Keep in mind, its still toxic for them to take too (but far less so than us)
I'm not aware of any data supporting your hypothesis that L-dopa is more toxic to the young.
Indeed, there's very little research to suggest that it's toxic at all. PMID 18781678, 9633686, 10554050, and 15675725 state that L-DOPA causes oxidative damage in vitro, but hasn't been shown to do the same in animal studies or clinical practice. There is some suggestion that it may serve a protective function to remaining neurons in PD. However, lack of comprehensiveness in these examinations is mentioned several times. 15372588 cites motor problems as an adverse effect of current concern.
Motor problems are obviously a major concern in Parkinson's disease, which is classified primarily as a movement disorder. That classification does, however, neglect the other symptoms of the disease, even though these symptoms can be more significant in reducing quality of life. L-dopa is used because it is the most effective substance known for treating the motor problems arising from the disease. It can, however, produce motor adverse effects such as dyskinesia, which is the opposite of the bradykinesia that the drug is used to treat. As the disease progresses, the capacity for storing dopamine is lost, and hence, the level of motor function becomes more directly and more closely related to the levels of L-dopa in the brain, and these levels are a function of circulating levels of the substance. This gives rise to motor fluctuations, often described as "on" and "off" periods. While dyskinesia is dose related and can be produced in people with an intact dopaminergic system, the motor fluctuations are unique to the Parkinsonian syndrome. It is more probable that non-motor adverse effects such as nausea will be of much greater concern when L-dopa is used for other purposes than the treatment of Parkinsonism. Such symptoms were the main reason why I only ever tried small doses of L-dopa+benserazide - doses too small to produce any noticeable benefits. Even for motor function, stimulants are likely to be of greater benefit than L-dopa in people with an intact dopaminergic system, and that is consistent with my personal experience.
I don't think there are greater dangers when L-dopa is combined with selegiline. I suggest reading the analysis at: http://ceri.com/depren.htm. The "window of death" indicates an unidentified temporary factor as the cause of increased mortality. This factor may have been a temporary glitch in the production of selegiline, resulting in a contaminated batch of the drug.I guess the point I was trying to make was that there are other agents available which do not have this possibility attached, especially the dangers when combined with deprenyl, and the inadvisability of recommending this without serious caveats. The thread I linked to provides a good analysis of the concerns about the mortality study, and posits that L-DOPA was in fact the agent to blame (perhaps in excess dosage, as you said).
The main argument against the use of L-dopa in non-Parkinsonian people is that there are other options that are more likely to produce the desired effects without significant adverse effects.
I've begun some more serious reading into dopamine neurochemistry in the past few days, and your post above and the one in the Piracetam Non-Responders thread are two of the most useful I've come across anywhere. I'm attempting to find more options for treading ADD, which manifests primarily in severe motivational difficulty and pronounced inability to perform tasks which are not very complex and/or novel (I made a very detailed post
Below, some comments on http://www.mindandmu...mp;#entry594315
You're very fortunate in that you don't seem to suffer from apathy, anergia, anhedonia, tolerance, and some other problems. This clearly distinguishes your condition from mine.
You seem to indicate that Adderall is identical to generic dextroamphetamine (DEX), which is not the case. Although salts of DEX predominate in Adderall, the drug also contain salts of the laevo/levo-isomer of amphetamine, giving Adderall a unique profile. For comparison, Dexedrine contains only DEX sulphate, while the metabolites of selegiline are all the laevo-isomers.
It's interesting that you feel a deterioration in short-term memory. I assume you do mean short-term memory and not working memory. Enhanced capacity for attention would be more logically expected to also enhance the capacity to remember. I personally experience what seems to be an improvement in most, if not all, types of memory. Possibly, the dose is too high, or the noradrenaline:dopamine ratio is suboptimal. The same comments about dose may apply to your apparent loss of creativity.
The crash seems inevitable. It is less intense, but more prolonged, with longer-lasting stimulants. With the long-lasting desoxypipradrol,. which I'm currently using the decline is generally smooth enough not to be clearly noticed - it still occurs, however. Long half-lives can also be troublesome in that there's an increased risk of prolonged insomnia, and while that can be avoided by staying awake until exhaustion, this is not ideal. The risk of accumulating sleep deficits is also increased with long-lasting stimulants. I know, because not long ago, I let such sleep deficits accumulate until first, after a few months, paranoia arose, and worsened for a few more months until psychosis resulted, and while that was an interesting experience, it wasn't worth the two months in the psychiatric hospital, especially since they didn't understand the difference between schizophrenia and a temporary drug-induced psychosis. They eventually sent me home with a prescription for high-dose antipsychotics.
You probably know this already, but if available, I recommend trying out the alternative stimulants, including pure dextroamphetamine (e.g. Dexedrine), d-methamphetamine (Desoxyn), methylphenidate (e.g. Ritalin), d-methylphenidate (Focalin), and modafinil (e.g. Provigil). Furthermore, you can experiment with combinations of dopamine reuptake inhbitors and amphetamines. Combinations of agents with identical mechanisms of action would not seem worthwhile.
