Provigil: Smart Drug

Rating: B. Great nootropic but limited by reports of rare Stevens-Johnson Syndrome (skin peeling allergic reaction) to persons with narcolepsy.

What is modafinil?

Modafinil is an oral wakefulness-enhancing medication used in the treatment of the following disorders:

• Narcolepsy
• Obstructive sleep apnea
• Shift work sleep disorder

Modafinil is considered a eugeroic, which is a substance that enhances wakefulness. In Europe, it is mandated only for the treatment of sleepiness associated with narcolepsy, due to post-marketing reports of serious adverse skin reactions to the drug.

Several governments have looked into using modafinil as a resource for military missions which may require long hours of wakefulness and performance under conditions of stress, fatigue, and sleep deprivation. These include long aviation, marine, and space missions.

History

Modafinil was developed in France at Lafon Laboratories in the 1970s. It is a derivative of adrafinil which was put on the market for narcolepsy in 1986. Adrafinil raised liver enzymes and modafinil proved to have less effect on the liver and so adrafinil was withdrawn but is still sold as a supplement in the US and other countries. In 1998, modafinil got the go-ahead from the FDA for narcolepsy. In 2003, it was approved for shift work sleep disorder (insomnia and excessive sleepiness during work hours in 3^rd shift workers) and also for sleep apnea and hypopnea (when the person gets low oxygen or stops breathing during sleep).

The right-handed r-enantiomer, armodafinil also called Nuvigil came on the market in 2007.

Supplement companies sell several other forms including:

• CRL-40,940 or flmodafinil, a bisfluoro derivative.
• CRL-40,941 or fladrafinil, a bis(p-fluoro) derivative of adrafinil.

Modafinil mechanism of action

Modafinil works as a mild dopamine reuptake inhibitor. This means it makes more dopamine available in the synapse of neurons which enhances dopaminergic neurotransmission. This dopamine stimulation increases the expression of orexin neuropeptides and also increases histaminergic neurotransmission, increasing alertness, arousal, and focus.

Modafinil was found to function as a dopamine transporter blocker. It had effects on various monoamines, raising dopamine, norepinephrine, and serotonin in several areas of the brain, including raising dopamine in the nucleus accumbens, a state often associated with pleasure and reinforcement, but also arousal.

Arousal and wakefulness produced by modafinil are incompletely accounted for by its dopaminergic effects. Some studies show that when the effect on dopamine is not present in modafinil analogs, wakefulness is still increased. It is hypothesized that this occurs via the release of histamine in the brain. In the body, histamine release is associated with an allergic reaction, but once in the brain, histamine increases alertness. This is why antihistamines cause drowsiness. There are reports that you can also use a regular dose of an antihistamine like Benadryl as an antidote to a panic attack caused by modafinil.

Modafinil also has anticonvulsant effects.

One of its metabolites, armodafinil (Nuvigil) has a strong effect as a dopamine 2 receptor partial agonist.

How does Provigil appear on a drug test?

Provigil is not currently often tested for on any drug tests and it is unlikely to show up as a false positive for amphetamines because it is not structurally similar to amphetamines.

Clinical experience and adverse reactions

The most frequently reported adverse reaction appears to be nausea, with 11 % in some studies experiencing this symptom. The stimulant effect can also cause nervousness. It manifests more as an internal nervousness than a physical type of nervousness with sweating and shaking. Anxiety is a frequent complaint and there can be panic attacks. Some participants reported dizziness. Less than 10 percent reported stomach and intestinal upset. There can be typical amphetamine-like side effects like sweating and tachycardia.

Rare but serious complications

The most serious reactions are rare but can be extremely catastrophic:

Stevens-Johnson Syndrome – This is a serious skin reaction that starts with flu-like symptoms. Days after these symptoms, the skin blisters and begins to peel, all over the body. This can be very painful and frightening. Mortality occurs in up to 5 % of those with 10 % or more of the body covered in blisters. Treatment is supportive, there is no direct treatment for the disease. The offending medication is most often withdrawn. Patients are generally treated as burn victims are treated.

Erythema Multiforme – This is another skin reaction. It consists of bumps or blisters on the skin which fills with puss. A mild form E. Multiforme minor consists of a limited rash symmetrical on the body. E. Multiforme major can be more serious. It may appear on less than 10 percent of the body. It usually resolves on its own and is not associated with significant mortality.

