Modafinil Tolerance | 7 Quick Tips to Avoid It

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Modafinil Tolerance

If you’ve recently used Modafinil but did not achieve the promised cognitive benefits, you may have developed: Modafinil tolerance.

A common reason for developing a tolerance to Modafinil is repeated daily use over a given time period (+14 days), which is a common trap many Modafinil users fall into.

For this reason, it is imperative to find the perfect setup for Modafinil cycling and dosing. Doing so will prevent the cognition-enhancing effects of Modafinil from wearing off.

Additionally, there are numerous factors that lead to the nootropic effects of Modafinil being absent after taking a standard 100-200mg dose.

This detailed guide will help you do two things: (1) Prevent Modafinil tolerance, and (2) combat any tolerance to Modafinil that may arise with frequent use.

You can choose to read this in-depth article from start to finish, or simply click on a section pertaining to your specific situation.

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This is not legal or medical advice. This article was strictly created for your entertainment. Please consult with your primary care physician or a medical professional with close working knowledge of your health -- before consuming pharmaceutical drugs or nootropics, like Modafinil. Please read my disclaimer.

What is Modafinil?

Before we dive too deep into the subject of Modafinil tolerance, let’s take a small step back and talk about what Modafinil is.

Modafinil is a prescription-only pharmaceutical drug that is approved for the treatment of narcolepsy, shift work sleep disorder, and obstructive sleep apnea. If you were to pick it up from the pharmacy, you would see it labeled as its brand name “Provigil.”

The common thread within all three conditions mentioned above is excessive daytime sleepiness, which Modafinil addresses by enhancing wakefulness.

This is the defining characteristic of Modafinil and explains why it is so popular for healthy adults seeking cognitive enhancement. Long before it developed its infamous reputation in the smart drug world, researchers were already using it to treat the fatigue present in medical conditions such as multiple sclerosis [1].

Biohackers and nootropic enthusiasts were curious to see if Modafinil’s fatigue-reducing and wakefulness-promoting properties would be equally present in healthy adults without any sleep deprivation problems.

In other words, is it possible that heightened focus could be an unofficial off-label use of the prescription drug?

Could Modafinil be the “magic pill” that enhances cognition, increases productive output, and grant any user the ability to work all night long?

When you consider the surging rise in its off-label over the past few years, the answer speaks for itself [2]:

“The number of patients receiving modafinil increased almost 10-fold during the study period, from 57,768 in 2002 to 555,691 in 2009. On-label use increased by less than 3-fold, whereas off-label use increased more than 15-fold.

Across all years, 89% of patients prescribed modafinil did not have an on-label diagnosis, and patients with depression and multiple sclerosis accounted for 18% and 12%, respectively, of all modafinil prescriptions.”

So what we have here is a drug that can supposedly “supercharge” the mind into a heightened state of peak mental performance.

But if we could take it all the time with zero repercussions, we wouldn’t have to worry about solving the problem of Provigil tolerance. Or the potential side effects associated with taking Modafinil.

Modafinil Tolerance

Modafinil Side Effects and Safety Concerns

Fortunately, Modafinil appears to be a relatively safe drug that is well-tolerated and has few side effects.

The side effects of Modafinil most frequently reported include insomnia, headaches, nausea, and dry mouth. Experienced test subjects conclusively agree that they are most common in first-time users. If they do not disappear after a few doses of Modafinil, lowering the daily dose usually takes care of them.

However, there are two rare yet serious adverse events you should know about [3]:

“Modafinil is associated with a very rare, life-threatening rash called Stevens-Johnson Syndrome (SJS). Many medications are associated with this rash; in the case of modafinil it is so rare that we don’t know if the medication causes it.

Modafinil contains a warning that it may reduce the effectiveness of hormonal contraceptives, lasting for a month after stopping it.”

The majority of side effects can be avoided if you simply use Modafinil responsibly and follow the directions on the label. This means taking a standard dose of 100-200 mg of Modafinil a day, for no more than 10-14 days in a row.

It’s no wonder that Modafinil was heralded as “the world’s first safe ‘smart drug'” back in 2015 [4]!

Do You Develop a Tolerance to Modafinil?

You might be asking yourself the following question: Why do you develop a tolerance to Modafinil in the first place and how can you avoid it?

The best way to answer this question is by explaining the general concept of drug tolerance [5]:

“Tolerance is a person’s diminished response to a drug, which occurs when the drug is used repeatedly and the body adapts to the continued presence of the drug…larger and larger doses must be taken to produce the same effect.

Usually, tolerance develops because metabolism of the drug speeds up (often because the liver enzymes involved in metabolizing drugs become more active) and because the number of sites (cell receptors) that the drug attaches to or the strength of the bond (affinity) between the receptor and drug decreases.”

