4 replies to this topic

[johnmk]

Hello folks,

I read an interesting (profound, for me -- actually) document recently discussing why methylphenidate doesn't lead to substantially increased dopamine levels in the cerebral cortex -- notably, the lack of dopamine transporters in this region compared to other brain regions, so methylphenidate's primary mechanism of action of re-uptake inhibition of dopamine (and norepinephrine too I believe) isn't nearly as strong as amphetamine's direct release of these neurotransmitters (and its own apparent mild re-uptake inhibition as well), in this particular region of the brain. So dopamine ends up being elevated elsewhere, but not as much in the cerebral cortex, with methylphenidate. I'm not sure of the significance of this, but I would imagine that boosting dopamine in the cerebral cortex is a good thing assuming one forgets about long-term toxicity.

I do feel a difference in effect of methylphenidate vs. amphetamine. Methylphenidate can slow me down and let me fill out paper work line by line, using complete sentences and thoughts. But it doesn't necessarily motivate me or tackle my low-grade depression. Amphetamine slows me down but has slight mood elevating effects and tends to motivate me more, all the while never making me feel "speedy". There is some exacerbation of my natural anxious tendencies with both medications. This doesn't worry me as much as it might otherwise because I have made changes to my environment to reduce anxiety as much as possible, and the more can-do attitude I have towards certain life functions itself puts my mind at ease since I know I'm more on top of things and this knowledge tends to cancel out the anxiety-increasing effects of stimulant medication.

Back to the question at hand. I'm thinking about adding selegiline to my daily regimen. I am clueless as to what kind of dosage I should consider. The upper limit I would try chronically would probably be 10mg/day. The literature points to this effectively halting MAO-B. But a person of my age (20's) usually has less MAO-B, according to the research I've seen, which may account for the lower figures I see recommened. Life extensionists I see around here commonly recommend dosages around 1mg/day for people in my age bracket. But I yearn for more than life extension. I need life quality, now, at the point in time where investment in myself is most lucrative, i.e. potentially going back to school. I need motivation, drive, focus, and other qualities that dopamine can give me, but I'm not too keen on continuing stimulant medication especially that of amphetamine, seeing as that I have developed some tolerance (not too much though), and of course with full knowledge that amphetamines are neuro-toxic quite possibly at therapeutic doses.

I guess this is my true question. Is it likely that selegiline, via MAO-B inhibition, can boost my cerebral cortex dopamine (and norepinephrine) function as much as amphetamine can? And at such a level of therapeutic effect, is tolerance something I need to worry about? How would said tolerance develop, and would it completely negate the therapeutic effect I am seeking? Two mechanisms I can guess might come into play here. The construction of dopamine itself might be reduced, and the receptors may become less sensitive. Which of these two seem to occur, do they both occur, and is the cumulative down-regulation of the dopamine system enough to completely wipe out, over time, the therapeutic effect? Over how long a period of time do you suspect such down-regulation would take place?

I truly appreciate you reading this lengthy post. Your time is precious, and I sincerely appreciate your help if you decide to give it.

Sincerely,

-JohnMK

PS: I'm also curious about dosing-type. Liquid vs. tablet. Is there a substantial difference between them? I would personally probably do better with a tablet than a liquid dropper. Are the 5mg tablets scored so I can take 2.5mg daily, if I chose to dose at that level? Is bioavailability of tablet-form selegiline slightly or very much less than a drop of liquid selegiline? I think most studies used tablet selegiline, but I might be wrong. If that's the case then the suggested doses would need to be re-calculated to take into effect the added bioavailability of liquid over tablet, if any such exists.

PPS: Does anyone here have any theories as to what causes ADHD?

PPPS: Does anyone here agree that selegiline seems to be the ideal treatment for it in theory?

[pSimonKey]

I have been researching this very topic.


Selegiline in adults with attention deficit hyperactivity disorder: clinical efficacy and safety.

Ernst M, Liebenauer LL, Jons PH, Tebeka D, Cohen RM, Zametkin AJ.

Brain Imaging Section, Intramural Research Program, National Institute on Drug Abuse (NIDA), Baltimore, MD 21224, USA.

