EUGOERICS: THE ULTIMATE STIMULANTS
By Robert Mason
PhD
Eugeroic simply means “good arousal,” but eugeroics form a unique class of
drugs, which contain only two at present, those being adrafinil and modafinil,
(both of which have been developed by Lafon Laboratories of France).
The basis of their uniqueness lies in their ability to only “stimulate when
stimulation is required.” As a result, the “highs and lows” associated with
other stimulants such as amphetamine, are absent with eugeroics.
Their initial use often produces comments such as, “I can’t tell any
difference.” But it is only several hours later, when one realizes that
attention and awakeness are the same as earlier, that one is made fully aware of
their benefit.
Eugeroics have been designed to treat narcolepsy (sleeping in the day),
hypersomnia (excessive sleep) and cataplexy, (a condition of sudden muscular
weakness or fatigue).
Yet eugeroics don’t affect normal sleep patterns, nor are they addictive and
they have far fewer side effects than the current prescribed stimulants.
MODAFINIL’S UNIQUE STIMULATION
One study, (5) on rats suggested that one possible vigilance enhancing
property of modafinil was its ability to inhibit the release of GABA, through an
action on 5HTP serotonin receptors. However, the doses used were far higher than
normal therapeutic doses. So meanwhile, most clinical studies point to modafinil
as a unique and highly selective agonist of brain postsynaptic receptor sites
called, alpha-1 adrenergic (1,2,7,8,9,10).
These alpha-1 sites are receptive to the neurotransmitter- Norepinephrine
(NE). The central function of NE is a fairly recent discovery, it appears to
regulate alertness and the waking/ sleep cycle and has a role in the maintenance
of attention, memory, learning, cerebral plasticity and even has
neuro-protection qualities (2).
Central nervous stimulants (CNS), such as amphetamine or pemoline are the
most widely used drugs to treat narcolepsy, hypersomnia and cataplexy, but these
have a number of well documented problems, particularly cardiovascular side
effects, interference with sleep, psychiatric disturbances and addiction.
Two studies, (3,10) directly compared the affects of modafinil and the
“classic” stimulant, d-amphetamine on sleep. Both double blind controls involved
about twelve individuals, one study was undertaken with individuals whose mean
age was 68, the other on much younger volunteers. They utilized 100mg or
200mg of modafinil, or 10mg or 20mg of d-amphetamine, or a placebo. All the
drugs were administered orally and sleep scales, awakening quality and
psychometric tests were completed in the morning.
The outcome of both tests showed that d-amphetamine caused a dose dependant
impairment of sleep maintenance, but modafinil did not. Here in lies a problem
for those who have difficulty staying alert and awake during the day. The use of
“classic” stimulants, such as amphetamines, threatens to reduce total sleep time
and REM sleep, and this will ultimately mean higher and higher doses are
required, thus creating a vicious circle.
On the other hand, modafinil has not been shown to interfere with night time
sleep, thus clearly indicating that the two compounds operate by different
methods.
CLINICAL TRIALS
Numerous studies on animals since the mid 1980’s, have confirmed the ability
of modafinil to increase awakeness and alertness, without serious side effects,
or dependency.
One test on rats, (4) produced an interesting result. The researchers
discovered that modafinil decreased feeding and thereby reduced body-weight! The
amounts of modafinil required were not dose dependent and there was no
alteration in the drink-feed ratio. Their conclusion was an interesting
reference to the possible mechanisms that underlie the relation between sleep,
feeding and metabolism.
Various human trials have concentrated upon modafinil as a therapeutic agent
to help maintain alertness and vigilance. A noteworthy conclusion of one
clinical trial, (10) compared modafinil to amphetamine and described amphetamine
as “vigilance increasing,” but modafinil as “vigilance promoting.” This is an
interesting comment because as we’ve seen, modafinil won’t prevent a person from
sleeping if they want to, but if they wish to remain awake, they will do so with
a far greater degree of alertness.
This was borne out in one clinical trial, (11) where volunteers were
subjected to 60 hours of sleep deprivation! During their continued wakefulness,
their vigilance was assessed using questionnaires; analogue visual scales and
sleep latency tests. The subjects received either 200mg modafinil, or a placebo
every 8 hours. The modafinil group sustained a satisfactory level of vigilance
with an absence of sleep episodes, unlike the placebo group who gradually
declined and slipped into “micro-sleep” episodes, (as one might expect when
awake for longer than 24 hours)…
A French study, (9) conducted over 3 years, discovered that modafinil reduced
drowsiness in 83% of hypersomniac patients and 71% of narcoleptics. Modafinil
did not produce peripheric side effects, disturb night sleep and it was never
responsible for drug dependence.
Another French study conducted with 149 patients over a period of 2 years,
(13) treated patients with narcolepsy-cataplexy at 200mg to 400mg daily. The
patients were then asked to score the benefit of modafinil themselves, from 0
(no affect) to 3 (excellent affect), 64.1% of the subjects scored it as
excellent.
