Modafinil (brand name “Provigil”) is a blockbuster eugeroic drug synthesized by Cephalon Pharmaceuticals (now Teva) and approved in 1998 for the treatment of excessive daytime sleepiness (EDS) associated with narcolepsy. It was since approved for the treatment of excessive daytime sleepiness associated with obstructive sleep apnea, as well as to normalize circadian rhythms in diagnoses of shift work sleep disorder. In select cases, modafinil is even prescribed as an off-label adjunct to address symptoms of ADHD, major depression, seasonal affective disorder (SAD), and mild cognitive impairment (MCI).
The usage of modafinil is not limited to individuals with medical conditions. It is commonly administered by astronauts, pilots, and the military to maintain vigilance during night-shifts and/or to attenuate the drowsiness associated with sleep deprivation. Additionally, it is sometimes ingested by healthy adults aiming to enhance cognitive function, thereby improving motivation, performance, and productivity in occupation-related or scholarly pursuits.
Regardless of the purpose for which modafinil is being utilized, it is necessary to acknowledge that the number of daily long-term users has likely increased since its (1998) inception. Although most scientific literature documents a relatively benign side effect profile associated with modafinil, it is unclear as to whether it may be associated with unwanted long-term effects. For this reason, it is necessary to explore whether users may experience long-term effects from modafinil, what these effects might be, as well as whether they should be considered deleterious or advantageous.
Modafinil Long-Term Effects: Hypothetical Outcomes
If you’ve been taking modafinil for a long-term, it is important to acknowledge that its long-term effects aren’t fully elucidated. Additionally, it’s difficult to hypothesize what such long-term effects might be when the exact pharmacodynamics of modafinil aren’t understood. That said, a subset of neurophysiologic changes as induced by modafinil are documented in scientific literature, and based on these, we can speculate hypothetical long-term implications of modafinil ingestion.
Hypothetical advantageous long-term effects of Modafinil (Rewards)
Despite the fact that many modafinil users highlight its potentially deleterious long-term effects, none seem to mention any potentially advantageous effects of modafinil usage. It is possible that modafinil acts as a neuroprotective agent, circadian rhythm modulator, and bolsters cognitive development. For certain individuals, the advantageous to be attained from long-term modafinil usage may be substantial.
Brain fog reversal: I’ve long stated that even if a person’s neurotransmission isn’t a direct cause of their “brain fog” or foggy thinking, a lift in brain fog as derived from modafinil can be of significant benefit to the user. Modafinil helps most individuals with brain fog, and as the fog lifts, it may help the user address underlying causes of the initial fog.
In other words, modafinil increases self-awareness to the extent that an individual that was previously unaware of his/her toxic mold, poor diet, lack of exercise, poor sleep hygiene, etc. – becomes aware of these habits and corrects them. Upon correction, it could be argued that benefits will linger long after modafinil is discontinued. The individual may have needed modafinil for pinpointing and correcting the environmental and/or behavioral causes of brain fog.
Economic stimulation: Millions (or perhaps billions) of dollars are squandered each year as a result of an understimulated economy. Not only is purchasing modafinil stimulating the economy by generating money for pharmaceutical companies, but it’s likely going to give the user additional energy and motivation to attain a high-performance job and maintain his/her productivity. This further stimulates the economy and it becomes a “success spiral” and reinforcing. Although economic stimulation is a macro-level benefit, it may be a helpful one.
Financial earnings: Taking modafinil doesn’t automatically transform you from homeless to a billionaire, but it can improve your performance enough to help you earn more. If you work an occupation in which it pays to be productive, modafinil may help bolster your earnings. If you’re able to double your work output per day and were earning $100 per day pre-modafinil, you can expect $200 per day post-modafinil based on this doubling.
This equates to roughly $73,000 per year rather than $36,500 – a major difference. While not everyone will notice improved finances after modafinil, it is a long-term effect that may occur and will likely be perceived as favorable. Especially when considering that, to a certain extent ($75,000), money can buy happiness.
Increased motivation / productivity: Productivity is fueled by the value of a task and expectancy that the task will be completed. However, if you’re like many individuals taking modafinil in that you struggle with excessive daytime sleepiness, the task value and expectancy of completion are relatively useless. If you don’t have the energy to complete the desired task, you won’t finish it. Modafinil is a eugeroic, meaning you’re unlikely to doze off or fall asleep at your desk while working on an important task. This increases your personal productivity, which likely elicits a cascade effect on other areas of your life including: satisfaction, happiness, and finances.
Learning retention: Those that use modafinil may find that they’re able to learn at a more rapid pace than non-modafinil-using counterparts. Hypothetically, let’s say you’re in school and need to study for a test. You take a modafinil each study session and it improves your learning and retention by nearly 3-fold. You’re flying through the material and learning extra on the side just for fun.
Assuming you were to discontinue modafinil thereafter, it is unlikely that you’d suddenly “forget” the information that you learned on the drug. Using the drug with some strategic goal of increasing your knowledge in a field and/or for skill development may have long-term benefits. Whatever you learn while taking modafinil is unlikely to simply vanish from your memory.
