Why is it that one person only needs a couple of cups of coffee per day, while another can barely make it to the afternoon without drinking four or five?
The answer is tolerance.
By drinking half a dozen cups each day, the second person’s body gets used to caffeine. Drinking coffee becomes much less effective, and they now need a lot more of it to get the same effect.
Tolerance can also happen with drugs and medication, though not necessarily all of them. It all boils down to their mechanism of action.
So, is modafinil one of those substances?
And if there is such a thing as modafinil tolerance, can you do something about it, or even avoid it in the first place? Read on and find out.
TABLE OF CONTENTS
What is Tolerance?
Before talking modafinil specifics, it’s important to understand what exactly tolerance is. There are different types of it and, depending on which you’re experiencing, you may need to take different actions.
Simply put, tolerance is when a substance becomes less effective over time. The most common cause of it is habitual use.
When it happens, to keep a substance’s effect levels constant, more and more of it needs to be taken.
Tolerance is frequent with opioids (codeine, heroin, morphine, etc.), antidepressants, and benzodiazepines. But, it can also easily develop with alcohol, caffeine, and nicotine.
In many cases, becoming tolerant to a drug is a significant problem. Think of someone suffering from chronic pain and no longer feeling the effects of pain relievers.
On the flip side, sometimes, tolerance can be a good thing.
It is how you can, for example, reduce allergies. By continually taking small doses of a problematic allergen, your body gets used to and stops reacting to it.
Obviously, when it comes to modafinil use, the former is the case. Tolerance is bad and will make it seem like the drug is not working.
Good News About Modafinil Tolerance
When you use a substance recreationally – not habitually or out of necessity – tolerance is a lot easier to manage. Using modafinil off-label as a cognitive enhancer or a study aid falls into that category.
In other words, modafinil tolerance – if such a thing exists (more on this shortly) – is easily avoidable and, if it does occur, is also easily reversible.
Types of Drug Tolerance
There are three primary types of drug tolerance.
Pharmacodynamic (Desensitization) Tolerance
This type of tolerance takes place at a cellular level and involves chemical structures known as receptors. The receptors are what respond to the presence of a given substance in your system.
In the case of pharmacodynamic tolerance, when there is too much of a substance, either the receptors become desensitized to it, or their numbers drop.
It’s the equivalent of a call center having too many outside lines for the staff to handle. Calls will get ignored, or management will reduce the number of external lines so that the work load becomes manageable.
The result of pharmacodynamic tolerance is that your response to a drug plateaus – no matter how much more you put it (usually at the risk of increasing side-effects), you stop seeing additional effects.
Pharmacokinetic (Metabolic) Tolerance
Pharmacokinetic tolerance has to do with your metabolism. It occurs when a reduced amount of a substance, like modafinil, reaches whatever system in your body it affects.
This type of tolerance most often involves an increase in the enzymes responsible for metabolizing the substance – it is processed quicker, and less of it gets to its ultimate destination.
A good example of this is a person who consumes large amounts of alcohol.
When someone drinks a lot and does so regularly over a long time, the amount of the liver enzyme responsible for breaking it down goes up (1). Progressively, they will need to consume more and more alcohol to reach the same level of drunkenness.
As an aside, using modafinil can increase alcohol tolerance, so, ideally, avoid taking the two at the same time.
Behavioral tolerance occurs with psychoactive drugs. Stimulants are classified as psychoactive substances, and modafinil is a stimulant.
You can think of behavioral tolerance as your body filtering specific effects brought on by a drug. Methamphetamine users, for example, learn to tolerate and effectively ignore the increased motor activity resulting from the substance’s use.
Can Modafinil Cause Tolerance?
The next thing to figure out is whether modafinil can cause any of the three types of tolerance discussed above.
And that, unfortunately, is a difficult question to answer. Some evidence suggests modafinil tolerance is real. Other evidence says the opposite.
When you look deeper into modafinil’s mechanism of action, it’s fair to conclude that not only can you develop a tolerance to it, but that modafinil may also be addictive.
Indeed, modafinil affects the same dopamine receptors as cocaine (2), albeit in a slightly different way.