Toxic Epidermal Necrolysis – This is the more severe skin reaction. It can start with flu-like symptoms just like in Stevens-Johnson Syndrome and progress to the skin blistering and peeling. It also affects the eyes and mucous membranes. With SJS, the occurrence is only 1 to 2 persons per million each year. Being female increases risk. HIV positive status increases the risk of 1000 fold. There is a 25 to 30 % mortality rate. Survivors are often left with chronic health problems. Due to SJS and TEN, European health authorities have limited prescriptions of modafinil to treat sleepiness resulting from narcolepsy. This makes it unavailable for on-label prescribing for other causes of excessive daytime sleepiness.

Modafinil & other drugs: interactions

Modafinil induces CYP3A4 hepatic enzymes and therefore may interact with opioid medications and other substances metabolized by this enzyme. This can cause a drop in plasma levels of the interacting drugs. Opioids include hydrocodone, oxycodone, heroin, and fentanyl. This could cause symptoms of rapid withdrawal from the opioid.

It also induces p-glycoprotein, CYP1A2, CYP2B6, and it inhibits CYP2C9 and the CYP2C19 hepatic enzymes. It may interfere with drugs like digoxin by induction of p-glycoprotein. The half-life of an oral dose is about 12 hours.

Modafinil side effects long term and short-term

Short-term side effects:

• Headache
• Anxiety
• Insomnia

Serious side effects:

Stevens-Johnson Syndrome

Anaphylaxis

Abuse, dependence, withdrawal

Hallucination (amphetamine-like psychosis)

Contraindications:

Malignant hypertension

Left ventricular hypertrophy

Arrhythmia

The LD50 of modafinil is around 1250 mg/kg. Overdoses of 4.5 grams were not observed to produce life-threatening outcomes, though hyperadrenergic symptoms like shaking, sweating, confusion, stupor, and panic have been observed. We have not found verified cases of a fatal overdose of modafinil alone though they may exist. Fatal overdose is rare for modafinil.

Modafinil dosage

Modafinil is supplied in round white tablets as a prescription medication in the US. These tablets contain either 100 mg or 200 mg.

Recommended dosage: 200 mg in the morning.

Some users start at 100 mg to assess tolerance, then move up to 200 mg. Doses above 200 mg have not been found to confer an extra benefit and may increase the chances of side effects such as anxiety and insomnia. It’s not known if the medication is safe during pregnancy.

Provigil overdose and withdrawal signs and symptoms

If you take too much Provigil, you can experience symptoms of hyperadrenergic excess including:

• tremor
• sleep disturbance
• palpitations
• nervousness
• nausea
• irritability
• diarrhea
• confusion
• anxiety
• aggressiveness

Post-marketing reports suggest there may have been fatal overdoses associated with modafinil, other sources say there have been no verified overdose deaths. Overdose is managed symptomatically and there is no standard antidote for modafinil overdose.

Modafinil high and Modafinil as a Nootropic

Modafinil is a top nootropic. It was popularized early by biohackers like Dave Asprey (the Bulletproof Coffee Guy). The movie “Limitless” inspired a lot of biohackers in search of a drug like the fictional NZT which gave the user incredible brain power.  It conferred the ability to think far beyond other humans, to multitask, feel everything, and remember everything. Modafinil has been compared to NZT, the drug that powered Bradley Cooper’s character. Biohackers, students, Silicon Valley programmers and entrepreneurs, even stockbrokers looking for an edge have moved off the harder stuff, and even off stuff like Adderall, to try modafinil and see if it gives them an edge. Some love it, others don’t. In our experience, people tend to try it and move on from it. It’s worth noting that in studies, modafinil produced less alertness enhancement than caffeine or other stimulants like amphetamine and methylphenidate. However, it can also have fewer side effects and since the mechanism of action is different, it can be used where other stimulant drugs cannot be used. It is therefore useful even if it produces less wakefulness than the traditional stimulants.