Clinical effects of high-dose and low-dose selegiline treatment were examined in 24 adults with attention deficit hyperactivity disorder (ADHD). The study used a double-blind randomized three-arm parallel-groups design with a 2-week placebo baseline followed by 6 weeks of treatment (placebo, 20 mg/day, or 60 mg/day selegiline) and then by 2 weeks of placebo post-treatment. A two-way repeated measures analysis of variance (ANOVA) showed no Drug x Time interaction and no main effect of Drug on severity of ADHD symptoms as self-rated by the subjects on the Conners Abbreviated Teacher Rating Scale (Conners ATRS). There was a significant effect of Time, indicating decreased ADHD symptom severity scores in all three groups. Selegiline treatment was not more effective than placebo. Side effects were more severe in the high-dose selegiline group than in either of the other groups. These preliminary results must be interpreted with caution because of methodological limitations in terms of sample size, patient population selection, and measurement tools.

Pharmacotherapy of attention-deficit/hyperactivity disorder in adults.

Wender PH.

Department of Psychiatry, University of Utah School of Medicine, Salt Lake City 84132, USA.

A history of childhood attention-deficit/hyperactivity disorder (ADHD) is a mandatory prerequisite for the diagnosis of adult type ADHD, for which no DSM criteria exists. Since the diagnosis must be made retroactively, tentative criteria have been designed to establish the presence of the childhood disorder. In the 1970s, I advanced the hypothesis that "minimal brain dysfunction" (as ADHD was called) might be produced by decreased catecholaminergic function. A total of over 300 ADHD patients have been included in treatment studies, including 224 patients who received stimulants in four double-blind, placebo-controlled trials: three of methylphenidate (N = 176) and one of pemoline (N = 48). An additional 79 patients have been included in open-label trials of pargyline, selegiline, bupropion, levodopa, phenylalanine, and tyrosine. Altogether, these studies have demonstrated the efficacy of methylphenidate, pemoline, and monoamine oxidase-B (MAO-B) inhibitors when administered to adult ADHD patients; a robust response was produced in 60% of the patients. Bupropion and selegiline were effective in the open-label studies and should be systematically evaluated. A long-term study is being conducted with methylphenidate maintenance; patients have been followed for as long as 5 years, and little, if any, drug tolerance has been observed. Treatment of adult patients who have ADHD is symptomatic, not curative, but the combination of medication and psychotherapy may offer life-changing opportunities to individuals who suffer from the disorder.


Selegiline in comparison with methylphenidate in attention deficit hyperactivity disorder children and adolescents in a double-blind, randomized clinical trial.

Mohammadi MR, Ghanizadeh A, Alaghband-Rad J, Tehranidoost M, Mesgarpour B, Soori H.

Department of Psychiatry, Tehran University of Medical Sciences, Psychiatry and Clinical Psychology Research Center, Roozbeh Hospital, Tehran, Iran.

OBJECTIVES: The aim of this study was to examine the selegiline treatment compared to methylphenidate (MPH) in children and adolescents with attention deficit hyperactivity disorder (ADHD). METHOD: Forty subjects, aged 6-15 years, boys and girls, who were diagnosed as having ADHD, using the criteria of the Diagnostic and Statistical Manual of Mental Disorders- Fourth Edition (DSM-IV), were randomly assigned to receive either selegiline or MPH for 60 days. Treatment outcomes were assessed using the Attention Deficit Hyperactivity Scale (ADHS) administered at baseline and on days 14, 28, 42, and 60 following the commencement of treatment. Side effects were also rated. RESULTS: There were no significant differences between sex, age, weight, and ethnicity of participants in the 2 groups. Both groups showed a significant improvement over the 60 days of treatment resulting from the teachers' and parents' ADHS scores across the treatment. CONCLUSION: Following the trial, MPH did not effect greater mean improvement as a result of the parents' or teachers' ADHS scores than selegiline. Thus, selegiline appears to be effective and well tolerated for ADHD in children and adolescents.


Chronic L-deprenyl treatment alters brain monoamine levels and reduces impulsiveness in an animal model of Attention-Deficit/Hyperactivity Disorder.

Boix F, Qiao SW, Kolpus T, Sagvolden T.

