Swim's cat heard a story about a young guy who died of a heart attack, had treatment-resistant depression and narcolepsy. Among other CNS meds, two that the cat knows of include phenelzine, an irreversible monoamine oxidaise inhibitor, and desoxyn, a pharmecutical preperation of methamphetamine. After doing some research, Swim found this was a more complex interaction that he could find, and was wondering if anyone had any input:
Can anyone help Swim elucidate the nature of the interaction between meth and an MAO-I? What exactly is happening in the brain when both of these are concomintantly administered?
Other meds include hefty doses of lorazepam, and some other unknown anti-depressant, and possibly other meds, but Swim is just interested in the meth/MAO-I combo.
Methamphetamine is itself a monoamine, meaning that an MAOI may actually increase levels of methamphetamine in the body and prolong duration, thereby increasing the chances of toxicity from the drug. Methamphetamine increases the intercellular concentrations of monoamine neurotransmitters. I am in no way an expert, but I can't imagine this combination being safe (at least not in higher doses). I certainly wouldn't try to play around with these.
Obviously the main risk here would be a hypertensive crisis. Which of course would explain the heart attack.
To answer your question more directly, the nervous system would be flooded with chemicals which increased the rate of neuron firing. Increased neurochemical and electrical activity could have all kinds of downstream effects. I'm not as familiar with peripheral effects of drugs, my area of study is the brain itself. Monoamine oxidase is extremely important throughout the body, so someone with more knowledge could probably explain a bit better than I.
Hm, I'm not an expert on methamphetamine (well, I'm not an expert on anything, but particularly not on methamphetamine), but I'll just say what I know.
I would first of all like to comment on that death, which is tragic of course. PC, have you know him personally? In order to assess that death, one would have to know the other drugs involved, particularly the other antidepressant, as well as their doses and whether these drugs were actually prescribed and part of a regimen or whether they were spontaneously combined. I must say though that such a heavy combination of drugs could in fact not even be an accidental death, so I would not categorically rule out the possibility of suicide in a patient suffering from treatment-resistant depression. Unless the prescribing doctor was careless, he will have informed the patient about interactions with other drugs, both antidepressants and recreational drugs. I'm not trying to start a rumour here, but that combination is very potent and it really is asking for trouble.
As for your question:
The combination of an MAOI (in this case Nardil, or phenelzine) with methamphetamine is already downright dangerous, without adding anything to it. Meth induces a serotonin release, while the MAOI significantly slows down the pace of monoamine degradation, thus also of serotonine. This can cause a receptor overstimulation, also known as serotonin syndrome. Serotonin syndrome can cause both tachycardia and hypertension, so that a heart attack might also be due to that, rather than to a hypertensive crisis (which, as Jasim pointed out, comes first to mind when thinking about MAOIs). Adding another antidepressant into the mix, possibly a tricyclic (tricyclics are sometimes combined with MAOIs, much rather than SSRIs or SNRIs), will furthermore slow down serotonin reuptake.
For these reasons, direct sympathomimetics (like amphetamine or methamphetamine) are generally contraindicated with MAOIs. In select, treatment-resistant patients, drugs like Adderall (dextroamphetamine) can be given in combination with an MAOI, but this happens exclusively in a hospitalized setting under medical supervision. Really, MAOIs are not to be messed with! As haanb said in another thread, one should only try mixing substances contraindicated with MAOIs if one is keen on getting attention from the toxicologic/forensic medical community!
Just to add a little more. Methamphetamine is primarily an NDRI (Norepinephrine, Dopamine Re-uptake Inhibitor), with lesser SRI (Serotonin Re-Uptake Inhibitor) effects. It also stimulates the neuronal release of these monoamines as well which increases their levels within the synaptic cleft. The result is massive amounts of all these three - dopamine, norepinephrine, and serotonin, though less than the other two, being released where they remain due to the re-uptake inhibition.
By itself methamphetamine is enough, when taken in large doses, to produce hypertensive crisis (high blood pressure), tachychardia (sustained heart rate typically above 110 bpm), and myocardial infarction (heart attack). It should be prescribed and taken with care, and treated with respect. Long-term use and abuse can even cause psychosis.
There are two forms of MAO (Mono Amine Oxidase), MAO-A and MAO-B. MAO-A is primarily responsible for the oxidation norepinephrine, epinephrine, serotonin and dopamine. MAO-B is primarily responsible for the breakdown of dopamine. These remove the excess levels of catecholamines from the system, and the production of MAO may be inhibited using an MAOI.