Cocaine is both a highly addictive drug and one you can develop tolerance to. In fact, studies have shown that a level of tolerance can happen after only one dose of it (3).
Both modafinil and cocaine increase the level of dopamine in your system (4). It is, therefore, no stretch to say that because cocaine is addictive, and you can develop a tolerance to it, the same is true for modafinil.
There is also much anecdotal evidence suggesting tolerance to modafinil is real.
And a New Yorker article on the world of neuro-enhancing drugs mentions the case of a someone who took so much modafinil that it, eventually, stopped working for him.
Research Supporting No Tolerance
On the flip side, a study that tracked 105 modafinil using patients concluded that no significant dose increases of the drug were needed over the two-month period during which the patients were observed (7).
In other words, long term use of modafinil did not reduce its effectiveness. So, no tolerance.
In fact, the same study found that several individuals were actually taking lower dosages by the end of two months while still benefiting from modafinil in the same way. Not only does that indicate no tolerance, but quite the opposite.
Other research supports that theory too (8).
Ways to Manage Modafinil Tolerance
If you think you’re experiencing tolerance to modafinil, there are several things you can do to avoid or to manage it.
Use High-Quality Modafinil
If the quality of the product you’re taking is questionable, that alone could be the reason why it feels like you’ve developed modafinil tolerance.
Sometimes – especially if you buy your modafinil on the internet – you can end up with a batch that simply doesn’t work. What you have been sent could, for example, be expired, or the compound could be inactive.
In either case, the modafinil won’t do much, even at an increased dose. Sounds a lot like drug tolerance, doesn’t it?
Only buy modafinil from trusted sellers – ones that have been around for years and have, over time, built up a good reputation with the online community.
Prevent Desensitization Tolerance
It usually takes quite a while to develop desensitization tolerance to drugs. The best way to avoid it in the case of modafinil is to limit its use – only take it when needed.
A good rule of thumb is not to use modafinil more than four days per week and, ideally, limit it to as few as two days. Try not to take it on back-to-back days either.
This is a process known as modafinil cycling.
Even if you follow the above guidelines, but have been taking the drug for a few months, take a break.
Two weeks without modafinil should give your body plenty of time to reset its tolerance levels and return the drug’s effectiveness to what it once was. For some people, even just one week may be enough.
You can also consider cycling modafinil with another similar smart drug to maintain the overall effect but avoid building up a tolerance.
Finally, avoid taking more than 200 mg of modafinil in a single dose. While 400 mg is, in theory, the maximum recommended daily amount for modafinil, going that high is rarely necessary and only increases the odds of running into side-effects.
Prevent Metabolic Tolerance
The best way to go about avoiding metabolic tolerance to modafinil is first to understand which enzymes your body uses to break it down, and then, how to inhibit them.
The first part is easy. A lot of research goes into all drugs before they’re approved, and information like how the body metabolizes them is widely available.
In the case of modafinil, the enzymes CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4/5 are primarily responsible for metabolization (9), with CYP2C19 being the key player.
The longer you continually use modafinil, the higher the level of CYP2C19. The higher that enzyme’s level, the quicker the drug is metabolized, and the less effective it becomes.
There are several herbal compounds which inhibit CYP2C19:
- Bacopa monnieri (10)
- Berberis vulgaris (Barberry) (11)
- Eschscholzia californica (California Poppy) (12)
- Vitex agnus-castus (Chaste Tree) (13)
All four are available as over the counter supplements.
Grapefruit juice is another well-known and often used inhibitor of enzymes responsible for the breakdown of modafinil (14).
If you decide to use grapefruit juice, however, for best results, be sure to squeeze your own versus buying a pre-packaged product. Avoid juice made from concentrate especially.
Don’t Mix Modafinil With Other Drugs or Stimulants
One other easy thing to do when trying to avoid or manage modafinil tolerance is to not mix it with other smart drugs or stimulants.
While some advanced nootropic users may stack modafinil with other compounds, it is often not necessary. And indeed, if you go back to just modafinil after using it as part of a stack, it may seem not as effective, making it feel like you’ve developed a tolerance to it.