Have you ever found yourself in a situation where you needed to drink three cups of coffee to feel like you did when you drank coffee for the very first time? That’s drug tolerance in action.

To make matters worse, the development of drug tolerance is independent of time. This is why everyone’s response to alcohol is unique [6]:

“The onset of tolerance may occur within minutes, during a single exposure to alcohol (i.e., acute tolerance), or over longer timeframes and with prolonged exposure to alcohol (i.e., rapid or chronic tolerance)”

As you can see, drug tolerance can become a major problem unless it is treated immediately with the right solution.

But the good news is this: Drug tolerance is 100% reversible.

One surefire way to eliminate Modafinil tolerance — and drug tolerance for select medications — is to go on a “drug holiday.” Otherwise known as a “medication holiday”, you abstain from taking the drug for a pre-determined period of time.

A drug holiday intends to achieve the following outcomes [7]:

  • Allow a drug to regain its original effectiveness via “resetting” your sensitivity to it
  • Lower your tolerance for a drug, eliminating the need to take larger doses for the same effect
  • Reduce the severity and frequency of side effects associated with the drug

With an understanding of how drug tolerance works, let’s see what the scientific research has to say about developing a tolerance for Modafinil.

Modafinil and Coffee

Understanding Modafinil Tolerance

The overwhelming majority of studies published to date have not established a clear relationship between Modafinil and drug tolerance.

As early as 2001, researchers already knew that Modafinil did not possess any addictive potential. And even if it did, the behavior changes would be distinctive from changes induced by central nervous system (CNS) stimulants [8].

Many more studies published since that time confirm an absence of evidence regarding Modafinil tolerance [9]:

“There is no evidence that tolerance develops to modafinil or that the drug impairs sleep quality (if taken in the morning). It has a number of advantages including once-daily dosing, low abuse potential, and the fact that it is not a schedule II medication.”

For readers who are concerned about one’s tolerance to Modafinil developing over time, clinical trials have demonstrated that patients generally do not develop Modafinil tolerance over 40 weeks of treatment [10].

Surprisingly enough, most Modafinil users are able to moderate their intake without developing any kind of tolerance [11]:

“There was also no significant difference in final modafinil dosage between patients who had a positive history of chemical abuse/dependence (290 mg/day) and those who did not (258 mg/day).”

“Adult affective disorder patients, whether unipolar or bipolar, can use modafinil to relieve symptoms of depression, including fatigue and sleepiness, without risking a switch in their mood or developing tolerance or abuse of this medication.”

In the few cases where Modafinil tolerance was present, it was usually in individuals who had a history of substance addiction. They ended up taking up to 1,000 mg of Modafinil a day – if not more – and those doses are not representative of how nootropics enthusiasts will use Modafinil [12].

Which leads to an important distinction that we must make in quoting these studies: Modafinil was not used as a cognition-enhancing smart drug in any of these studies.

Put another way, Modafinil tolerance could potentially be a real issue for individuals relying on the smart drug, day in and day out.

There are several forum posts and articles written by test subjects who have noticed themselves needing larger doses of Modafinil to feel the same cognitive effect [13].

So while Modafinil tolerance is not proven in scientific circles, it is indeed a real phenomenon in the unregulated world of nootropics.

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Types of Tolerance

Without adding more complexity to the discussion, there are three types of drug tolerance you should know about [14]:

  • Pharmacokinetic clearance: The amount of drug reaching its target site is reduced, as more of the drug is getting cleared by the body
  • Pharmacodynamic tolerance: Either the number of receptors available for the drug to bind to are fewer in number, or they function in a way where they do not respond to the drug
  • Behavioral tolerance: The individual learns how to compensate for a given drug’s effect, which in turn diminishes said effect.

All three of these mechanisms are simultaneously taking place when Modafinil tolerance develops. One mechanism may be more prevalent than the others, depending on the individual and their use of Modafinil.

In any case, the heightened focus and energy that a Modafinil user experiences are not as strong as it was compared to the dose they took for the very first time. All of the benefits just don’t seem to exist, or they exist to a much lesser degree.

But as we mentioned earlier, drug tolerance is reversible. Your tolerance to Modafinil can be fixed with a few simple tips outlined in the next section.

How to Control and Minimize Modafinil Tolerance | 7 Quick Tips

If you’re considering taking Modafinil or believe you may be developing a tolerance to the smart drug, then here are a few tips you can use.

They are not ranked in any particular order, so please use your best judgment in deciding which of these tips may be most relevant for you. We are assuming that you are using high-quality Modafinil sourced from a legitimate vendor, as impure and contaminated samples may lead to unwanted outcomes.