Mood improvement: It is well-established that long-term depression can detrimentally affect brain function, leading to cognitive deficits and increased risk of neurodegeneration. Modafinil is an effective antidepressant for some individuals, and may therefore be decreasing cases of depression-induced cognitive decline and/or neurodegeneration. For this reason, modafinil should be considered a logical antidepressant for elderly patients.
Mood improvement stemming from modafinil may improve the individual’s overall quality of life. If an individual with severe depression gets relief from modafinil, and the relief is maintained for a long-term (e.g. 10-years), it may not only have prevented a suicide, but may have helped the individual to cope with depression long enough to receive a superior antidepressant that hit the market 10-years later.
Neuroprotective effects: It is plausible to hypothesize that modafinil could be neuroprotective when administered over a long-term. Modafinil is understood to decrease levels of oxidative stress and elicit cytoprotective effects. It is unclear as to whether the neuroprotective effects of modafinil are maintained over a long-term, but if they are, regular administration of modafinil may be beneficial for preserving neural function. Some speculate that modafinil could reduce risk of neurodegenerative diseases like Parkinson’s.
Symptom management: If you’re taking modafinil for a serious medical condition (e.g. narcolepsy), long-term symptom relief needs to be considered as an advantage. Modafinil appears to have a track-record for maintaining efficacy over a long-term. Symptom management over a long-term may improve your quality of life because you’re no longer sleepy during the day or prone to bouts of unexpected sleepiness.
Hypothetical deleterious long-term effects of Modafinil (Risks)
Since the research is limited on modafinil’s long-term usage in humans, predicting deleterious long-term effects with any degree of accuracy is difficult. That said, we can consider what is known about modafinil and use this information to hypothesize deleterious ramifications stemming from regular, long-term administration. Understand that these long-term effects are solely hypotheses and should not be considered accurate.
Blunted creativity: While taking modafinil, many users have reported subjective decreases in creativity. They feel robotic, almost as if they’re a machine at finishing tasks that don’t require any creativity, but are poor at solving complex problems that require thinking “outside the box.” Some speculate that over the long-term, modafinil may impair lateral thinking or performance on tasks with no logical progression from start to finish.
Whether there’s any sort of permanence to this creative blunting post-modafinil discontinuation (after a long-term of administration) is unknown. It is possible that modafinil could rewire the brain in such a way that regions responsible for facilitating creativity are downregulated.
Cognitive impairment: Although a favorable effect associated with modafinil is cognitive enhancement, this effect may not be sustained over an extremely long-term. In fact, it is possible that over a long-term of modafinil administration, cognitive deficits may occur. A modafinil user that once experienced enhanced cognition may develop deficits as a result of frequent, ongoing usage; it’s nootropic properties may diminish.
This may be similar to other agents such as nicotine in which cognition improves over a short-term, but with long-term usage, users need the nicotine simply to maintain baseline cognitive function. Discontinuation after a long-term, may therefore result in temporary (perhaps long-lasting) cognitive deficits. These deficits may be equally as significant as the enhancement that was initially attained.
Dependence: Since modafinil affects neurotransmission of dopamine and norepinephrine (acting as a DAT/NET reuptake inhibitor), individuals may become dependent upon this effect for daily functioning. Without modafinil, individuals (even without narcolepsy) may be unable to perform at school, work, or in social settings. It wouldn’t be surprising to discover that certain long-term, regular users can no longer maintain adequate cognitive function or wakefulness after an extended term of administration.
Depression: It is possible that modafinil users may sink into a state of mild, melancholic depression after long-term administration. This depression may be related to altered function of dopaminergic and noradrenergic transmission (endogenous levels and receptor densities). Depression may become apparent if an individual becomes tolerant to their modafinil dosage and/or may linger following discontinuation (after long-term usage).
Headaches: Research suggests that up to 9.4% of users experience headaches when taking modafinil over an extended term. Headaches are considered an “adverse” long-term effect in that they may become severe enough to warrant discontinuation of treatment. This implies that headaches that emerge over a long-term may be of moderate and/or significant severity. It is unclear as to what causes these headaches, but they could be a result of underactive parasympathetic function, blood pressure increases, and/or vasoconstriction.
Hepatic dysfunction: It’s known that the predecessor to modafinil known as adrafinil can cause hepatic dysfunction. Although modafinil doesn’t appear to impair liver function, it is necessary to consider that long-term, high-dosage administration could affect one’s liver. This could trigger mild, moderate, or even severe forms of impairment. If you’ve been taking modafinil for a long-term, it may be smart to get your liver function checked.
Hypertension: A risk that modafinil users may face with repeated long-term administration is that of hypertension. This risk is most prominent among those with a history of hypertension prior to using modafinil. If you have a history of hypertension, but have been taking modafinil for a long-term, it is necessary to monitor your blood pressure. Blood pressure may increase significantly with continuous modafinil usage – especially at high dosages.
Immune system impairment: Many individuals wrongfully use modafinil to combat a poor night’s sleep and or sleep deprivation. The problem with this is that sleep deprivation and/or frequently getting poor sleep may compromise immune function. One study noted that increased risk of infection (11.3%) was incurred after long-term modafinil usage; possibly as a result of less overall sleep and/or poorer sleep quality. It could also be that modafinil alters neurophysiology in such a way as to decrease parasympathetic function (of the ANS), leading to poorer immune function.