An earlier study, (17) with 123 patients, (which also included those
suffering with hypersomnia), the physicians evaluated the patients on a scale of
1 (no affect) to 4 (excellent affect). The results? 17% excellent response, 63%
good response, 17% fair and 3% no affect. The incidence of side effects were
minimal, (14 of the 123 patients had side effects, 11 of whose side effects
disappeared when doses were reduced).
These results have been repeated in a number of smaller clinical trials, (8,
12, 14, and 15) and confirm modafinil’s excellent response to treating
individuals suffering with narcolepsy, hypersomnia and cataplexy. Its
efficacious use, in conjunction with a virtual absence of side effects,
non-contraindication with normal sleep patterns and lack of drug dependence,
certainly indicates that eugeroics are a breed apart from conventional
stimulants.
THE MILITARY INVOLVEMENT
It is fascinating to see that several countries armed forces have studied and
indeed use, (sic) modafinil for military operations.
The use of stimulants to keep troops awake and alert is not a new one. It is
known that British troops used them during the Falklands conflict and that USAF
aircrews took amphetamines during the Libyan air strikes.
The French government even admitted that its crack Corp- The Foreign Legion-
used modafinil for covert operations inside Iraq, during the Gulf war.
In-fact, Professor Michel Jouvet, an authority on sleep, claimed during an
international defense meeting in Paris that, “modafinil could keep an army on
its feet and fighting for three days and nights with no major side effects.”
Not surprisingly then, we have heard that modafinil is in use in some
sections of the Belgian, Dutch and US airforces.
DOSAGES AND SIDE EFFECTS
Side effects in continuous studies of therapeutic dosages of modafinil,
lasting 3 or more years have been minimal and usually noted as nothing more than
headache or nausea (17, 18). In rare cases there has been hyper-salivation (19)
and moderate tachycardia (increased pulse rate- 20), this probably accounts for
modafinil’s instruction sheet, which states that those suffering from a heart
condition must consult their physician before use. However, blood and pulse
rates usually remain unchanged at normal therapeutic doses. In-fact, a suicidal
21-year-old female who ingested 4500mg demonstrated the relative safety of
modafinil. Her side effects were limited to tachycardia, excitation and insomnia
(9). As is common with most drugs, modafinil should not be used by those with
serious liver disorders, nor those women who are pregnant or nursing.
The official insert for the modafinil package remains unclear as to the
precise drug contraindications, but as it is an alpha-adrenergic agonist, those
drugs that represent alpha-adrenergic antagonists should be avoided. These
include prazosin, phentolamine or beta-blockers such as propranolol (Inderal).
Furthermore, drugs that enhance norepinephrine activity, (such as yohimbine)
should only be used with care, as there may be a synergistic affect. Adrafinil
is noted as contraindicated with epilepsy and has been shown to enhance the
potency of anti-epileptic drugs such as phenytoin, (Dilantin/ Epanutin).
Although this isn’t mentioned in any of the modafinil literature we have read,
it is best being advised of.
As for dosages, there seems to be little difference in doses and more
importance is placed upon regular administration (12). Those who simply wish to
remain awake and alert will benefit from a single 100mg dose. To remain
“on-call” all day, 100mg in the morning and another 100mg in the afternoon is
probably all that is required. For those wishing to remain awake during the
night, then another 100mg in the late evening, (in other words approximately
every 8 hours).
Dosages for those suffering from narcolepsy, hypersomnia and cataplexy are
100-200mg morning and afternoon. Some of the doses in trials have been as high
as 600mg to 700mg daily, (9) although doses over 500mg daily may cause euphoria,
slight motor excitation or even insomnia!
ADRAFINIL AND MODAFINIL COMPARED
At first glance there may appear to be little difference between the two. It
is true that modafinil is more potent, “average” doses of adrafinil are in the
region of 600mg to 1200mg daily, compared to modafinil’s 200mg to 400mg daily
and this is self evident by the respective tablet sizes.
However, if one were to compare adrafinil and modafinil on price alone then
adrafinil would win hands down! So the question must be asked, why did Lafon
produce a newer analogue of adrafinil?
The answer probably lies in two parts. Firstly, it is thought that adrafinil
may not be such a highly selective alpha-1 adrenergic as originally thought and
may also affect other alpha receptors, (albeit in a minute fashion).
Secondly, adrafinil is attributed to some other possible side effects that
have not been associated (to date) with modafinil, including, stomach pain, skin
irritations, inner tension and in long term use, (over 3 months usually), an
increase in liver enzyme levels, (which is reversible by reduction or
withdrawal). It is our guess that it is the last potential side effect that lead
to the development of modafinil. Clearly, continuous adrafinil use would require
regular blood testing to monitor liver enzyme levels, and this is obviously
inconvenient to those patients who need to use eugeroics on a regular basis.
As none of the clinical reports we have read indicate any such problem with
modafinil, it would appear that the analogue has achieved its desired aim.
SAFE AS CAFFEINE, STRONG AS AMPHETAMINE?
We were going to reiterate and condense the above article into a few lines,
but the conclusion of the Aerospace Medical Association article, (16) on
modafinil was so good we will leave the last words to them.