Now, here's where the problem comes in, and it's usually due to SSRI's and MAOI's being co-administered, not enough time between administration (typically a few weeks, but some MAOI's can take months) for reversal of the MAOI is theorized to cause serotonin syndrome. Some foods high in tyramines like red wine, aged cheese, and many more, when taken with MAOI's can cause hypertensive crisis as well since tyramine is the precursor for norepinephrine, epinephrine, and dopamine and this will increase the amount of these catecholamines since they are not broken down by MAO.
Add to that amphetamine, which is also a primary active metabolite of methamphetamine, binds to MAO effectively inhibiting MAO.
See where this all leads? As SWIC.D.rose mentioned, MAOI's are not to be messed with. Methamphetamine when combined with an MAOI is just a plain deadly combination. The amphetamine metabolite is active as well in the same manner as the methamphetamine and binds to MAO, which further prevents the catecholamines along with serotonin from being broken down. Who really knows what happened, but whatever it was the result is the same, in this case death - perhaps due to a combination of factors brought on by this lethal combination.
The hamster hopes he's clarified the action of MAOI's and methamphetamine in the neurological system.
Yeah, I have to admit I checked wikipedia's article on methamphetamine (section 'Pharmacology') before I wrote my post, because it's really a drug I have looked into very little, but the wiki article says that NE:DA:5HT release occurs at a rate of 1:2:30, i.e. the amounts of serotonin it releases are far higher than the amounts of norepinephrine and dopamine. Dunno whether that's a mistake, or whether the amounts of NE/DA released, although numerically inferior, are responsible for its main effects...?
Either way, the bottom line is it does indude serotonin release, thus contributing considerably to the risk of serotonin syndrome, particularly when combined with an MAOI.
Swim did not know the person personally, so this is a 2nd hand account. The combo is dangerous that, as swim understands it, the lad had to sign a waiver before being put on them. He was engaged as the time, leading one to assume that the anti-depressants were working, hence not a suicide.
This did clear up quite a bit, but with one problem, ere, point of clarification. Nardil is an irreversible inhibitor, so one imagines that after prolonged administration, even a detox wouldn't be very effective, but perhaps I dont understand Wiki's answer for irreversible inhibitor. Ideas?
The difference between reversible and irreversible MAOI's is that irreversible MAOI's will permanently bind to the MAO enzyme and then that molecule can no longer break down monoamines which causes them to become elevated. Reversible MAOI's are ones which are short -term and bind tightly to the enzyme, but are eventually broken down by the MAO.
The body produces MAO at a much slower rate than it produces monoamines (serotonin, dopamine, norepinephrine and epinephrine). This is because the enzyme is kind of like a tiny machine which does its job and moves on to the next molecule to break down and continues to function until it becomes irreversibly bound to some other substance, it is broken down by something else, or it is excreted by the body.
Another example of how something functions in a similar manner would be the body's hemoglobin which is responsible for transferring oxygen to cells in the blood's platelets. Oxygen is not tightly bound to hemoglobin and is released from the red blood cell (platelet) so the cell can use it in creating the energy it needs to keep functioning.
Carbon monoxide, is very tightly bound to hemoglobin, and the hemoglobin must be replaced, or the red blood cells must be replaced since once their hemoglobin is bound to carbon monoxide, the hemoglobin can no longer transport oxygen. This irreversibility of carbon monoxide on hemoglobin is why carbon monoxide is especially lethal.
What's important though is that that irreversible MAOIs are not actually irreversible, in that their effects last forever after one has been on them. It means that their action at the particular MAO enzyme is irreversible. MAO enzymes are constantly being reproduced, hence the need to continuously take MAOIs, even the irreversible ones, because the body produces new MAO to replace the old, inactivated enzymes.
About two weeks after stopping long-term administration of an irreversible MAOI, MAO activity should be back to normal, because the body has the replaced the entirety of MAO enzymes with fresh, fully functioning ones. That's why it's important to keep in mind the MAOI diet even during the two weeks following (irreversible) MAOI treatment.
By the way, irreversible MAOI antidepressants currently available are: phenelzine (Nardil, Nardelzine); tranylcypromine (Parnate, Jatrosom); isocarboxazid (Marplan). There used to be more, but most others have been withdrawn from the market in most countries of the world.