Nausea: In around 5% of long-term users, nausea is experienced as a long-term effect. Although you may not feel nauseated when you first start taking modafinil, the nausea may emerge after several months and/or years of treatment. If the nausea is intermittent and/or mild, you may be able to cope with it. On the other hand, if the nausea is severe and interferes with your quality of life, you may need to discontinue treatment.
Nervousness: If you notice that you’ve never felt nervous and/or anxious until you started using modafinil for a long-term, it is necessary to acknowledge that this may emerge as a long-term effect. Research suggests that in cases of long-term usage, up to 9% of users experience an increase in nervousness. This nervousness may become so severe that individuals may discontinue modafinil usage and opt for a different pharmacologic option. It remains unclear as to whether this nervousness lingers after modafinil discontinuation and/or whether it’s a byproduct of high dosages.
Neurotransmitter imbalances: Most understand that repeated administration of any pharmacologic agent over a long-term alters neurotransmission. If you were to take modafinil every day for an extended term, it’s likely that levels of neurotransmitters and receptors would differ from had you avoided modafinil usage. Long-term administration may significantly disrupt homeostatic neurotransmission, which could take awhile to readjust after cessation.
- Dopamine: Over time, it is possible that you may exhibit low dopamine or symptoms of a dopamine deficiency. This may be due to modafinil’s modest effect as a dopamine reuptake inhibitor, which in turn could deplete endogenous dopamine stores, especially over a long-term and/or at high doses. Dopamine dysfunction may cause a host of mood problems and be of detriment to cognitive abilities.
- GABA: Modafinil is known to lower GABA concentrations in multiple regions of the brain, likely a mechanism contributing to its eugeroic effect. A reduction in GABA could lead to inability to remain calm and/or be detrimental to certain aspects of cognitive function (e.g. learning and memory). Additionally, the brain may overcompensate by producing excess GABA upon discontinuation to compensate for the reductions while an individual was taking modafinil.
- Glutamate: It is thought that modafinil alters glutamatergic transmission, thereby enhancing alertness and cognitive function. Perhaps modafinil administration over an extended term may reduce baseline glutamate levels. Lower glutamate concentrations could affect ability to encode memories and learning.
- Histamine: Modafinil increases histamine levels, which can prompt allergy-like reactions in some users. If a user becomes tolerant to modafinil at standard doses, and continues to increase his/her dosage, histamine levels may surpass a threshold in which the user experiences severe allergy-like symptoms. Upon discontinuation, histaminergic function may take awhile to correct and/or may dip below a baseline; leading to a quasi-antihistaminergic effect.
- Norepinephrine: Evidence suggests that modafinil acts as a norepinephrine transporter (NET) reuptake inhibitor. The long-term implications of altering noradrenergic transmission may be more significant than is suspected; as evidenced in cases of withdrawal from NRIs (norepinephrine reuptake inhibitors). This may lead to low energy, poorer cognitive function, and fatigue – requiring a dosage increase. Effects may be even more noticeable upon discontinuation until homeostatic NET function is restored.
- Orexin: Modafinil is known to increase concentrations of orexin (hypocretin), a neuropeptide responsible for promoting wakefulness. Long-term, regular modafinil administration may deplete and/or downregulate endogenously produced orexin. Users that have taken modafinil for a long-term may exhibit abnormally low (lower than baseline) levels of orexin upon discontinuation and/or inability to generate adequate orexin without modafinil.
- Serotonin: Although modafinil doesn’t affect serotonin to a substantial extent, it is believed to exert a slight effect on serotonergic transmission. Perhaps no long-term serotonergic abnormalities would stem from modafinil, possibly because serotonergic alterations may not exceed a certain noticeable neural threshold in which a user would be depleted of serotonin stores. It is possible that high-dose users may experience slightly reduced serotonin over an extended term of administration.
Neuroplastic variation: No researchers have examined how modafinil changes brain connectivity over a long-term. It is possible that long-term modafinil users may exhibit distinct changes in regional activation and/or structural changes in regions such as the prefrontal cortex. For this reason, it may be necessary to conduct long-term trials that attempt to gauge neuroplastic effects of long-term modafinil usage with advanced neuroimaging technology (e.g. fMRI scans).
Some regions may appear abnormally overactive and/or underactive as a result of cumulative neurologic changes as induced by modafinil. Additionally, since the brain is highly plastic, modafinil may exhibit a specific propensity by which it alters activation/development (especially among users without fully developed brains). One should assume that any long-term pharmacologic intervention will exert neuroplastic changes reflective of its pharmacodynamics. In other words, long-term modafinil users will likely share certain neuroplastic commonalities.
Personality changes: Some users hypothesize that modafinil may alter personality over a long-term. Whether it “significantly” alters personality is a matter of subjective interpretation and would be difficult to pinpoint – especially considering that other environmental factors may also affect personality (e.g. social life, toxic mold, stress). That said, it isn’t too farfetched to assume that modafinil may alter brain structure (neuroplastic changes), neurotransmitter levels, and receptor densities – all of which could change personality traits.
It is unknown as to whether these personality changes may be permanent as a result of modafinil. Increased risk of permanent personality changes may be apparent among individuals taking modafinil with undeveloped brains (e.g. individuals under the age of 25). If you want to avoid potentially life-altering neuroplastic changes as-induced by modafinil, keep your risk low by using it in middle-age, rather than in your 20s.