The same applies to stimulants. The only such substance people sometimes mix modafinil with is caffeine – specifically coffee. Avoid everything else.
There are some potential synergistic effects than can be achieved with the caffeine and modafinil combo, but it’s also easy to overdo. Your body could end up in a state of imbalance, which, theoretically, can lead to something resembling tolerance.
Before you even consider going down the coffee and modafinil mixing path, have a clear understanding of what you’re doing.
Ultimately, it’s not clear whether modafinil tolerance is real. Some research and plenty of anecdotal reports suggest it does exist. But, other research has shown contradictory results.
The best thing you can do to avoid developing tolerance to modafinil – and indeed, other drugs – is to cycle it. Take it only when you need to and give your body plenty of breaks in between.
If there is a time where you need to take modafinil daily, consider taking select natural herb supplements or drinking grapefruit juice. Doing so will prevent your liver from metabolizing the drug’s active ingredients too quickly.
And, above all, always make sure you’re buying quality modafinil. A subpar product will not be nearly as effective and make it seem like you’ve developed a tolerance when, in reality, that is not at all what’s happening.
- Päivikki I Alatalo, et al. Effect of moderate alcohol consumption on liver enzymes increases with increasing body mass index. The American Journal of Clinical Nutrition. Volume 88, Issue 4, October 2008, Pages 1097–1103.
- Dackis CA, et al. Modafinil and cocaine: a double-blind, placebo-controlled drug interaction study. Drug Alcohol Depend. 2003 May 1; 70(1): 29-37.
- Mendelson JH, et al. Cocaine tolerance: behavioral, cardiovascular, and neuroendocrine function in men. Neuropsychopharmacology. 1998 Apr; 18(4): 263-71.
- Nora D Volkow, et al. Effects of Modafinil on Dopamine and Dopamine Transporters in the Male Human Brain: Clinical Implications. JAMA. 2009 Mar 18; 301(11): 1148–1154.
- u/howardroark16. Modafinil tolerance Retrieved March 6, 2019, from https://www.reddit.com/r/afinil/comments/2ffwmj/modafinil_tolerance/.
- u/jyot5. Anyone succeeded in reversing Modafinil tolerance, specifically its nootropic effects? Retrieved March 6, 2019, from https://www.reddit.com/r/afinil/comments/8bp0kt/anyone_succeeded_in_reversing_modafinil_tolerance/.
- Nasr S, Wendt B, Steiner K. Absence of mood switch with and tolerance to modafinil: a replication study from a large private practice. J Affect Disord. 2006 Oct; 95(1-3): 111-4.
- Mitler MM, et al. Long-term efficacy and safety of modafinil (PROVIGIL((R))) for the treatment of excessive daytime sleepiness associated with narcolepsy. Sleep Med. 2000 Jul 1; 1(3): 231-243.
- Robertson P, et al. In vitro inhibition and induction of human hepatic cytochrome P450 enzymes by modafinil. Drug Metab Dispos. 2000 Jun; 28(6): 664-71.
- Ramasamy S, Kiew LV, Chung LY. Inhibition of human cytochrome P450 enzymes by Bacopa monnieri standardized extract and constituents. Molecules. 2014 Feb 24; 19(2): 2588-601.
- Guo Y, et al. Repeated administration of berberine inhibits cytochromes P450 in humans. Eur J Clin Pharmacol. 2012 Feb; 68(2): 213-7.
- Manda VK, et al. Modulation of CYPs, P-gp, and PXR by Eschscholzia californica (California Poppy) and Its Alkaloids. Planta Med. 2016 Apr; 82(6): 551-8.
- Ho SH, et al. The effects of commercial preparations of herbal supplements commonly used by women on the biotransformation of fluorogenic substrates by human cytochromes P450. Phytother Res. 2011 Jul; 25(7): 983-9.
- u/koroshm. Grapefruit juice + Modafinil? Retrieved December 13, 2019, from https://www.reddit.com/r/afinil/comments/2j4kww/grapefruit_juice_modafinil/.