Posted by Rick on November 8, 2001, at 0:42:30
In reply to Vivid Evidence of Provigil Anti-Anxiety Effects, posted by Rick on November 6, 2001, at 19:16:24
>I notice that a lot of episodes of social anxiety happen at work when I am 'surprised' by a conference call. NOBODY tells me diddly-squat about it, of course-the phone just rings and there are half a dozen others on the other end sitting around a speaker-phone God knows where. One of those events happened just last week and I had to shift gears suddenly and try to remember what the hell they were trying to ask me...I just paused started to hem/haw and then I felt the panic starting to hit me. Finally, I just told them to summarize what the hell they were wanting, from who, and for what reason and send that to me in an email and then I would get back to them! Our salesperson involved was pissed, but I had to get out of that, my head was just mush.
I’ve been there! For me, though, the inability to remember was usually a social phobic reaction to being put on the spot. I used to start to panic, too. Now, I stay calm and can think more clearly. And even when some fuzziness remains I’m able to project confidence and even B.S. a little if I need to. While I still care what others think, I don’t obsess over it and let it thrust me into that awful downward spiral. Ironically, some of the “drawing a blank” that used to come from being put on the spot now comes from periodic, temporary memory lapses that may be caused by the Serzone or Klonopin. But overall, the way I react mentally and outwardly in such a situation is night-and-day compared to before. I don’t feel like I’m losing control anymore. I still have some degree of insecurity sometimes, but so do most people.
>I wonder if a lot of social anxiety I experience is directly related to ADHD symptoms?
It very well could be. Anything that (however irrationally) makes you feel deficient or scrutinized in the eyes of others can lead you in that direction if you’re mentally susceptible.
>Anyhow, isn't Provigil an adrenoreceptor *agonist*?? Also, what role could it play in Parkinson's? I have seen posts about it, but most seemed to be thumbs-down stuff in relation to successful AD augmentation for TRD. What are the most common side-effects?
While there’s some debate over certain aspects of how modafinil works (and more agreement in other respects), the initial thought that it acted as an adrenoreceptor agonist seems to have been abandoned. While others on this board may disagree, Provigil seems to have very few side effects. For me, the only side effect seems to be that if I take too much – meaning going more than two days at 200 mg vs. my usual dose of 100 mg, I get a little wired, which can be a little irritating and also cause some of my somatic SP symptoms to return a bit. E.g, I might still very confident, but my voice could start getting a little shaky when I get angry. But this rarely happens, because I watch my dose. (100 mg for me might be equivalent to a higher dose due to Serzone’s enzyme-system-driven potentiation of modafinil). A few other minor side effects MAY be caused partially by Provigil, but they could very well be caused by (or additive with) the Serzone instead (I started them together): mild dry mouth and a harder time getting out of bed than when I was taking Klonopin alone or in various other combos. According to the manufacturer – obviously NOT an unprejudiced source – side effects are uncommon, but the most common seem to be nervousness, headache and insomnia. (I have a have a hard time understanding the last one. While Provigil keeps me awake and alert, I have no trouble sleeping soundly when I want, whether it’s 11 Am. or 11 p.m. And I used to be an insomniac. (Of course, I’m taking Serzone and Klonopin, too. But I’ve seen many people – and of course studies -- cite the same benefit.)
As for some of the less-than-rave reviews here, I have several comments about that which I’ve already made in recent posts (e.g., see mine and a new Provigil user’s comments in the thread “Stimulants, How Do You Get Them?” further down the page). I will mention that one good thing about Provigil from a practical standpoint is that you should know within a few weeks – certainly no more than three weeks – whether it’s going to help you. Like the poster below, I felt distinct benefits the first day. I started with 200 mg and later pared back to 100 with occasional spikes to 200. I may be repeating myself, but I think some people mistake loss of an early mild-euphoria side effect as poop-out. Also, Provigil can eventually cause its own metabolism, which can also be mistaken for poop-out. Instead, it just means you need a TEMPORARY dose increase.
I’ve attached the text of a fairly good summary of the current thought on Provigil pharmacology, from Medscape. As I said, there are still some areas of debate on modafinil’s mechanisms of action, as a recent thread on this board attests.
BTW, Provigil can apparently actually inhibit GABA, but this seems to be limited to specific areas of the brain, and at specific dose levels. In my own experience, Provigil certainly doesn’t appear to have any negative impact on Klonopin’s social anxiety benefits. To the contrary, they seem synergistic. If you’d like to see more about modafinil and GABA (and Glutamate), search on these terms in Medline.