Sleep impairment: Researchers have hypothesized that long-term modafinil usage could cause deficits in slow-wave sleep (e.g. delta waves). In fact, one researcher noted that sleep deficits resulting from long-term modafinil administration may be similar to those documented in cocaine users. However, it is unclear as to whether the slow-wave sleep deficits would linger after modafinil discontinuation and if so, for how long.
Perhaps neuroplastic changes associated with long-term modafinil usage may blunt the brain’s ability to modulate circadian rhythm. That said, the onus of sleep deficits associated with modafinil may also be on the user. Taking modafinil at the proper dosage in the morning (as to avoid disrupting the circadian rhythm) may mitigate any long-term deleterious effects from modafinil-induced sleep deficits.
Social deficits: Many individuals believe that modafinil may dampen pleasure derived from social pursuits and relationships with others. While taking modafinil, some individuals report that they’d rather be getting work done than hanging out with friends. Modafinil may affect relationships such as via decreasing empathy, altering nonverbal communication, and may cause social anxiety rather than a relaxed-vibe. Some speculate that long-term modafinil usage may provoke lingering social deficits.
Tolerance: It is relatively likely that repeated administration of modafinil at the same daily dosage for years will yield tolerance. Although research suggests that users don’t become tolerant to modafinil’s effects, an array of anecdotal reports suggest tolerance is possible. Some have documented that modafinil “stopped working” after a year or two of regular administration. A user’s neurophysiology will likely eventually adapt to the stimulus that is modafinil. That said, it is unclear as to how long tolerance takes to develop, whether it is reversible, and how long it takes to reverse.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/19293415
- Source: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4026746/
- Source: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3723829/
- Source: http://www.ncbi.nlm.nih.gov/pubmed/20800665
- Source: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2654794/
- Source: http://www.ncbi.nlm.nih.gov/pubmed/18060037
What does the literature suggest regarding modafinil’s long-term effects?
Upon assessment of currently available literature regarding long-term modafinil administration, we can make several conclusions. Foremost, modafinil appears to be a relatively safe psychiatric drug in that it is well-tolerated with a low risk of adverse effects. A bulk of patients do not exhibit any tolerability issues even after regular (daily), long-term administration (10 to 12 months).
This indicates deleterious long-term effects are unlikely to be induced by modafinil. Additionally, modafinil appears to maintain therapeutic efficacy for the treatment of excessive daytime sleepiness without any signs of patients developing tolerance or exhibiting signs of dependence. Interestingly enough, there appear to be no debilitating modafinil withdrawal symptoms upon discontinuation after a long-term.
- Maintains therapeutic efficacy: Clearly, for a majority of long-term users, modafinil maintains therapeutic efficacy over a long-term. This should be considered advantageous in that users may be able to effectively manage excessive daytime sleepiness associated with narcolepsy (potentially) for their entire lifespan with no dwindling efficacy. The available research suggests that regardless of whether its your first week or 52nd week taking modafinil, it should be equally as effective.
- Minimal adverse effects: Research indicates that in favorably-designed long-term trials, modafinil is well-tolerated over long-term. In other words, there’s a low likelihood that modafinil users will experience adverse reactions. In one study, only 9% of patients reported adverse effects after 40-weeks of daily modafinil usage. From this information, we can conclude that tolerability issues are unlikely to emerge after an extended term of treatment.
- Most common adverse long-term effects associated with modafinil include: infection, headaches, nervousness, nausea, and hypertension.
- Tolerance unlikely: One concern associated with any psychotropic drug is that a user will develop tolerance to its favorable neurophysiologic effects, and inevitably, require an upward titration in dosing to maintain therapeutic efficacy. Tolerance development is common with similar agents such as psychostimulants (e.g. Adderall), especially when administered regularly over a long-term. Available research suggests that tolerance is unlikely to develop from long-term modafinil usage, allowing users to stay at the same dosage to treat symptoms of excessive daytime sleepiness (EDS).
- Dependence unlikely: Another concern associated with modafinil is that long-term usage may result in neurophysiologic dependence. In other words, you may become dependent upon modafinil to perform and/or function in society, and without it, you cannot perform and/or dip below your pre-modafinil baseline function. Of the available literature, there’s no evidence to suggest that individuals become dependent upon modafinil, hence its classification as a Schedule IV controlled-substance.
- Hippocampal neurogenesis: In a rodent study, it was noted that short-term modafinil administration enhanced hippocampal neurogenesis, and although long-term administration provided similar benefits, it failed to yield additional benefit. It could be suspected that, in regards to neuronal proliferation and survival in the hippocampus, long-term modafinil usage may be unnecessary. That said, in this study “long-term” was considered 14 days, which is a relatively brief duration.
Long-Term Effects of Modafinil (The Research)
When investigating the long-term effects of modafinil, it is necessary to examine all available literature documenting long-term administration. Understand that the research is far from perfect in regards to tracking and elucidating all long-term effects. Most long-term studies fail to track long-term cognitive changes from baseline (pre-administration), neuroplasticity and/or structural changes (as could be tracked with neuroimaging), and usually don’t investigate whether a rebound effect occurs upon discontinuation.