Predominantly adrenergic and cholinergic agents are likely to be insufficient on their own, but may warrant investigation nevertheless, in combinations with stimulants. By adrenergic, I'm referring primarily to the alpha2-agonists, which affect noradrenergic presynaptic autoreceptors as well as postsynaptic alpha2-adrenoceptors. However, there are possible roles for beta-receptor agents too, but I don't have a good understanding of this, and the research on the influence of beta-agonists is scarce. As far as agonism at the alpha1- or beta1-receptors is concerned, one must also consider possible cardiovascular effects, such as hypertension, impaired circulation, and long-term effects on the heart. Agonism at alpha2-, beta2- and beta3-receptors seems a lot safer in this regard although this too has cardiovascular and other effects. Also remember that the dose-effect curves can be U-shaped.
By the way, the other poster at M&M says noradrenaline has a prominent role in motivation and reward. There may be a role for NA in these functions, but neither the literature I'm familiar with nor my personal experience indicates that this role is "prominent". Indeed, my personal experience suggests it's negligible, but needless to say, such experience may not be applicable in the general case.
Highlighting the risk of overgeneralising based on personal experience, I did not notice any positive effects from nicotine, which is in contrast to your experience.
or two describing my specific symptoms in the Pramipexole thread at M&M). My reactions to most psychoactives seem significantly similar to yours; adderall is the only agent so far which affords motivation, but does so amazingly well.
Regarding agomelatine, it doesn't seem to be very helpful in my experience, although this doesn't mean it's not worth trying. It has melatonin agonism in addition to serotonin 5-HT2C antagonism, and it's recommended for bedtime. Its half-life is also short, less than or equal to 2 hours, according to Wikipedia. I've had no success with another drug affecting 5-HT2C either, more specifically sertindole, which is a 5-HT2C inverse agonist, among other things.
The tramadol you're taking also affects serotonin and noradrenaline reuptake, and this probably contributes to your experience. If possible, you may wish to try other weak opioids for comparison.
Buprenorphine deserves separate mention, because it's only a very ineffective agonist at the mu-opioid receptor and uniquely among clinically available agents, an antagonist at the kappa-opioid receptor. Both of the actions enhance dopaminergic function, and combined with methylphenidate, the drug provided the best relief of ADHD symptoms that I've achieved so far. While the drug is approved for pain management in addition to opioid substitution therapy, it can be so useless for pain that it's better to take paracetamol (acetaminophen), and that was my experience. (Not that I have chronic problems with pain.)
By the way, I agree with the other poster that you may be trying to eat the cake and have it too. It's not necessarily possible to achieve all desired effects at any single moment.
Amphetamines are the most potent. Low doses of selected antipsychotics can be remarkably effective too (sulpiride and amisulpride primarily). The dopamine reuptake inhibitors help too. Finally, opioids can help, but they can cause the opposite effect by inducing somnolence. All of these agents are associated with potential problems, which I will not go into in detail in the interest of brevity.I'm looking for other medications (or combinations) which might affect motivation, but not alter the more delicate aspects of headspace/thought processes the way amphetamine can (and without stimulating and neurotoxic effects, hopefully). I have so much reading to do (what's new?), but I wonder if I could prevail upon you to throw out a few more ideas to help me focus in a bit:
What targets and medications are most selective and efficacious for increasing motivation? (D1/D2?) To what extent have you found motivation ("effort-based decision making") decoupled from other indicators of ADD?
The different ADD symptoms seem to respond differrentially to treatment. In my experience, motivation is easier to improve than the working memory function and organisational skill.
I think the issue of combinations has been addressed already. I don't see any particular concerns when combining alpha2-agonists with non-stimulants, other than in combination with agents that lower blood pressure, where the possible additive effects from the combination should be taken into account.Can you suggest any more-specific combinations of agents appropriate for ADD? What are your thoughts about combining A2A agents with the non-psychostim dopaminergics?
For some people even a dopamine reuptake inhibitor is too much dopamine, so the question of how many agents one can combine before trouble arises cannot really be answered. Too much dopamine can result in various effects such as impaired working memory, paranoia, hallucinations, psychosis, nausea, obsessive and compulsive behaviour, hypomanic-like behaviour, excessive euphoria and addictive behaviour, dyskinesia. People are more and less vulnerable to such effects, and the list is not exhaustive.What are the guidelines to consider in general when combining these medications—what does "too much dopamine" look like? How many of these agents can one use before problems arise? What should be the aim in selecting combinations which are useful?
The issue of tolerance can be extremely difficult to deal with in some cases, and in others, little tolerance seems to occur. Memantine seems to work particularly well with amphetamines. With dopamine reuptake inhibitors, memantine seems to work less well, and the only methods that I've had success with are breaks in the treatment (drug holidays) and the combination with buprenorphine.Regarding downregulation and tolerance: how should this be approached when designing combos/cycles for therapeutic action? How do consant-use meds like pramipexole and deprenyl interplay with shorter-acting/more tolerance-producing ones? Is the type of therapeutic use we're discussing sustainable, or is some kind of cycle more realistic with regard to receptor regulation?
I seem to recall an effect the first time I took it, but not at other times.Also, since my reactions are so similar to your, I'm curious what you think of sulbutiamine?
Edited by chrono, 05 August 2010 - 03:04 PM.
fixed tags broken after software upgrade
