I've recently started taking Modafinil for its nootropic and eugeroic effects; and was interested in anecdotal reports that long-term use leads to tolerance and decrease, or cessation of effectiveness.

A Google search for "modafinil tolerance" produces many dozens of blog posts, forum comments etc., of people reporting building tolerance or wondering how to reduce the effects of tolerance.

However, searches of PubMed or Google Scholar do not produce any substantive results on the matter. I have been unable to find any publications mentioning tolerance, except to say it is "well tolerated" toxicologically.

As a practical matter, I am interested in the following question:

Is this tolerance effect real? If so, under what conditions does it appear and can it be mitigated by appropriate dosing; supplementation with other drugs; or otherwise?

At this point, I would like to mention that I do not have a background in pharmacology, only that I have spent a few hours researching and synthesising the literature.

I hypothesise several explanations for this discrepancy:

1. The anecdotal reports are incorrect, whether due to psychosomatic effects or just unreliable, subjective observers.

2. The anecdotal reports refer to different dosing regimes, e.g higher doses with specific effects that build tolerance.

3. Tolerance is only built to certain effects (nootropic) which were not examined in clinical studies as they are irrelevant to its prescribed indication (narcolepsy, SAD, work-shift disorder, etc.)

4. Observed tolerance is due to interaction with other drugs in the nootropic "stack"

5. Tolerance effects have been missed in clinical studies, or were too minor to mention

6. Tolerance is due to sleep deprivation with Modafinil being used as a replacement for sleep

I found two major reviews of Modafinil in the literature:

A Systematic Review of Modafinil - Journal of Clinical Psychiatry (2006)

This review is aimed at clinical psychiatrists and does not make any mention of long-term tolerance. If tolerance were mentioned in the literature, it should be here due to its relevance to a prescribing psychiatrist.

Modafinil: A Review of Neurochemical Actions and Effects on Cognition; Minzenberg, Carter - Neuropsychopharmacology (2008)

This is a comprehensive review, from which I have summarised a few relevant points:

• "Major pharmacokinetic parameters are independent of doses in the range 200-600 mg/day"

• "Elimination occurs primarily in the liver, via amide hydrolysis and a lesser component by cytochrome P450 mediated oxidation"

• "Exerts a [small] but concentration-dependent induction of CYP 1A2, 2B6 and 3A4"

• CYP3A4 induction produces a significant interaction with ehinylestradiol and triazolam (Robertson et al, 2002)

• Does not affect the spontaneous release of dopamine from mouse striatal synaptosomes

• DAT knockout mice do not experience waking effect

• "...have found modafinil to have long-term efficacy for sleepiness extending for as long as 136 weeks, and to be well-tolerated, with no evidence of significant adverse events or abuse (Besset et al, 1996; Hirshkowitz et al, 2006; Mitler et al, 2000)"

• Directly binds to dopamine and noradrenaline transporters with "modest potency"

• Produces significantly elevated extracellular dopamine, noradrenaline, seretonin, hyaluronan, glutamate and decreased GABA

• Elevated Dopamine, Noradrenaline appear to be primary, other effects are hypothesised to be secondary.

• Does not stimulate the release of dopamine from synaptic vesicles or turnover in the caudate nucleus

Long-term efficacy and safety of modafinil (PROVIGIL®) for the treatment of excessive daytime sleepiness associated with narcolepsy (2000)

This is the Mitler et al cited in Minzenberg et al, 2008. The protocol varied but the majority of patients received a dosage of 400 mg/day and showed a significant improvement at week 2 and remained at that level through week 40.

Discussion: Pharmacokinetic Tolerance

Tolerance could be caused by an increase in elimination rate after long-term use. This would produce a shorter half-life and increase the first-pass effect, reducing bioavailability.

Apparently, Modafinil is metabolised on the P450 path by CYP3A4. Modafinil also induces CYP3A4, meaning that it increases the speed of its own metabolism. This could potentially cause it to be eliminated more quickly after long-term use. The pronounced interaction Modafinil has with the oral contraceptives ehinylestradiol and triazolam through CYP3A4 induction (Robertson et al, 2002) lends credibility to this. Of note, too, is that Robertson et al, 2002 discovered a stronger induction in intestinal than hepatic CYP3A4.

On the other hand, Minzenberg et al describes both the metabolism through the P450 path and the induction of CYP3A4 as relatively minor effects, making it unlikely they would dominate amide hydrolysis. Also, any pharmacokinetic tolerance mechanism would reduce the effectiveness of all of Modafinil's effects and should have been picked up in clinical studies.

Overall, a metabolism/induction feedback of CYP3A4 seems possible, in principle; but would imply a fairly serious omission in the literature. If this is the mechanism, tolerance could be reversed by supplementation with a CYP3A4 inhibitor such as bergamottin (grapefruit juice) or milk thistle. Alternatively, Robertson et al discovered a stronger induction in intestinal than hepatic CYP3A4. If sublingual bioavailability is sufficient, it could bypass both intestinal breakdown and the first-pass effect.

On a side note, apparently Modafinil is water insoluble and mostly lipid insoluble. I was unable to find any information on its sublingual bioavailability.

Discussion: Pharmacodynamic Tolerance

Despite its dopaminergic effects, it is extremely well established that Modafinil does not exhibit the addictiveness of other dopaminergic drugs (e.g amphetamine). Also dopaminergic tolerance should affect Modafinil's eugeroic effects, which should have been picked up in clinical studies. Dopaminergic tolerance (e.g dopamine receptor down regulation) is an unlikely tolerance mechanism.

Beyond this, the pharmacology of Modafinil is complex and not entirely understood. However, it is possible some mechanisms responsible for its nootropic effects develop tolerance and were not discovered in clinical studies.

If you have any insignt into possible tolerance mechanisms in GABA/glutamate, gap junctions etc., I would be interested.

Conclusion

Above, I proposed a number of explainations for the discrepancy between anecdotal reports and the literature.

1. It remains possible the anecdotal reports of tolerance are incorrect or inaccurate. Though the number of reports (Google it for yourself!) makes this is unlikely.

2. Doses typical for nootropic effects (50-200mg/day) are at or below those observed in clinical studies to be well-tolerated for long periods of time.

3. Tolerance specific to nootropic effects remains a possibility. But anecdotal reports include a cessation of eugeroic effects.

4. I couldn't find any interactions that could explain the discrepancy.

5. Clinical studies missing the tolerance entirely remains a very real possibility, especially if only certain people develop tolerance. Modafinil wasn't clinically shown to universally cure narcolepsy etc., just that it had significant effects on most people that were stable after several weeks.

6. Sleep deprivation is a likely explanation. Many of the anecdotal reports concern people who have used Modafinil to go for long periods of time with little or no sleep.

The CYP3A4 feedback is the only substantive tolerance mechanism I have found, however it is only hypothetical. Several people have presented milk thistle as a cure for tolerance. In general, it should increase the half-life somewhat, but it is unknown if it would otherwise reduce tolerance. This should be straightforward to experimentally test.

If you have any suggestions, hypotheses, anecdotal observations or insights into Modafinil's pharmacology, please tell me. I'm interested both for academic and pragmatic reasons.

Edit: I misspelled eugeroic