In other words, we don’t know whether symptomatic severity of a condition being treated with modafinil (e.g. narcolepsy) would significantly worsen upon discontinuation as compared to a pre-treatment baseline. Most studies simply focus on determining whether modafinil maintains eugeroic efficacy and whether undesirable side effects emerge over a long-term. Some could also argue that modafinil usage in literature documented as “long-term” may not be a long-enough-term to elucidate the full extent of neurophysiologic alterations as induced over an extended duration (e.g. several years).
2014: A paper published by Brandt, Ellwardt, and Storch (2014) noted that short-term and long-term effects of modafinil treatment differ in regards to triggering hippocampal neurogenesis (the growth of new neurons). They decided to conduct a study with 8-week old mice to elucidate how modafinil affects hippocampal neurogenesis when administered over a short-term (4 days) or a long-term (14 days). To track how modafinil affects hippocampal neurogenesis, researchers used thymidine analogues for labeling and tracking: 5-bromo-2-deoxyuridine (BrdU), chlorodeoxyuridine (CldU), and iododeoxyuridine (IdU)
Modafinil was administered at a dosage of 64 mg/kg via intraperitoneal injection every 24 hours for 4 consecutive days. Researchers noted that after this short-term modafinil treatment, neuronal proliferation increased in the dentate gyrus (as evidenced by BrdU labeling). New neurons were generated for up to an additional 3 weeks after modafinil discontinuation. Short-term treatment for 4 days also was noted to bolster the number of postmitotic calretinin-expressing progenitor cells; indicating increased survival rates for immature (granule) cells.
When administered consecutively for a long-term of 14 days (2 weeks) modafinil increased the survival of immature (granule) cells, but differences in proliferation and survival didn’t differ among those taking modafinil for short-term and long-term. Although these results cannot be generalized to humans, one may hypothesize that similar effects may be observed in human subjects.
Therefore, in regards to hippocampal neurogenesis (cell proliferation and survival), modafinil doesn’t appear to yield extra benefit when administered for longer than 3 days. That said, it would be interesting to conduct a follow-up study in which modafinil was administered for considerably longer than 14 days (e.g. 2 years) for a true understanding of its long-term implications. Perhaps neuronal proliferation and survival may reach a peak and eventually diminish as the nervous system becomes sensitized to its regular administration.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/25158676
2012: A meta-analysis published by Kelley et al. (2012) investigated modafinil’s efficacy as a cognitive enhancer in healthy adults. Their purpose for this investigation was to understand whether modafinil may be a viable, safe performance enhancer for individuals in the military. Of the available scientific literature, only 3 studies met inclusion criteria for this meta-analysis.
Results indicated that modafinil seemed to improve several aspects of cognition in normal, rested adults. Aspects of cognition that were enhanced included: attention, attentional interference, executive function, spatial planning, and working memory. Interestingly, it was noted that a smaller dose (100 mg) appeared superior to a larger dose (200 mg) for cognitive enhancement.
This finding was isolated from a study documenting that 200 mg doses failed to affect cognitive function. At the time this meta-analysis was published, modafinil had been on the market for over a decade (14 years). Researchers stated that although modafinil can enhance cognitive function, it’s long-term effects aren’t understood. Therefore, despite ability to enhance cognition, it could be a risky long-term option.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/22779312
2007: A study published by Hirshkowitz and Black (2007) evaluated the long-term effect of modafinil on several variables: wakefulness, functional status / quality of life, and tolerability. Research was conducted at 37 sleep centers throughout the U.S. and U.K. among individuals taking modafinil as an adjunct for excessive daytime sleepiness (EDS) associated with obstructive sleep apnea. The study was randomized, double-blinded, and placebo controlled – incorporating 266 participants.
Over the course of 12-months, participants received nCPAP therapy along with either: 200 mg modafinil/day during week 1, 300 mg/day during week 2, then either 200 mg, 300 mg, or 400 mg per day based on efficacy and tolerability during the initial 2 weeks. Prior to the study, researchers collected baseline measures with the Epworth Sleepiness Scale (ESS), Functional Outcomes of Sleep Questionnaire (FOSQ), and Short Form-36 Health Survey (SF-36).
A total of 175 participants completed the study (66% of the entire enrollment). Results indicated that modafinil maintained a clinically significant effect in promotion of wakefulness (as evidenced by ESS scores) compared to baseline. This indicates that over a “long-term” of 1 year, modafinil seems to maintain therapeutic eugeroic efficacy.
Furthermore, individuals taking modafinil for 12-months also exhibited significant improvements (compared to pre-treatment baseline) on FOSQ and SF-36 scores, indicative of improved sleep and quality of life. No significant tolerability issues were reported, suggesting that deleterious long-term (12-month) effects are likely minimal. Most commonly reported adverse effects were: infection (11.3%), headaches (9.4%), and nervousness (9%).