“The development of modafinil brings to light a crucial social question. What
would be the impediment for its use, if a compound such as modafinil is more
like caffeine than amphetamine in terms of safety, and yet, as effective as the
amphetamines?”
Copyright 2003. This article may not be reproduced for public
broadcast in any form, without the written permission of: International Antiaging Systems
REFERENCES
1) Lamberg L “Narcolepsy researchers barking up the right tree” JAMA
Sep. 96, 11 276 (10) 765-766.
2) Jouvet M, Albarede JL, Lubin S,
Meyrignac C “noradrenaline and cerebral aging” Encephale May 1991 17 (3)
187-195.
3) Saletu B, Frey R, Krupka M, Anderer P, Grunberger J,
Barbanoj MJ “Differential effects of a new central adrenergic agonist- modafinil
and d-amphetamine on sleep and early morning behaviour in elderly”
Arzneimittelforschung Oct 1989 39 (10) 1268-73.
4) Nicoladis S,
DeSaint, Hilarre Z “Nonamphetamine awakening agent modafinil induces feeding
changes in the rat” Brain Res Bull 1993 (32) 2 87-90.
5) Ferraro L,
Tanganelli S, O’Connor WT, Antonelli T, Rambert F, Fuxe K “The vigilance
promoting drug modafinil decreases GABA release in the medial preoptic area and
in the posterior hypothalamus of the awake rate; possible involvement of the
serotonergic 5-HT3 receptor” Neuro Sci Lett 1996 Dec 6 220 (1)
6) Gold
LH, Balster RL, “Evaluation of the cocaine like discriminative stimulus effects
and reinforcing effects of modafinil” Dept of Phar & Tox, Med Coll VA, USA.
7) Maffont F, Mayer G, Minz M, “Modafinil in diurnal sleepiness, a
study of 123 patients” Expl Fonct Neuro CHU Parid France. Sleep 1994 Dec 17 (8)
5113-115.
8) Billiard M, Besset A, Montplasir J, Laffont F, Goldenberg
F, Weill JS, Lubin S “Modafinil, a double blind multicentric study” Sleep 1994
Dec 17 (8) 5107-112.
9) Bastuji H, Jouvet M “Successful treatment of
idiopathic hypersomnia and narcolepsy with modafinil” Prog Neuro Psy Pharm 1988
12 (5) 695-700.
10) Saletu B, Frey R, Krupka M, Anderer P, Grunberger
J, Barbanoj MJ “Differential effects of a new central adrenergic agonist-
modafinil and d-amphetamine on sleep and early morning behaviour in young
healthy volunteers” Int J Clinical Pharm Res 1989 9 (3) 183-185.
11) Lagarde D, Batejat D, Van Beers P, Sarafian D, Pradella S “Interest
of modafinil, a new psycostimulant during a sixty hour sleep deprivation
experiment” Fund Clin Pharmacol 1995 (9) 3- 271-9.
12) Broughton RJ,
Fleming JA, George CF, Hill JD, Kruger MH, Moldofsky H, Montplasir JY, Morehouse
RL, Moscovitch A, Murphy WF “Randomised double blind placebo controlled
crossover trial of modafinil in the treatment of excessive daytime sleepiness in
narcolepsy” Neurology 1997 Aug (49) 2 P444-451.
13) Basset A, Chetrit
M, Carlander B, Billard M “Use of modafinil in the treatment of narcolepsy, a
long term follow up study” Neurophysiol Clin 1996 26 (1) 60-66.
14) Arnuff I, Homeyer P, Garma L, Whitelaw WA, Derenne JP “Modafinil in
obstructive sleep apnea hypopnea syndrome, a pilot study in 6 patients”
Respiration 1997 64 (2) 159-161.
15) Boivon DB, Montplisir J, Petit D,
Lambert C, Labin S “Effects of modafinil on symptomatology of human narcolepsy”
Clin Neuropharmacol 1994 Fed 16 (1) 46-53.
16) Lyons TJ, French J
“Modafinil the unique properties of a new stimulant” USAF School of Aerospace,
Brooks TX (Science News Note 1991, 62 432-5).
17) Laffont F, Cathala
HP, Kohler F “Effect of modafinil on narcoleptic and idiopathic hypersomnia” 5th
Euro Cong sleep research, Copenhagen 1987 586.
18) Laffont F,Cathala
HP, Waisbord P, Kohler F “Effect of modafinil on narcoleptic patients” 9th Euro
Cong sleep research, Israel 1988; 26.
19) Bastuli H, Jouvet M
“Traitement des hypersomnies per la modafinil” La Press Medicale 1986 15 (28)
1330.
20) Goldenberg F, Weil JS, Van Frenkeel R, “Effects of
modafinil on diurnal variation of objective sleepiness in normal subjects” 5th
Int Cong Sleep Research 1987 (149).
21) Mason R “Modafinil, the ultimate
stimulant?” Anti-Aging Bulletin, Volume 3 Issue 3, November 1997, International
Anti-Aging Systems.
