The mysteries of L-threo-methylphenidate

[hamhurricane]

About a year ago I switched from Ritalin to Focalin. I noticed two things; the first is that Focalin feels much cleaner, the second is that despite the higher potency of focalin my tolerance skyrocketed and I now require 3x my Ritalin dose which had remained stable for years. Though the L-isomer of MPH is classically said to be the dystomer, or inactive isomer, there are dozens of studies which demonstrate this mysterious isomer is quite active indeed! Focalin is more than twice (or even thrice) the potency of Ritalin and this can only be possible if L-MPH has an inhibitory effect. L-MPH has been patented for use as an antidepressant, anxiolytic, and antipsychotic and has been demonstrated to inhibit locomotor activity in rats. It's reminiscent of the CBD/THC relationship in marijuana; a psychotomimetic and antipsychotic in the same pill.

Here is my question: is it possible that L-MPH could attenuate the accumulation of tolerance to D-MPH?

 

[hamhurricane]

The effect of dopamine receptor blockade on the development of sensitization to the locomotor activating effects of amphetamine and morphine
Paul Vezina and Jane Stewart*Centerfor Studies in Behavioral Neurobiology, Department of Psychology, Concordia University, Montreal (Canada)
(Accepted 7 March 1989)

In the present experiments, it was found that pretreating animals with some, but not all, of the DA receptor antagonists tested prior to each of 5 injections of amphetamine or intra-VTA morphine completely blocked the development of sensitization to the locomotor activating effects of these drugs. Further, this blockade seemed to depend on the choice of the antagonist used together with the drug used to produce sensitization....SCH-23390 blocked the development of sensitization to amphetamine but not to intra-VTA morphine...All 3 of these antagonists, at the doses tested, completely blocked the acute locomotor activating effects of these drugs.

 

[Wizzle]

I have no idea but I will be following this as it sounds very interesting..

Does the tolerance issue bother you enough that you'll switch back to DL-MPH?

 

[ebola?]

I'll have to read the original article--why are the researchers making a comparison between IV amphetamine and intra-VTA morphine?

ebola

 

[hamhurricane]

Elaborating on the mysteries

Method of Dopamine Inhibition using L-threo-methylphenidate.

The invention features novel methods of treating psychiatric or neurological disorders characterized by enhanced activity of dopaminergic receptors. It is based on the finding that the l-isomer of dl-threo-methylphenidate (the drug sold as Ritalin) inhibits activity at dopaminergic receptors, and can also inhibit the action of agonists of this receptor. This leads to possible strategies for using this purified isomer for the treatment of psychiatric disorders involving enhanced activity of dopaminergic receptors, or for treatment of abuse of controlled substances like cocaine or amphetamines which act as agonists to this receptor.

Potential Commercial Uses: The invention comprises methods of treating or preventing manic disorders, psychotic disorders or anxiety disorders. It can also be used to inhibit the effects of stimulants like cocaine, amphetamines or caffeine, or for treating or preventing the toxic effects of an overdose of such a stimulant.

Differences in plasma concentrations of the D- and L-threo methylphenidate enantiomers in responding and non-responding children with attention-deficit hyperactivity disorder.

This study deminstrates that plasma concentrations are about 30% lower for the L-isomer when the racemate is administered. It is then suggested that plasma concentrations of D,L-MPH are higher in non-responders because less of the drug is used in the brain, I understand this sounds a bit nonsensical but I quote "It could be that the plasma D-enantiomer concentrations in responders are lower because more of the D-enantiomer might be active in the brain." If this logic holds true then the even lower concentrations of L-MPH would indicate that it is even more "active" in the brain in both responders and non-responders. Read on...

A Comprehensive In Vitro Screening of d-, l-, and dl-threo-Methylphenidate: An Exploratory Study

Although l-MPH exhibits lower oral bioavailability, l-MPH has also been reported to be more stable in human plasma than d-MPH (Srinivas et al. 1991). Furthermore, radiolabeled l-MPH, or a metabolite with the same chromatographic retention time as an active metabolite of l-MPH, p-hydroxymethylphenidate (Patrick et al. 1981), was recently reported to be taken up into the brain to a greater extent than d-MPH following oral administration of each isomer to rats or baboons (Ding et al. 2004). Interestingly, a recent report describes a normal volunteer study subject identified as a “poor metabolizer” of MPH, exhibiting an extended overall drug half-life and an unprecedented enrichment of l-MPH in plasma relative to d-MPH (Patrick et al. in press 2006).

Finally, the recent availability of the dl-MPH transdermal patch reveals much higher plasma concentrations of l-MPH (i.e., values approaching those of d-MPH concentra- tions in some instances) throughout the day, a profile far different from any existing oral for- mulation of racemic MPH (Pierce et al. 2005).

In a recent rodent study, the l-MPH isomer inhibited, in a dose-dependent fashion, the locomotor stimulation by d-MPH, cocaine, or apomorphine in rats (Baldessarini and Cambell 2001). These results differ from those observed in mice, where l-MPH has been reported to enhance the locomotor stimulatory activity following cocaine (Ding et al. 2002; Ding et al. 2004).

Challenges with d-MPH, l-MPH, racemic MPH, or saline in [lesioned] rats demonstrated that d-MPH was over three times more active in reducing motor activity than the racemate. A two-fold reduction would be expected if l-MPH were inert. Furthermore, pretreatment of the lesioned rats with l-MPH attenuated the motor activity response d-MPH.

So back to the question at hand, there is no doubt L-MPH exerts a significant effect, but could it work to reduce the accumulation of tolerance to the D-MPH? And is this why a responsible young student such as myself, who once got by just fine on 20mg/Ritalin/day for years is now shamefully ingesting quantities of D-MPH in excess of 30mg/day?

 

[atara]

could it work to reduce the accumulation of tolerance to the D-MPH?

There has been a lot of similar research about small amounts of naltrexone preventing the accumulation of tolerance to opioids, and small amounts of flumenazil preventing the accumulation of tolerance to benzodiazepines. So, it's very possible, even likely.

 

[hamhurricane]

So then the next question is, and I'm quite surprised that this has not been tried with all the speed freaks on BL, can low dose NE/DA antagonists reduce tolerance to NDARIs? If I were to take 12.5µg of resperidone at night might this this slow or reverse tolerance and is there a better suited NE/DA antagonist?

 

[tamtoot]

Well, one guy from russian board were telling this to everyon for years - if you abuse speed, then take a low dose of a dopamine antagonist every night and you will be ok. I personally didn't tried this, cause i was never abusing speed daily even in such called "therapeutic doses".

So then the next question is, and I'm quite surprised that this has not been tried with all the speed freaks on BL, can low dose NE/DA antagonists reduce tolerance to NDARIs? If I were to take 12.5µg of resperidone at night might this this slow or reverse tolerance and is there a better suited NE/DA antagonist?

 

[pofacedhoe]

i know people on ritalin who were prescribed risperidone

 

[Slapdragonx]

Anti-Psychotics should only be used for what they are indicated.

 

[sleepysaint]

I'll have to read the original article--why are the researchers making a comparison between IV amphetamine and intra-VTA morphine?

ebola

To understand it fully I'd need to see the full article as well, but it seems to me that they may have just been using it as a control of sorts. It was noted that one of the antagonists affected sensitization to the amphetamine but not to the morphine. I don't know enough about intra-VTA administration of morphine to tell you how it compares to amphetamine from a dopaminergic standpoint anyway.