The aforestated adverse effects occurred in just 13 of the 175 participants. A total of 6 individuals exhibited increases in blood pressure (hypertension), but 5 of the 6 had a history of hypertension, making it difficult to determine whether blood-pressure increases were a long-term effect of modafinil or simply a resurgence of a preexisting condition. From this research, we can conclude that modafinil is well-tolerated and effective over an extended 12-month term.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/17447828
2000: A study published by Moldofsky, Broughton, and Hill (2000) analyzed the efficacy and safety of modafinil over an extended term. Prior to their study, all research investigating the efficacy and safety of modafinil was conducted over extremely brief durations (short-term). For this study, researchers recruited 69 individuals with narcolepsy suffering from excessive daytime sleepiness.
Prior to the study, researchers collected measures of excessive daytime sleepiness (EDS) using the Epworth Sleepiness Scale. All patients then completed a 6-week crossover study followed by 16 weeks of open-label treatment at 300 mg (+/- 100 mg). Following the additional 16 weeks, participants were blindly and randomly assigned to either: continue modafinil (30 individuals) or were given a placebo (33 individuals).
Results noted that administration of modafinil over an extended term maintained efficacy in decreasing excessive daytime sleepiness. Additionally, long-term modafinil administration was considered well-tolerated with no serious adverse effects such as: sleep disturbances, blood pressure changes, heart rate abnormalities, weight changes, or mood fluctuations. Researchers concluded that when administered daily for 4 months, modafinil maintains efficacy and is well-tolerated.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/10767651
2000: Researchers Mitler et al. (2000) published a study assessing the long-term efficacy and safety of modafinil among individuals with excessive daytime sleepiness (EDS) associated with narcolepsy. For the study, they designed 2 large-scale trials, each of which were double-blinded, placebo-controlled, and multicenter – spanning over a period of 9 weeks. A total of 478 adults completed the initial 9-week trials and thereafter continued in 40-week, open-label, extension studies.
In one of the two follow-up 40-week extensions, flexible dosing was implemented, allowing patients to receive 200 mg, 300 mg, or 400 mg daily to best treat their excessive daytime sleepiness. In the second study, patients received 200 mg per day for the first week, and 400 mg per day for the next week. Baseline measures of sleepiness and health were determined pre-treatment with the CGI-C (Clinical Global Impression of Change), the Epworth Sleepiness Scale, and Short Form-36 Health Survey (SF-36).
These measures were administered again at weeks 2, 8, 24, and 40 to assess severity of daytime sleepiness and general health. Results indicated that modafinil maintained therapeutic efficacy and improved quality of life over a long-term. Around 9% of patients (43 individuals) reported adverse effects including: headaches (13%), nervousness (8%), and nausea (5%).
Researchers concluded that modafinil maintains efficacy and tolerability over a long-term of 40-weeks. There were no apparent signs of tolerance development among patients throughout treatment. That said, some may argue that 10 months is simply not long-term “enough” to make any conclusions regarding deleterious long-term effects that may emerge after a much longer duration (e.g. 24 months).
- Source: http://www.ncbi.nlm.nih.gov/pubmed/10828434/
1996: A French study conducted by Besset et al. (1996) documented the long-term effects of modafinil in 140 patients. It should be noted that modafinil was approved as a pharmaceutical treatment in France prior to its approval in the United States. All individuals in the study were diagnosed with narcolepsy and were administered modafinil at dosages of 200 mg to 400 mg.
The average duration of treatment was reportedly ~22 months, indicating that patients had been using modafinil regularly for nearly 2 years. Certain patients had been using modafinil for 114 months upon completion of the study. Results indicated that modafinil was effective for improving symptoms of excessive daytime sleepiness even after a long-term, suggesting that dependency and/or tolerance was unlikely.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/8657099
Limitations of Long-Term Modafinil Studies
Although if we were to assume that the available literature is an accurate reflection of long-term modafinil usage, we would conclude that it’s a relatively safe drug. However, it is necessary to acknowledge that there are limitations associated with long-term modafinil research. Therefore, it is necessary to remain cautious in drawing definitive conclusions from these studies.
Long-term isn’t long enough: Researchers document “long-term” administration of modafinil at varying durations. Of long-term human studies, long-term is considered: 4 months, 10 months, 12 months, and 22 months. In other words, a bulk of the research analyzed the effects of modafinil for 1 year or less, yet these were considered long-term.
In terms of pharmaceutical administration, any duration longer than several months is considered long-term. However, there are individuals that use modafinil regularly for considerably longer durations than 12 months. To fully understand that long-term effects of modafinil ingestion, it may be necessary to conduct research spanning at least 2+ years – certain neurophysiologic adaptations may not appear until modafinil had been taken for at least several years.
Measures: The available literature assesses whether modafinil maintains long-term therapeutic efficacy, tolerability, as well as patient quality of life. Unfortunately, since modafinil isn’t approved as a cognitive enhancer, research isn’t focused on tracking long-term cognitive changes. Additionally, no long-term studies have examined structural and/or neuroplastic changes induced by modafinil in humans or animal models.
Discontinuation effect: Research implies that modafinil has a low propensity to induce withdrawal symptoms. However, it remains uninvestigated as to whether discontinuation of modafinil may temporarily result in greater severity of medical symptoms, cognitive performance, quality of life, etc. – as compared to pre-treatment baseline. In other words, researchers should investigate whether there’s a period (e.g. weeks, months, etc.) after discontinuation in which symptoms and overall function worsen in respect to pre-treatment baseline measures.