Nootropic benefits:

• Boosted cognition
• Boosted intelligence
• Better executive functioning
• Strong Focus
• Improved Motivation
• Greater intensity
• Improved productivity
• Better task-switching ability
• Better multitasking ability
• Improved awareness in the senses
• Boosted mood
• Greater enjoyment of work
• Faster running in racing competitions
• Greater physical endurance
• Greater physical strength

At nootropic doses which are the same as medical doses or lower, you could get the same side effects as occurs in medical users, namely increase in anxiety, panic attacks, and insomnia, especially when first using the substance. Rare skin issues have affected some biohackers. Though Stevens-Johnson syndrome is rare, such reactions have affected a handful of biohackers, more than has been reported. If one began to have skin issues while using modafinil as a nootropic, it would be prudent to discontinue use and see a doctor. A skin reaction to the medication can develop even after years of continuous use. It can suddenly begin to cause a very dangerous reaction in the skin. Anecdotal accounts on social media document people who began to get these allergic reactions who finally discovered modafinil was the cause and discontinued use. They were able to recover but in the worst cases, there will be chronic skin health issues throughout life as a result.

Biohackers may use forms such as adrafinil, CRL-40,940 or flmodafinil, a bisfluoro derivative, or CRL-40,941 or fladrafinil, a bis(p-fluoro) derivative of adrafinil. These may require different dosing or be sold only as research chemicals.

FAQ about modafinil

Q: Modafinil and depression. Can modafinil be used to treat depression?
A:   A review in Depression and Anxiety, published in 2005 reviewed patients at a single clinic being treated for major depression with modafinil monotherapy or modafinil to augment their existing medication. These patients showed significant improvement on several depression rating scales (Price and Taylor).

Q:   Is there an interaction between alcohol and modafinil?
A:   Physicians urge patients not to use alcohol with modafinil. There have not been reports of any excessive interaction; however, alcohol might negate the effects of modafinil and cause sleepiness. Modafinil might also augment some of the effects of alcohol or increase alcohol tolerance which could lead to further disinhibition.

Q:  Modafinil for the treatment of patients with cocaine dependence: what do the studies say?
A:   Because modafinil is like a stimulant but with a different mode of action and lighter side effect profile than other stimulants, it is a great candidate for treating addiction to cocaine. A 2009 study published in Drug and Alcohol Dependence found that modafinil can reduce cocaine craving and increase the number of days where the patient did not use cocaine.
A review published in Current Drug Abuse Reviews in 2008 took a look at studies using modafinil to treat cocaine addiction and found that modafinil not only did not have negative interactions with cocaine but appeared to reduce some of the harmful cardiovascular effects that occur with cocaine use (Martinez-Raga, Knecht, and Cepeda).

Q:   Will modafinil show on a drug test?
A:   Modafinil is not typically tested for in a drug test, for example, for employment. It may be tested for in a test given to athletes. The World Anti-Doping Association banned modafinil use in athletes as it can provide an unfair advantage in focus, speed, and endurance.

Q:   Does it cause addiction?
A:   Addiction risk from modafinil is said to be comparatively low. It can have some mood-elevating effects which may be similar to the effects of other stimulants. In monkey studies, monkeys who had been taught to take cocaine would do the same with modafinil.

Studies have not found that any significant tolerance to the effects of modafinil develops.

Q:   Is Provigil withdrawal a frequent occurrence?
A: Provigil addiction and withdrawal is rare because it does not provide an acute, euphoric high like methamphetamine or cocaine, even if you raise the dose. However, it is possible to become addicted. There is a case report on pubmed.gov of a 44-year-old male who was a shift worker and who experienced excessive daytime sleepiness. He also had a schizoaffective disorder with hallucinations and had to take anti-psychotics. In order to stay awake, he obtained modafinil over the counter and started dosing 100 mg every few hours, increasing the dose until he was reaching 1200 mg per day. That is a heroic dose. However, he found that if he missed a dose, he would be unmotivated, anhedonic, tired, unable to sleep, lethargy, fatigue, trembling, and anxiety, which would resolve when he reduced (Krishnan and Chary).

Q:   How do you get over high dose modafinil abuse?
A:   In the case mentioned above, they tapered the patient off of modafinil by reducing his dose by 100 mg every few days. As he experienced depression during the taper, it was augmented with bupropion (Wellbutrin) and finally clonazepam upon which mood and energy improved.

Q:   Do you go cold turkey or decrease the dose gradually?
A:   The protocol used by the doctors in the case study was to reduce the dose gradually by 100 mg every 2 or 3 days. The patient appeared to respond well to this and the augmentation with bupropion and clonazepam.

