N&PD Moderators: Skorpio
Co-Administration of Prescription Serotonin Ant/agonists - The Implications?
atrollappears
Bluelighter
On a side note, one interesting thing when looking at those graphs: compare amphetamine and methamphetamine. Amphetamine is actually a little more potent than methamphetamine when in the brain, especially on noradrenaline, but in vivo it's not as potent because it can't cross the blood brain barrier as well as meth can.
Vaya
Bluelight Crew
I see this, and what you say makes sense. For a lay person, however, it is difficult to interpret how the X and Y values on each graph can be practically converted to "human levels". For example, regarding chart 1D - Methamphetamine - where the value for hSERT is plotted at X=1.0 and Y= approx. -5.4, vs. the next hSERT value plotted at X= approx. 0.81, Y=-5, there is a reduction in the amount of hSERT, correct? Is it possible to use these chart values to generalize towards a milligram amount that would be applicable to actual human therapeutic use?
It seems, hypothetically, that this may rely on too many concomitant factors, as the human body cannot be accurately represented by these charts using cell-counts. I'm enjoying using the charts comparatively, though, many thanks for posting them.
~ vaya
Epsilon Alpha
Bluelighter
Don't take this the wrong way but do you have an autism spectrum disorder? They're primarily what risperidone is given out for as far as irritability goes in Canada at least.
Also, have you experimented around with atypicals? I've heard of ridiculous differences between them as far as ADHD and bipolar goes.
negrogesic
Bluelight Crew
^Not to nit-pick but, risperdal is an atypical. What I think you were driving at was a drug such as aripiprazole, etc.
atrollappears
Bluelighter
The graph is of transport activity, Y, (so how effective the drug is at blocking reuptake) by the log of drug concentration, X. So, each tick mark on the X axis is a 10 fold increase. Basically, the chart says that, for methamp, to reduce transporter activity to ~.8, for example, the concentration must be >30 fold for mSERT compared to mDAT. If we assume that this point is the threshold dose, then you would have to administer >30x the threshold dose to have a threshold effect on mSERT, and higher for hSERT. If a threshold dose for methamp is 2.5 mg, then that means you'd have to take >75 mg, well outside of the clinical range. The point is, regardless of what you consider the threshold dose, you would have to administer many times the threshold dose to have a significant serotonergic effect. Yes, I'm oversimplifying this a lot, and there are factors that could come into play and could turn my analysis on its head, but it still looks pretty unlikely that serotonin is relevant for a clinical dose of methamp.
And you're very welcome. I try to make good use of the access to scientific journals I'm allowed on my college's network :D
negrogesic
Bluelight Crew
[Note: i was interrupted while dictating the following]
And yes, such drugs have the ability (no pun intended) to treat the ADHD-like elements of BPD/compulsive disorders, or potentially used to treat comorbidities. As a whole, ADHD diagnostic criteria is flawed, particularly (in my opinion) with regard to the rather ambiguous ADHD-primary inattentive subclass.
I am not quite sure of the legitimacy of my ADHD-hyperkinetic Dx, aside from the fact that I have no symptoms that could be otherwise classified under BPD/OCD or autism spectrum. However, I have noticed a preference towards DNRI-treatment/abuse in individuals who also appear to fall within the rather narrow category of adult 'primarily hyperactive' ADHD. Even in efforts to abuse drugs such as illicit meth, I have found the class to have limited utility. And as with most psychoactive compounds, my efforts to abuse meth were made with the greatest diligence and utmost sincerity. Interestingly, while far more enjoyable than meth, I never felt sufficient compulsion to use cocaine with any regularity; instead it was opioid's that took the prize. . such risk-taking behavior is quite prominent in my apparent ADHD, and is not limited to drugs
Personally, I am able to function quite well without psychostimulants such as d-MPH (having discontinued its use for years), and while the following is entirely speculative on my part, I can't help but to wonder how many individuals taking psychostimulants (as indicated) can also function similarly without their use. It is quite plausible that long-term treatment with powerful psychostimulants may render a patient with a syndrome that artificially necessitates their continued use, or evokes a transient discontinuation syndrome which leads the patient to believe they cannot truly function in their absence. This may be particularly true with the amphetamine class, if dosed high for long periods, or if treatment has begun at an early age.