Population: All long-term modafinil studies are limited to individuals with excessive daytime sleepiness as a result of narcolepsy. This is a subset of all modafinil users and may not be reflective upon the actual long-term outcomes in a healthy population. Additional long-term research should be conducted among healthy adults without preexisting medical conditions.
Few studies: A major limitation associated with long-term modafinil research is the number of published studies. There are only a handful of studies investigating treatment outcomes after long-term modafinil usage. For this reason, there is a need for additional well-designed (placebo-controlled, double-blinded, randomized, large-scale) long-term studies.
Sleep deficits: Should any deleterious effects be associated with long-term modafinil usage, it is necessary to contemplate whether these deleterious effects were directly from the modafinil or simply from poor sleep hygiene of the user. Poor sleep hygiene should be considered engagement in activities that are known to impair sleep quality/quantity and/or the circadian rhythm.
It is known that the cumulative effect of poor night’s sleep after poor night’s sleep can yield disastrous consequences in regards to brain function. Some may wrongfully attribute compromised neural function to the long-term modafinil usage, when in fact, the ongoing poor sleep hygiene as a result of the user’s behavior and/or irresponsible modafinil usage – may have been the real culprit.
For example, if a user is engaging in activities that disrupt the circadian rhythm (e.g. staring at blue light before bed) and taking modafinil in the mid-afternoon, deleterious effects may accumulate over a long-term as a result of sleep deprivation – not modafinil. Therefore, it is necessary for researchers to determine whether modafinil taken once per day in the morning and/or or properly (before late afternoon) is the cause of sleep deficits that lead to adverse effects OR whether only irresponsible modafinil usage and/or sleep hygiene lead to deleterious effects.
Factors that may influence modafinil long-term effects
It is necessary to consider that not all long-term effects associated with modafinil are likely to occur in all users. One person may report no noticeable long-term effects, another may report favorable long-term effects, and a third individual may report deleterious long-term effects. Since differences in long-term outcomes are likely, it is necessary to note factors that may influence these outcomes including: dosage, frequency of usage, sleep (quality/quantity), term of administration, and other individual factors.
Dosage (Low vs. High)
If you’re taking a low dosage of modafinil, you’re less likely to experience major long-term effects than if you’re taking a high dose. At higher dosages, a greater overall neurophysiologic effect is exerted by the modafinil compared to at lower dosages. This becomes relatively obvious when some users don’t receive an adequate wakefulness effect at 200 mg, yet when the dosage is doubled to 400 mg, they feel extremely alert.
When administering a high-dose over a long-term (e.g. 400 mg), the cumulative neurophysiologic adaptations may be more significant than at lower doses. More changes are likely to have been made by the modafinil to your neurotransmission and CNS among high dose long-term users. Low dose long-term users should be (theoretically) less susceptible to adverse long-term effects because their neurophysiology is unlikely to have changed significantly from a small quantity of modafinil.
Frequency (Daily vs. Intermittently)
The frequency at which you administer modafinil may also influence long-term effects. Those taking it on a daily basis are most likely to endure significant long-term adaptations associated with the drug. Repeated usage without any “dosing gaps” means that neurotransmitters and receptors will adjust (in level and density) to accommodate the modafinil that is to be expected each day.
Long-term daily users are therefore the most likely to experience long-term effects. Individuals using modafinil on an “as needed” basis may administer modafinil for a few days straight, then discontinue for awhile, then resume taking it, then discontinue. This fluctuation between modafinil and non-modafinil results in neurophysiologic adjustments and may prevent deleterious consequences associated with modafinil usage.
For example, someone using modafinil just once per week allows their CNS to maintain homeostatic functioning for 6/7 days per week. Disruption in homeostasis for just one day per week is unlikely to prompt noticeable long-term adaptation. However, once a threshold of usage is passed, and gaps between administrations become shorter, we can expect more adaptations as induced by modafinil to be maintained, and ultimately long-term effects may result.
Sleep (Quality + Quantity)
When contemplating the long-term effects of modafinil, most fail to consider sleep hygiene as an important variable. Sleep is known to clear brain waste (e.g. amyloid plaques) and quality sleep may prevent neurodegenerative diseases. Since modafinil is a wakefulness-promoting agent, many users don’t put effort into maintaining sleep quality/quantity – they simply pop another modafinil.
While modafinil may mask the effects of sleep deprivation, damage as a result of the actual deprivation likely still occurs. For this reason, it is necessary to consider the sleep quality/quantity of the modafinil user. Someone who is using modafinil responsibly as to not disrupt their nightly sleep quality/quantity is unlikely to experience deleterious long-term effects compared to someone who uses modafinil as a crutch to disregard sleep hygiene.
Logic would suggest that any individual capable of getting quality sleep while taking modafinil should have the most favorable long-term effects. Individuals that skip sleep and/or are taking modafinil all day as to avoid sleep may pay serious long-term costs. Evaluating sleep of the user may be the single most important variable influencing long-term effects.
Term of administration
Whenever considering whether an individual is likely to experience long-term effects, it is necessary to evaluate the total term over which they’ve used modafinil. Some individuals may have used modafinil for 6 months, yet consider that duration “long-term.” Scientific researchers have documented 4-month studies as fitting criteria to be considered “long-term” – the interpretation of “long-term” seems to be subjective – some consider it months, others 1 year, others several years.