Don’t Develop Any Tolerance

While this is much easier said than done, a preventative and proactive approach is key to ensuring you do not develop any kind of tolerance to Modafinil.

This will not be relevant for people who are brand new to using Modafinil as they do not have a “Modafinil tolerance” in the first place.

If you are in this situation right now, please be mindful of the subsequent tips being shared. Many research subjects have found them to be effective in preventing Modafinil tolerance.

Limit Usage

As with any other nootropic in existence, the key to successfully take Modafinil without developing tolerance is to practice moderation.

It goes without saying that taking excessively high dosages of Modafinil for several days and weeks in a row will develop a strong tolerance to the smart drug.

Here are some recommendations for using Modafinil responsibly:

  • Do not take Modafinil more than 4 times a week. 1-2 days within the week works best for most people
  • Your daily dosage should be 100-200 mg for best results. Never take more than 200 mg in a single dose.

Following the two rules above will ensure you don’t have too many tolerance issues with Modafinil.

Never On Back-to-Back Days

Extending on the recommendations above, avoid taking the drug on consecutive days. If you’re taking Modafinil 4 days a week, you want to space your doses out by at least day.

So if you take Modafinil on a Monday, you should wait until Wednesday to take it again.

By not taking Modafinil on back-to-back days, you’ll ensure the drug’s effects remain strong.

The people who develop major issues with tolerance and smart drugs end up abusing them. This means taking the same nootropic every single day at abnormally high dosages, then increasing the dose even further when the drug “stops working.”

Take Breaks

If you’ve been using Modafinil 1-4 days a week for a few straight months, you will need to take a break from the smart drug.

Many research subjects who use nootropic 1-2 times a week for around two straight months will completely stop taking Modafinil for two full weeks [15]:

“…it takes about 3 – 7 days for the tolerance to be reduced to half and 1 – 2 weeks to be back at baseline (in the absence of further consumption).

Modafinil may present a cross-tolerance with all benzhydryl nootropics, meaning that after the consumption of modafinil, all related eugeroic compounds such as armodafinil and adrafinil will display a reduced effect.”

By not consuming the nootropic for two straight weeks, your body will automatically reset its Modafinil tolerance levels. Coming off a break from Modafinil, users typically feel the smart drug’s strength is restored when they start using it again.

Usually, a 1-4 week break is sufficient to reset one’s tolerance to Modafinil.

Some users personally prefer a “two week on, two week off” cycle where Modafinil is used in cycles. Such an approach allows one to experience the maximum cognitive benefits while preventing themselves from developing a tolerance to Modafinil.

Alternatively, you may decide to reserve Modafinil use for emergency events (all-nighters, overnight work shift, tight deadlines, etc.).

Cycle Smart Drugs

Despite Modafinil’s reputation as the only nootropic one might need, experienced smart drug users will cycle the use of smart drugs.

This allows them to avoid becoming 100% reliant on Modafinil, or any smart drug for that matter.

There are many great Modafinil alternatives for users who are seeking a different kind of cognitive boost.

NOTE: If you decide to use Armodafinil (a.k.a. Nuvigil) instead of Modafinil, know that Armodafinil tolerance is also possible. The tips in this guide are equally effective for eliminating any Nuvigil tolerance you may have.

Limit Other Drugs & Stimulants

In addition to regularly rotating your nootropics, it is highly advisable to avoid using other smart drugs with Modafinil on the same day.

This means if you are taking Modafinil on one day, you should not be taking something such as Mind Lab Pro.

The same rule applies to stimulants. Combined with the wakefulness-promoting properties of Modafinil, the increase in energy levels may be too overwhelming for some users.

Other users have had mixed results using Modafinil and fresh organic coffee (1-2 cups maximum) on the same day, but this is as far as our recommendations go.

Supplement with Magnesium

There is some experimental data suggesting that magnesium supplementation can lower one’s tolerance levels to addictive drugs [16]:

“Magnesium reduces the intensity of addiction to opiates and psychostimulants (cocaine, amphetamine, nicotine, and others).

It also decreases the auto-administration of cocaine and the relapse into cocaine and amphetamine intake, as well as reducing the experimental addiction to morphine, cocaine and other substances in animals.

…Apart from the action of magnesium ions during emerging addiction, administration of this cation after the appearance of withdrawal syndrome reduces the intensity of the clinical symptoms.”

If you’ve already developed issues with dosing and tolerance, then supplementing with magnesium and stopping usage may be your best bet to reset your tolerance to Modafinil.

There are many ways to go about consuming magnesium, and it appears that magnesium oil may be the easiest form of administration for most individuals.