Q:   Do you have to get professional therapy?
A:   If you become addicted to modafinil, talk to your doctor about it. He may recommend a taper or refer you to drug treatment. There is one case report in an 18-year-old female taking the starter dose of modafinil, 100 mg, who developed psychosis with paranoid delusions. The medication was withdrawn and the psychosis resolved within days.
Tip:  At the initiation of modafinil therapy, there can be an increased risk of side effects as the dosage is being stabilized. For this female, perhaps the starter dose was too high, so anyone who might try this medication should consider one’s size and how you react to medications. If you are sensitive, ask your doctor if you may want to start with half of the starter dose and work your way up.

Q:   How much does it cost?
A:   In the US, the price per month is about $34.20 in 2018, which makes it fairly affordable. It is often ordered online from various sites but this may not be legal in your jurisdiction so check your local laws.

The Buzz on Social Media:  What are they Saying about Modafinil?

Modafinil for ADHD

This guy has ADHD and claims modafinil changed his life. He can read books and focus on completing tasks as he had never been able to do before. This is a glowing report for the power of modafinil for some users.

“…more talkative…”

This is from a Reddit user as well. We include it because it summarizes the positive effects he picked up. It promotes wakefulness, makes him more talkative, suppresses appetite which can be useful for those of us who also do intermittent fasting, which is becoming very popular in the biohacking community.

“…gave a tablet to my mum …she had the most productive day…”

This user gave a tablet to his mother and saw her productivity at cleaning increase. We generally see this as a slippery slope to addiction and side effects but that is not always the case and it appears to be far less the case with modafinil than most other stimulants. Modafinil generally has a low potential to cause abuse, dependence, addiction, and withdrawal. It does not produce an acute and sustained high like drugs of abuse that people and animals seek out and self-administer in studies.

Conclusion

As a nootropic, we will give modafinil a B.

It is a promising nootropic but the risk of Stevens-Johnsons syndrome should limit its use to those with narcolepsy at least until we can find out why some people develop SJS and be able to screen for it.

Modafinil isn’t quite NZT, but it can be very helpful for those who have conditions for which it is indicated. Though derivatives and analogs are sold openly as research chemicals, it is a legal grey area if you are in possession of it and do not appear to have plans on using it in a research study. Modafinil has a unique mechanism of action, different from other stimulants, but not as strong as that of caffeine or amphetamines. However, it also does not have the physical side effects of stimulants like caffeine and amphetamine once you reach your target dose and get acclimated to it. If you start to have any skin reaction to it, you would want to discontinue use pretty quickly.

Legality:  Modafinil is a Schedule IV Controlled Substance in the United States. Benzodiazepines like clonazepam fall in the same category.

1. Lower potential for abuse than substances like Ketamine, GHB, and anabolic steroids.
2. Has legitimate medical uses.
3. Abuse leads to less physical and psychological dependence than drugs like ketamine, and GHB (Schedule III drugs).

Bibliography

Krishnan, Raman and Krishnan Vengadaragava Chary. “A rare case modafinil dependence.” Journal of Pharmacology and Pharmacotherapeutics 6.1 (2015): 49. 19 6 2019.  https://ncbi.nlm.nih.gov/pubmed/25709356.

Martinez-Raga, Jose, Carlos Knecht, and Sonsoles Cepeda. “Modafinil: A Useful Medication for Cocaine Addiction? Review of the Evidence from Neuropharmacological, Experimental and Clinical Studies.” Current Drug Abuse Reviews 1.2 (2008): 213-221. 19 6 2019. https://ncbi.nlm.nih.gov/pubmed/19630720.

Price, Charles S., and Fletcher B. Taylor. “A retrospective chart review of the effects of modafinil on depression as monotherapy and as adjunctive therapy.” Depression and Anxiety 21.4 (2005): 149-153. 19 6 2019. https://ncbi.nlm.nih.gov/pubmed/16035049.

Disclaimers

General Medical Disclaimer

Leaf Expert does not give medical advice. Consult your doctor if you believe you have a condition for which modafinil is a treatment option.

FDA Disclaimer

Modafinil is regulated as a Schedule IV controlled substance by the US FDA. Analogs such as flmodafinil are sold as research chemicals and may not be legal to use internally without a prescription or outside of a medical study because of the Analog Act. This 1986 act says that any chemical which is substantially similar to a controlled substance will be treated like that substance. Therefore, if you are caught with modafinil for human use, you could be charged with possession of a Schedule IV controlled substance.

Drug Screening Disclaimer

Modafinil is not regularly screened for in drug screens; however, no one can promise you that use will not be detected or will not interfere with drug tests in unforeseen ways.