap, but there doesn't seem to have been much research on its use in humans.

And second, how bad are the neurotoxic effects of these drugs? The internet has anecdotes in all directions, from people claiming serious issues from only a few low doses of (cocaine/opiates/MDMA/etc) to people claiming no issues whatsoever from significantly more extensive use at higher doses. I realize that every person is very different, and this is a sort of "how long is a piece of string" question, but what is your personal feeling? More and more college students are experimenting with MDMA and cocaine especially - do you think a few low doses cause serious permanent damage, or do you think the neurotoxicity wouldn't be serious enough for concern, or somewhere in the middle?

[1MachineElf]

>Alcohol, on the other hand, is a glutamate blocker, which increases sensitivity to glutamate signals.

Is there more information or sources you can share on that? I'm interested because 1) I'm close to someone who suffers from both alcoholism and an eating disorder, and 2) I worry about excess amounts of glutamate on the brain.

[curious_fella1]

Thank you for the comprehensive response! That was very interesting :)

I took a Biopsychology of Drugs class in college and found it fascinating. Do you know of any good (text)books on the subject?