Catecholamines have a tendency to form dopaquinones, which are oxidising agents that oxidise sensitive targets that they come into contact with. This is perfectly normal, and inevitable. It's when neurotransmitter concentrations become high enough to overwhelm antioxidant capacity that damage results.
Dopamine (DA) reuptake inhibitors (DRIs) like cocaine and methylphenidate (Ritalin) do not elevate extracellular DA levels sufficiently to give rise to oxidative stress severe enough to cause structural damage, even in high doses. With amphetamines, on the other hand, it's easy to achieve neurotoxicity, and direct evidence of such toxicity can be readily observed in experiments on various species of animals. Studies with radiotracers in long-term recreational users of methamphetamine indicate that similar toxicity occurs in humans, and remains significant for at least several years after cessation of the drug. Furthermore, a syndrome indicating dopaminergic deficits can persist in such users for a long time after withdrawal. The relevance of these findings to the therapeutic use of amphetamines, however, remains to be determined, as the doses are usually lower and there may be unnaturally low extracellular dopamine concentrations of begin with. Considering the similarity in the pharmacological actions of phenylethylamine (PEA) and the amphetamines (alpha-methyl PEAs), it seems logical to hypothesise that long-term use of PEA in high doses would give rise to similar neurotoxicity. My own personal experience is consistent with this hypothesis - for more detail, see my article at
http://www.imminst.o...mp;#entry397521.
High doses of L-dopa are likely to produce significant oxidative stress, and in animal models, the co-administration of L-dopa exacerbates toxicity from amphetamines. The use of L-dopa at more modest doses seems unlikely to be a cause for serious concern, but L-dopa is a very imprecise tool to elevate synaptic DA concentrations, which is the desired goal. In Parkinson's disease, where there is a serious loss of DAergic nerve cells, L-dopa is often necessary, but in the absence of such loss, tyrosine, stimulants and monoamine oxidase inhibitors (MAOIs) are likely to produce the desired results with fewer side effects. L-dopa has side effects that are not seen with stimulants, and yet does not produce as significant elevations of synaptic DA, except at excessive doses. It is for these reasons that L-dopa is rarely abused, although reports of such phenomena exist. Even doses of L-dopa that produce irritating side effects, including nausea and vomiting, are not necessarily sufficient to achieve the desired effect on the CNS. In the treatment of Parkinson's disease, L-dopa is almost always given with a peripheral inhibitor of aromatic amino acid decarboxylase (AADC) in order to allow sufficient CNS concentrations of the drug to be achieved with acceptable side effects. Even with an AADC inhibitor such as carbidopa or benserazide, the peripheral side effects can be troublesome enough to justify the addition of the peripheral DA antagonist domperidone, or an inhibitor of catechol-O-methyltransferase (COMT), usually entacapone, although the alternative COMT-inhibitor tolcapone is sometimes used due to its ability to cross the blood-brain barrier, despite potential hepatoxicity,
Combinations of two or more classes of dopaminergic agents can be used for enhanced effect or for similar effects but a superior side-effect profile. Depending on the desired goals, non-dopaminergic treatments can be added as well, and in the case of ADHD, especially the alpha2-adrenergic agonist guanfacine deserves mention. In the case of depression, there are so many options that an essay would be required for any useful discussion, and books have been written on the topic. I recommend starting with the Good Drug Guide, found on-line at
http://www.biopsychiatry.com/To summarise, an incomplete list of options includes:
1. phenylalanine
2. tyrosine
3. L-dopa
4. selegiline or rasagiline
5. methylphenidate
6. amphetamines
A reasonable treatment algorithm may be:
a) 1, 2 or 4
b) any combinations of 1, 2 and 4
c) 5
d) 5 and a)
e) 5 and b)
f) 6
g) combinations of 6 with 5, 4, and/or 2
h) revisit d), e) and g), replacing 2 with 3.
Personally, I would be liberal in my titration of 5, but restrictive with 6. There are also several options that haven't been covered, including the following and their combinations with each other and with the above:
7. pramipexole or ropinirole
8. entacapone
9. sulpiride (from 100 mg up to 600 mg/day divided into two or three doses), or amisulpride (25 mg to about 300 mg/day as a single dose). Higher doses will be counterproductive due to blockade of postsynaptic DA receptors.
10. flupenthixol (up to 2 mg/day)
11. buprenorphine up to at least 4 mg - for maximum blockade of the kappa-opioid receptor.
12. memantine (up to 40 mg)
13. amantadine (up to 300 mg)
And so on - it's already too complex to describe the above options and their sensible combinations fully. Certain combinations are particularly useless, while certain others are especially sensible. For example, 2 is superfluous with 3, and 9 is great with 5, but not so much with 6. Furthermore, there are a number of fine points, for instance: too high doses of 5 will be counterproductive with 6, due to their mechanisms of action.
Regarding the addition of selegiline to sertraline, beware of possible hyperserotonergic symptoms such as fever, especially at higher doses. Long term selegiline at 10 mg produces significant MAO-A inhibition.
