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                 Smart Drug Update: Adrafinil and Modafinil
                            by Steven Wm. Fowkes
        Published in the Ceri Newsletter Vol. 3 No. 8 December 1994
         Transcribed to the electronic media by Swedish Infomania

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        Over the last twenty years, the French pharmaceutical company Lafon
has been developing a new class of smart drug which specializes in
promoting vigilance and alertness. Their first drug, adrafinil (trade name
Olmifon) has been approved in numerous European countries for the treatment
of narcolepsy, a condition of excessive daytime sleepiness, and cataplexy,
a condition of transient muscular weakness that is often associated with
narcolepsy. Adrafinil (and their newer analog, modafinil) selectively
stimulate adrenergic neurons which are responsible for general alertness
towards the external environment. This enhancement of vigilance effectively
compensates for the lack of alertness in narcolepsy. Adrafinil and
modafinil have also been shown to increase vigilance in patients with
Alzheimer's disease and senility syndromes, as well as in normal
individuals.
        The action of adrafinil and modafinil is specific to (alpha-1)
adrenergic receptors. These receptors respond to norepinephrine, a
neurotransmitter involved in alertness, learning and memory. The
antidepressant drugs imipramine and desipramine increase norepinephrine by
inhibiting its re-uptake (blocking its recycling). Adrafinil and modafinil,
on the other hand, act directly to stimulate the norepinephrine receptor.
Scientifically, they are referred to as alpha-1 receptor agonists.
        Adrafinil's and modafinil's mode of action is quite different from
that of other adrenergic stimulants like amphetamine and methylphenidate
(Ritalin). Unlike these other drugs, adrafinil and modafinil do not
stimulate dopaminergic neurons in the nigrostriatal region of the brain [De
Sereville et al. ,1994]. As a result, the stimulatory effect of adrafinil
and modafinil on vigilance and locomotor activity (movement) is not
associated with anxiety side effects [Simon et al,1994). Furthermore, in a
double-blind cross-over study of 16 "healthy volunteers" (half men and half
women, all moderate caffeine users), Warot and colleagues [1993] found that
the subjective effects of modafinil "differed markedly" from amphetamine
and were "close" to those of an equal amount of caffeine. They concluded
that modafinil "does not possess amphetamine-like subjective effects in a
healthy population," and speculated that it probably has low abuse
potential.
        In cats, both modafinil and amphetamine cause a dose-dependent
increase in wakefulness and brain temperature, but only amphetamine caused
"marked signs of behavioral excitation" [Lin et al., 1992]. Inhibition of
catecholamine synthesis (epinephrine, norepinephrine and dopamine) resulted
in almost complete blocking of the effects of amphetamine, but "only
slightly reduced the duration of the waking effect of modafinil" at the two
higher doses used in the study. Haloperidol (a dopamine antagonist) also
significantly blocked amphetamine but not adrafinil. These results confirm
that adrafinil and modafinil work directly on the target cell
(postsynaptic) adrenergic receptors.
        On the other hand, adrenergic blockers (alpha, alpha-1 and beta)
significantly reduced the action of adrafinil at the lowest dose used, but
not that of amphetamine. In addition, modafinil activity is enhanced by
yohimbine, an alpha-2 receptor antagonist (Lin et al,1992]. These
observations suggest that adrafinil and modafinil are highly selective and
specific stimulants of al adrenergic receptors and do not significantly
stimulate dopaminergic pathways. In other words, they produce a
dose-dependent increase in alertness and vigilance without the classic side
effects of MAO inhibitors.
        In rats, modafinil failed to modify the electrical firing activity
of dopaminergic and noradrenergic neurons, whereas amphetamine consistently
inhibited their activity [Akaoka et al, 1991). They conclude, "Contrary to
amphetamine, the waking effect of modafinil does not seem to be mediated by
the catecholaminergic neuron activity per se." Modafinil's stimulation of
locomotor activity was prevented by two centrally acting al antagonists
(prazosin and phenoxybenzamine, but not by a peripherally acting al
antagonist (phentolamine) [Duteil et al., 1990]. These observations
localize adrafinil's and modafinil's activity to the central nervous system
(i.e., the brain). The "interesting" and "unexpected" absence of peripheral
sympathetic stimulation is noteworthy.
        Adrafinil and modafinil have been extensively studied in monkeys.
An increase in nocturnal activity is noted without "stereotyped" behavior
with modafinil [Hermant et al.,1991; Duteil et al,1990] and adrafinil
[Milhaud and Klein, 1985]. The stimulating activity of modafinil is
prevented by the at antagonists prazosin [Hermant et al.,1991; Duteil et
al.,1990) and phenoxybenzamine [Duteil et a1,1990), confirming the results
in rats and cats. With repeat dosing, attenuation of effect was noted
[Hermant et aL,1991]. During the recoveiy phase after drug treatment, no
sedation or withdrawal signs were observed for adrafinil (Milhaud and
Klein,1985] and modafinil [Hermant et al.,1991]. In addition, withdrawal
from modafinil produced "no rebound of sleep" (Hermant et al. 1991). As
noted in human studies, there was "no sign of anxiety" in the primates.
        In an EEG study of rhesus monkeys, 6 mg/kg was found to be the
threshold dose for a wakening effect [I.agarde and Milhaud, 1990]. Doses of
12 mg/kg modafinil produced a "sharp" wakening effect with a "significant
decrease" in all stages of sleep. Repeated dosing at 22.5 mg/kg over 4 days
produced "quasicontinuous wakefulness" (insomnia), but without behavioral
disorders (Lagarde and Milhaud,1990). This effect is unique among
Vigilance-enhancing drugs. In another study, oral doses of 60, 90 and 120
mg/kg were used. At 60 mg/kg, the nighttime activity of rhesus monkeys was
doubled (measured with ultrasound). Nocturnal activity was quadrupled at
the 90 and 120 mg/kg dosages. At the highest dosage, the monkeys were
almost as active at night as they were during daylight hours [Milhaud and
Klein,1985).
        In the Milhaud and Klein study, the 60 mg/kg dose required two days
to become "significant." The 90 and 120 mg/kg dosages were "significantly
significant" after the first dose. The stimulating effect of two doses of
90 and 120 mg/kg adrafinil persisted for approximately 36 hours [Milhaud
and Klein, 1985). This suggests an extremely long duration of action.

        Adrafinil comes in 300 mg tablets under the Olmifon brand name.
Standard dosing is 2-4 tablets per day. For the treatment of narcolepsy,
even higher dosages have been used. Normal individuals with lesser
vigilance deficits may prefer lower dosages.
        Although the individual dose for modafinil is slightly less
(200 mg), it has only been in clinical use since 1988. Consequently, it is
more expensive and harder to obtain.
        Adrafinil is metabolized by the liver and long-term use requires
monitoring of hepatic alkaline phospahatase levels. We also reccomend
monitoring SGOT, SGPT and GGTP. We suggest that liver functioning tests be
performed prior to starting, after the first three months of use, and then
every six months thereafter.
        In terms of acute toxicity, the LD50 dose (lethal dose to 50% of
mice) for adrafinil is 800-1000mg/kg [Rambert et al., 1986]. This compares
favorably to the 24 mg/kg dosage level for a 1200mg adrafinil dosage in a
110 pound (50 kg) person.

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