MODAFINIL ORAL
Pharmacology & Chemistry
Description from AHFS DI™
Modafinil, a benzhydryl sulfinylacetamide derivative, is a CNS stimulant that is structurally and pharmacologically distinct from other currently available CNS stimulants (e.g., amphetamines, caffeine, cocaine, methylphenidate). Modafinil promotes vigilance and wakefulness and decreases the number of daytime sleep episodes associated with narcolepsy. Although the wakefulness-promoting effects of modafinil are comparable to those exhibited by amphetamines or methylphenidate, modafinil alters metabolic activity and increases neuronal activity in specific areas of the brain that control sleep/wakefulness and the biologic clock while amphetamines increase neuronal activity more widely throughout the brain, suggesting distinct mechanisms for modafinil and relatively high selectivity.The exact mechanism(s) of action of modafinil is unknown, but animal studies have shown that the drug inhibits the release of Gamma-aminobutyric acid (GABA) and increases the release of glutamate from the cerebral cortex, hippocampus, nucleus acumbens, medial preoptic area, and posterior hypothalamus. GABA is an inhibitory neurotransmitter that acts as a CNS depressant while glutamate is an excitatory neurotransmitter. Modafinil does not appear to be an indirect- or direct-acting dopamine-receptor agonist nor to act as a sympathomimetic agent. Haloperidol, a dopamine-receptor antagonist, inhibits the activity of amphetamine but not the activity of modafinil.
The manufacturer states that modafinil does not appear to be a direct or indirect alpha1-adrenergic agonist, as evidenced by lack of activity in assay systems known to be responsive to such agonists. However, the drug’s stimulant effects (e.g., on wakefulness, locomotion, and the EEG) are antagonized by alpha1-antagonists (e.g., prazosin, phenoxybenzamine), thus indicating that an intact central alpha1-adrenergic system is necessary for modafanil’s CNS activity. In addition, it has been suggested that the drug itself may stimulate central alpha1-adrenergic activity (e.g., at the postsynaptic level). Modafinil does not appear to exhibit clinically important peripheral adrenergic activity, even at high doses. In animals, modafinil increased locomotor activity but didnot increase dopamine activity; however, in vitro studies showed that modafinil binds to dopamine reuptake sites and increases extracellular dopamine concentrations.
At usual pharmacologic concentrations, modafinil does not bind to certain norepinephrine, serotonin, dopamine, GABA, adenosine, histamine H3, melatonin, or benzodiazepine receptors that regulate sleep and wakefulness. The drug also does not inhibit type B monoamine oxidase (MAO-B) or phosphodiesterase and does not alter plasma melatonin or cortisol hormone profiles, which may limit short-term adverse effects. Modafinil does not decrease the incidence of cataplexy in dogs. Although the effects, ifany, of modafinil on blood pressure during long-term therapy remain to be elucidated, 300 mg (200 mg before breakfast and 100 mg before lunch) given on a single day in normotensive patients with obstructive sleep apnea did not appear to substantially affect blood pressure, although increases were noted relative to placebo under mental and physical stress tests.
Like other CNS stimulants, modafinil is reinforcing in animals and produces psychoactive (e.g., alterations in mood and thinking), euphoric, and subjective effects typical of classic psychomotor stimulants (e.g., amphetamines) in humans. Despite this pharmacologic similarity to such stimulants, the chemical properties of modafinil (e.g., not water soluble, decomposes in heat) may limit its abuse potential. In addition, there are substantial relative potency differences between modafinil and CNS stimulants that are subject to control under the Federal Controlled Substances Act as schedule II drugs. These differences reduce the likelihood that modafinil could be abused by the parenteral, intranasal, or inhalation route, as are cocaine, methylphenidate, and amphetamine; therefore, modafinil is subject to control as a schedule IV rather than II drug.
With chronic dosing, modafinil induces its own metabolism via induction of the cytochrome P-450 (CYP) isoenzyme 3A4. Clearance of modafinil may be altered by other inducers (e.g. phenobarbital, carbamazepine, rifampin) or inhibitors (e.g. ketoconazole, itraconazole) of this isoenzyme. (See Drug Interactions.) Inhibition of the CYP isoenzymes 2C9 and 2C19 by modafinil results in several potential drug interactions (e.g. warfarin, phenytoin, diazepam, propranolol, clomipramine, desipramine). (See Drug Interactions.)
General from AHFS DI™
Administration
Modafinil usually is administered orally once daily in the morning. The drug also has been administered in 2 divided doses daily, in the morning and at noon.
Although administration with food can delay GI absorption of modafinil by approximately 30 minutes, food does not affect the extent of absorption and the drug can be administered without regard to meals.
Dosage
The usual recommended dosage of modafinil to improve wakefulness in adults and adolescents 16 years of age and older with excessive daytime sleepiness associated with narcolepsy is 200 mg daily. Although a dosage of 400 mg daily has been well tolerated, there is no consistent evidence indicating that this dosage provides additional clinical benefit beyond that provided by the 200-mg daily dosage.
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-- Re your Pakinson’s question, here’s one of the lab studies suggestive of Provigil’s potential value for Parkinson’s, but tests on humans have been mainly to show anti-fatigue benefits. I’m guessing Cephalon may not put much effeort against Provigil for Parkinson’s, since they’re working on a novel potential-breakthrough medication specifically targeting this disease.
poster:Rick
thread:83383
URL: http://www.dr-bob.org/babble/20011104/msgs/83501.html