Vaya
Bluelight Crew
I don't believe I have an ASD; that's something I may bring up to my doctor next week when I address my feelings on risperidone. Yes, I've tried several other AAP's in the past; most recently, these include aripiprazole, ziprasidone and quetiapine. The former two were without much clinical effect IMO; Seroquel knocked me on my ass at doses as low as 12.5mg (not very clinically useful, either)!
atrollappears said:
Great explanation, I appreciate that! How I miss having access to my University's scholarly article database...
negrogesic said:
Very well put; this is a much better articulation than I could have produced of precisely why I've been concerned about having been prescribed amphetamine at so young/for so long. I'm making the assumption that just how "transient" this proposed discontinuation syndrome might be would have a strong correlation with how long (and, obviously, in what dosages) the drug had been taken for. Upon re-examination, I'm not sure two years (after the initial five years taking amps) was enough time to accurately judge my abilities with an amphetamine-less mind.
Spurring some serious thought, here.
ADD (the forum) is amazing 
~ vaya
SNR
Bluelighter
Risperidone most definitely. Methamphetamine doesn't have affinity for any of the 5-HT receptors. It simply releases and prevents reuptake of 5-HT, which causes excessive 5-HT signalling. Methamphetamine certainly has 5-HT activity at clinical doses.
But yes, risperidone will block METH serotonergic activity at the 5-HT2A receptor, and any other receptor in which it has higher binding affinity than the endogenous ligand. (Note, it will only block receptors with which it has stronger binding affinity than the endogenous ligand, 5-HT)
Vaya
Bluelight Crew
atrollappears
Bluelighter
Vaya
Bluelight Crew
(Not a be-all, end-all citation) Middle of Page 522, left column, although I can't discern whether they are referring to clinical or recreational doses. I would assume that, even if it were clinically insignificant, methamphetamine affected the 5-HT system as reported.
~ vaya
Vaya
Bluelight Crew
Along the lines this thread has traversed, I was wondering if someone could respond to a question I've developed as I've learned a bit more about risperidone's mechanism of action:
Risperdal is a D2-receptor antagonist (and D2 is responsible for release and reuptake of DA in the synaptic cleft), as well as a 5-HT2a antagonist (and 5HT2a antagonism decreases synaptic levels of DA).
Given this, is it reasonable to assume that concomitant use of Risperdal and a DA-agonist stimulant (d-METH, d-AMP, d,l-AMP, MD(M)A) would reduce the dopaminergic effect of the stimulant drug on the brain? Will risperidone render amphetamines and their methylenedioxy-derivatives less "effective"/potent?
Thanks in advance,
~ vaya
Epsilon Alpha
Bluelighter
Everything I've read so far points to yes unless you benefit mainly from NE release or some other obscure binding site for XXXXamphetamine, which probably isn't the case if you're on legitimate D-METH.
Amphetamines are by and large drugs that act on the monoamine systems, while atypicals tend to block every DA and 5HT receptor they can, thus working in opposite manners at the same sites.
I recall meth causing 5HT release via indirect mechanisms which is interesting as sin.
http://www.springerlink.com/content/06n4110t36557l24/
Also, 5HT2A is involved quite heavily in drug liking for methamphetamine and is blocked to all hell by atypicals
http://www.sciencedirect.com/science/article/pii/S0014299901015989
Vaya
Bluelight Crew
Thank you very, very much for your feedback and insight, Epsilon Alpha. It is greatly appreciated.
~ vaya
Epsilon Alpha, I think you are giving too much weight to the simple dopamine hypothesis, things are complicated when it comes to pre and post-synaptic DA binding, a lot of atypicals do indeed increase DA signalling, but also activate DA autoreceptors while efficient DA releasers often overwhelm this mechanism.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2898838/
Vaya
Bluelight Crew
Holy shit. This was my question but in a scholarly discussion format. THANK YOU for posting this here.
~ vaya
edit:
But activation of autoreceptors usually decreases subsequent release of the monoamine, in this case DA via negative feedback; how, then, do atypicals increase DA signalling?
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atrollappears
Bluelighter
That is very interesting, but this isn't the study you are referring to, is it? We already know that amphetamine induced monoamine release can be influenced by autoreceptor activation, I don't think that means that meth causes release through those mechanisms.
Correction: I meant antipsychotics' activation of post-synaptic DA receptors will limit DA transmission beyond it's initial increase due to DA auto-receptor activation