BONUS TIP: Be Mindful Of What Enzymes Are Affected By Modafinil

Modafinil is metabolized in the liver by the CYP3A4 enzyme, but it apparently affects other enzymes during the metabolization process [17]:

“…modafinil has the potential to inhibit CYP2C19, suppress CYP2C9, and induce CYP3A4, CYP2B6, and CYP1A2.

Because modafinil and modafinil sulfone are reversible inhibitors of the drug-metabolizing enzyme CYP2C19, co-administration of modafinil with drugs such as diazepam, phenytoin and propranolol, which are largely eliminated via that pathway, may increase the circulating levels of those compounds.”

When an enzyme is inhibited, its metabolic efficiency goes down. If a drug is normally metabolized by said enzyme, more of the prodrug (usually the inactive form of the drug) and the active form of the drug will be present. Thus, an individual will feel “less” of the drug’s effect.

Vice versa, an induced enzyme is more metabolically efficient. More of the active drug will be present in your body and you will feel “more” of the drug’s effect.

Check the product information with any additional supplements or medications you are taking to see if Modafinil’s enzyme-affecting properties will affect their distribution in your body.

To demonstrate this using an example, grapefruit is a powerful inhibitor of CYP3A4. Since Modafinil itself is the active drug, less of it is broken down and you will experience a more powerful boost in cognition.

Modafinil Tolerance | The Verdict

Modafinil tolerance may not be commonly reported in the scientific literature, yet it is a common occurrence amongst people who use the drug.

But a developed tolerance to Modafinil can be reversed by using a proper dose and taking it infrequently.

The tips discussed in this article will help you decide what the best course of action should be for your circumstances.

Whether you are new to using Modafinil or have extensive experience with the smart drug, preventing tolerance is key to maximizing its benefits.

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References

  1. Shangyan H, Kuiqing L, Yumin X, Jie C, Weixiong L. Meta-analysis of the efficacy of modafinil versus placebo in the treatment of multiple sclerosis fatigue. Mult Scler Relat Disord. 2018;19:85‐89. doi:10.1016/j.msard.2017.10.011
  2. Peñaloza RA, Sarkar U, Claman DM, Omachi TA. Trends in on-label and off-label modafinil use in a nationally representative sample. JAMA Intern Med. 2013;173(8):704‐706. doi:10.1001/jamainternmed.2013.2807
  3. Modafinil. Retrieved May 18, 2020. moodtreatmentcenter.com
  4. Cephalon’s Narcolepsy Drug Modafinil May Be World’s First Safe ‘Smart Drug,’ Study Says. Retrieved May 19, 2020. biospace.com
  5. Tolerance and Resistance to Drugs. Retrieved May 20, 2020. merckmanuals.com
  6. Pietrzykowski AZ, Treistman SN. The molecular basis of tolerance. Alcohol Res Health. 2008;31(4):298‐309.
  7. Drug Holiday Risks and Benefits. Retrieved May 20, 2020. verywellhealth.com
  8. Deroche-Gamonet V, Darnaudéry M, Bruins-Slot L, Piat F, Le Moal M, Piazza PV. Study of the addictive potential of modafinil in naive and cocaine-experienced rats. Psychopharmacology (Berl). 2002;161(4):387‐395. doi:10.1007/s00213-002-1080-8
  9. Berry RB. Chapter 24 – Hypersomnias of Central Origin. Fundamentals of Sleep Science. 2012:451-479. doi:10.1016/B978-1-4377-0326-9.00024-5
  10. Mitler MM, Harsh J, Hirshkowitz M, Guilleminault C. Long-term efficacy and safety of modafinil (PROVIGIL((R))) for the treatment of excessive daytime sleepiness associated with narcolepsy. Sleep Med. 2000;1(3):231‐243. doi:10.1016/s1389-9457(00)00031-9
  11. 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;95(1-3):111‐114. doi:10.1016/j.jad.2006.01.010
  12. Hashemian SM, Farhadi T. A review on modafinil: the characteristics, function, and use in critical care. J Drug Assess. 2020;9(1):82‐86. doi:10.1080/21556660.2020.1745209
  13. Modafinil Tolerance: Possible Modes of Action. Retrieved May 22, 2020. r/Nootropics
  14. Mechanisms of tolerance and tachyphylaxis. Retrieved May 21, 2020. derangedphysiology.com
  15. Modafinil. Retrieved May 22, 2020. psychonautwiki.org
  16. magnesium in drug abuse and addiction. Retrieved May 18, 2020. ncbi.nlm.nih.gov
  17. PROVIGIL® (modafinil) Tablets [C-IV]. Retrieved May 21, 2020. accessdata.fda.gov

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