Department of Neurophysiology, University of Oslo, Norway. fernando.boix@basalmed.uio.no

Effects of chronic L-deprenyl administration on hyperactive behaviour and brain monoamine levels were studied in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats. SHR were hyperactive, impulsive and had impaired sustained attention when tested with a multiple 2-min fixed interval (FI) 5-min extinction (EXT) schedule of reinforcement. Even low, 0.25 mg/kg, doses of chronically-administered L-deprenyl reduced the impulsiveness (bursts of responses with short interresponse times) of SHR, without altering the general hyperactivity or the impaired sustained attention. The drug had no effect on WKY behaviour. The levels of noradrenaline (NA), dopamine (DA), serotonin (5-hydroxytryptamine, 5-HT) and their metabolites, measured in neostriatum, nucleus accumbens and frontal cortex, showed that L-deprenyl effectively inhibited monoamine oxidase (MAO) activity. These results suggest that impulsiveness is a behavioural component that may be operating independent of the other components, like hyperactivity and deficient sustained attention, and that can be reduced by chronic MAO-B inhibition with L-deprenyl in this strain of rats. The positive effect of L-deprenyl on impulsiveness is discussed as due either to normalization of an asymmetric dopaminergic activity in the nucleus accumbens, or to a restoration of normal DA function in the prefrontal cortex.





Does phenylethylamine act as an endogenous amphetamine in some patients?

Janssen PA, Leysen JE, Megens AA, Awouters FH.

Centre for Molecular Design, Janssen Research Foundation, B-2340 Beerse, Belgium.

In brain capillary endothelium and catecholaminergic terminals a single decarboxylation step effected by aromatic amino-acid decarboxylase converts phenylalanine to phenylethylamine, at a rate comparable to that of the central synthesis of dopamine. Phenylethylamine, however, is not stored in intra-neuronal vesicles and is rapidly degraded by monoamine oxidase-B. Despite its short half-life, phenylethylamine attracts attention as an endogenous amphetamine since it can potentiate catecholaminergic neurotransmission and induce striatal hyperreactivity. Subnormal phenylethylamine levels have been linked to disorders such as attention deficit and depression; the use of selegiline (Deprenyl) in Parkinson's disease may conceivably favour recovery from deficient dopaminergic neurotransmission by a monoamine oxidase-B inhibitory action that increases central phenylethylamine. Excess phenylethylamine has been invoked particularly in paranoid schizophrenia, in which it is thought to act as an endogenous amphetamine and, therefore, would be antagonized by neuroleptics. The importance of phenylethylamine in mental disorders is far from fully elucidated but the evolution of phenylethylamine concentrations in relation to symptoms remains a worthwhile investigation for individual psychotic patients.


I am thinking that the treatment of ADHD seems to be rather a polarity response type of chemistry ie speed things up to slow them down. Somewhere in there seems to be an answer says my intuition. What are your thourghts on that.

I am thinking that my brain works fine just very fast so/and is there a way for me to harness or task my brain appropriately (other than finding out about itself). What task would that be?

I'm still trying to get to the bottom line/s with an ever evolving theory/s that I have, but hey, thats ADHD for y' ;- )

[johnmk]

What I'd like to do ideally is switch to methylphenidate as a stimulant and use selegiline to help boost my cerebral cortex dopamine more than methylphenidate would do so alone. I'm not sure if the combination will actually do that, but it's my hope. I'm not even sure if that's a desirable subjective outcome. Is cerebral cortex dopamine level causal of your motivation? Or does that come from striatum, etc.

[lynx]

John, where did you read that Methylphenidate doesn't effect cortical dopamine? I thought that I had read just the opposite. I'd like to see the reference. Thanks.

[johnmk]

http://www.addforums...ead.php?t=14712

Methylphenidate is primarily a dopamine re-uptake inhibitor, as you well know. It functions by halting the activity of the dopamine re-uptake transporters (of course I know it does some other fancy stuff to like possibly reducing norepinephrine re-uptake, which in its own right that activity does tend to increase dopamine since norepinephrine re-uptake transporters in the cerebral cortex preferentially re-uptake dopamine). Apparently, there aren't that many dopamine re-uptake transporters in the cerebral cortex however. So you tend to boost dopamine in that region less than amphetamine, in theory.