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Re: Provigil-Modafinil-Adrafinil?

Posted by Rick on January 6, 2002, at 14:58:37

In reply to Re: Provigil-Modafinil-Adrafinil? Rick, posted by on January 6, 2002, at 9:52:10

Craig -

Most of the studies I've seen suggest that modafinil has minimal dopaminergic activity.
A quote from the mongraph:

Modafinil is not a direct- or indirect-acting dopamine receptor agonist and is inactive in several in vivo preclinical models capable of detecting enhanced dopaminergic activity. In vitro, modafinil binds to the dopamine reuptake site and causes an increase in extracellular dopamine, but no increase in dopamine release. In a preclinical model, the wakefulness induced by amphetamine, but not modafinil, is antagonized by the dopamine receptor antagonist haloperidol.

Neither have I seen anything to suggest that clonazepam is dopaminergic. In fact, some work at Ontario's McMaster University (which coincidentally is one of the primary Social Phobia research insttutions) has suggested that clonazepam may have antidopaminergic effects in the striatum:

Now, as for serotonergic AD's, that's a very different story. One theory of their frequent efficacy in social phobia relates to the dopamine reuptake blockade some of the SSRI's possess. And we know that the MAOI Nardil which is has an excellent track reord treating SP, preserves dopamine in addition to serotonin and noradrenaline.

But the point is that these agents that have shown success treating SP are NOT 100% dopaminergic meds. Again, studies of purely dopaminergic drugs - whether direct or indirect acting -- have all failed to produce significant benefit in social phobia treatment, and have sometimes worsened the condition.

Reiterating, I'm by no means arguing the point that dopamine dysfunction could be a key factor in Social Phobia (as are serotonin, noradrenaline and GABA). And that very likely applies to me, too. I'm only stating that, for whatever reason, purely dopaminergic meds tested thus far generaly don't work, and may in fact increase anxiety. In essence, the "brute force" methods for preserving/increasing dopamine don't seem to work for SP. But that doesn't mean dopamine enhancement couldn't be very beneficial to SP in a less direct, synergistic way. Note that Wellbutrin, which has proven helpful in at least some cases of SP, has adrenergic activity in addition to its dopaminergic properties.

BTW, 2.5 mg selegiline diminished the effectiveness of my Klonopin a bit, but provided enough cognitive, energy, and sexual benefits that I'd likely try adding it back if I had to give up Provigil -- assuming, for safety's sake, that I was still off Serzone.


P.S. If you haven't already done so, I suggest you get your hands on the fascinating article "Drugs in Development for Social Anxiety" Disorder: More to Social Anxiety Than Meets the SSRI. The 11- page (not including references) article was written by Van Ameringen et, al. of McMaster, and is in the October 2000 issue of "Expert Opinion in Investigational Drugs."
> Rick -
> I had a hard time not acknowledging the "SP and dopamine" issue:
> I definitely do *not* think dopamine agonists are required for all people with SP.
> I'm also not too clear if dopaminergics work equally well for women as men.
> I *do* think a majority of males with moderate to severe SP AND timidity AND high rejection sensitivity will attain their best results with dopamine augmentation.
> Although I could cite solid suggesting evidence (best) or my own regimen and experience, instead I suggest your regimen acts as a dopamine and GABA agonist with less effect on SE and NE.
> 100 Provigil (5ht, DA): (effect perhaps partially indirect via GABA) Site specific but clearly has characteristics of DA agonist and ex vivo shows DA re-uptake. Higher doses lead to increased wakefullness, stimulant and (at first) euphoric properties. Is self-reinforcing. Increased libido, hair loss, effective antagonist of the atypical antipsychotic clozaril.
> 300 Serzone: Often "prosexual" (suggestive dopamine agonist or at worst lacks net DA decline, probably indirectly by primary action as 5ht-2 antagonist.) Common side effects: increased sex drive, agitation, irritablity, hypotension. Up to date info (Medline) indicates that Serzone has *weak* 5ht re-uptake and it's *primary* effect is as 5ht-2 antagonist.
> 1.25 Klonopin: May cause Increase libido (in PDR also), paradoxic reaction at high dose such as aggressive behavior, hyperactivity, increased locomotion, agitation, impulsiveness, increased self-confidence, reduced rejection sensitivity. Klonopin is a 2nd line MOOD STABILIZER for bipolar swings. This suggests Klonopin compensate for low dopamine levels. Also, Davidson (1992) suggest Klonopin may have dopaminergic agonism, possibly by the overall anti-serotonin properties of Klonopin (unlike Xanax for example, which is sometimes used as anti-depressant).
> Sum: Provigil: DA++ (dose dependent)
> Serzone: DA or DA+
> Klonopin: DA, DA+, unlikely DA-
> Provigil's ability to effectively antagonize clozaril,
> and ability to offset amisulpride induced energy/motor deficits
> both additional evidence for DA agonism.
> "Dopaminergics and anxiety": Many DA agonists also boost NE, and NE is typically more responsibe for anxiety reactions.
> Examples: Eldepryl: DA++, NE++ (predict anxiety)
> Wellbutrin: DA++, NE++ (predict anxiety)
> Ritalin: DA++, NE++ (predict anxiety)
> aminetpine: DA++, NE++ (predict anxiety)
> Provigil: SE+,DA+ (predict stimulating mood lift)
> Dexedrine: SE++,DA++,NE++ (predict activating feel good, confidence, energy)
> amantadine: DA++, NE+ (high energy, boost sex, mild anxiety)
> kregpark
> > No, never been on amphetamines. The selegiline metabolites are the closest I've come.
> > But the key here is that the amphetamine metabolites are likely *not* the cause of the anxiety selegiline produced. Instead -- despite the talk of dopamine deficiency in social phobia -- I find that dopaminergic agents in general make me a lot more anxious. And I'm not the only one...most attempts to harness dopamine for social phobia have been major failures, such as the selegiline study I mentioned as well as a pergolide study where the results were so negative that the study was quickly aborted.
> > That doesn't mean dopamine enhancement can't play a role in social phobia treatment in some as-yet undetermined fashion. But dopamine's a complex and rather mysterious substance that can have diametrically opposing mental and physical (e.g., blood pressure modulating) impact at different binding sites, etc.
> > Rick
> >
> >
> > > > Even a tiny dose that I later used to (successfully) offset slight Klonopin-induced dulling added back some anxiety.
> > > Have you ever been on an amphetamine (Adderall, Dexedrine, Desoxyn)? If so, did it cause the same anxiety you experienced with selegiline? (As I'm sure you know, two of selegiline's metabolites are l-amphetamine and l-methamphetamine.)
> > > I'm considering trying selegiline for my depression & social phobia. (Amphetamines don't really increase my anxiety (in fact, sometimes they relieve it).)
> > > Thanks,
> > > Christophre




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