In any regard, the longer the term of administration, the more likely you are to experience long-term effects. Some neurophysiologic changes don’t occur to a significant enough extent after several months or a year – they may take several years to manifest. Therefore, it should be hypothesized that a 5 or 10-year modafinil user will experience long-term effects to a greater extent than a 6 month or 1-year user.
It is also necessary to consider the individual using modafinil when attempting to determine likelihood of long-term effects, as well as whether these effects will be advantageous, disadvantageous, or a combination of advantageous and disadvantageous. Considering a user’s: diet, exercise, stress, genetic expression, hepatic metabolism, whether they’re taking other drugs and/or supplements, etc. – may help us understand likelihood and/or extent of long-term effects stemming from modafinil. For example, a user taking a carefully engineered stack of supplements as to prevent modafinil tolerance may experience no significant long-term effects, whereas another may become tolerant, increase his/her dosing, and experience unwanted effects over a long-term.
Verdict: Modafinil’s Long-Term Effects Likely an Individualized “Mixed Bag”
The long-term effects experienced by any particular modafinil user should be considered contingent upon the aforestated factors. Select modafinil users may experience nothing but benefits (with no long-term drawbacks), while others may note serious long-term complications from modafinil usage (with diminishing therapeutic returns). Logic would suggest that most “average” modafinil users may experience a blending of advantageous and deleterious effects associated with long-term usage.
In other words, you may realize that after 5 years, there are some clear advantages that you’ve incurred over a long-term such as: maintained eugeroic efficacy without tolerance, an increase in salary (at your job) resulting from productivity/motivation, and no bouts of excessive daytime sleepiness. However, you may realize that some clear long-term deleterious effects have begun to manifest including: intermittent migraines, low-grade anxiety, and hypertension.
Portraying long-term modafinil as “nothing but good” is likely misleading. However, portraying modafinil as “nothing but bad” may be equally misleading. Long-term effects of modafinil (or any drug for that matter) may not be as “black and white” as researchers, current users, pharmaceutical companies, etc. – speculate. To determine how you’ll respond to long-term modafinil administration, you’ll likely need to be your own guinea pig and track your performance (pre-usage, at various checkpoints throughout usage, and post-cessation).
Do the hypothetical rewards of long-term modafinil usage trump the hypothetical deleterious effects?
Based on the information available, we can conclude that the benefits of long-term modafinil usage outweigh any potential deleterious long-term effects – especially if you are using it to treat a legitimate medical condition (e.g. excessive daytime sleepiness). Consider that even if daily, long-term modafinil administration for 20 years resulted in premature death by 5 years, the benefit of being awake and alert throughout the day for 20 years straight likely trumps any premature death – and to a significant extent. The contrast would be sleeping your day away with minimal productivity for 20 years straight and living 5 extra years.
In the aforementioned hypothetical scenario, most sensible people would choose the modafinil. When also considering that you may be in the prime of your life (as a younger individual taking modafinil), and that even if you were to die early from taking it, your health in those final 5 years may have been awful – the investment to take modafinil may have been well-worth it. Only if modafinil caused some significant impairment over the long-term that could’ve been avoided with a different treatment option – would you want to avoid it if you have excessive daytime sleepiness.
Since modafinil appears to be safer than nearly every other related pharmaceutical option, it seems like the most logical choice as a long-term treatment. Even among those taking modafinil for cognitive, motivation, and/or productivity enhancement – deleterious long-term effects may be outweighed by advantageous long-term effects. And when putting the average life expectancy in perspective and our evolutionarily hard-wired brain for a world that no longer exists, it may be logical for many people to use modafinil for a long-term vs. not-use modafinil.
Strategies to minimize deleterious long-term effects of modafinil
If you’ve been taking modafinil for a long term, listed below are some strategies that may prove efficacious in mitigating deleterious long-term effects associated with modafinil. Prior to implementing any of these strategies, discuss their alleged efficacy and verify safety with a medical professional. Also realize that certain individuals may derive more benefit from these strategies than others.
- Minimal effective dose: The greater the dosage of modafinil that an individual takes, the greater overall neurophysiologic influence it exerts. Assuming there’s “no biological free lunch,” the greater the benefits derived from high modafinil dosages, the more prominent the deleterious long-term biological consequences are likely to be. For this reason, nearly all users may want to take the minimal effective dose. This will ensure that they are getting the therapeutic benefits, with perhaps less of a neurophysiologic toll than one would incur from a higher dosage.
- Sleep: A major problem among modafinil users is that they fail to get adequate sleep. Sleep is known to clear brain waste (especially when sleeping on your side). If you aren’t getting proper sleep, you likely aren’t clearing waste products (e.g. amyloid plaques) and other toxins that may kill brain cells and/or induce neurodegeneration. For this reason, you may want to adjust the time of your modafinil administration as to ensure that you’re able to get a good night’s sleep. Do your best to optimize sleep quality, and sleep quantity to let your brain restore itself after each dosage.
- Take “As Needed”: Many modafinil users don’t need to take it every single day; not everyone struggles with excessive daytime sleepiness. For this reason, it may be smart to prevent habituation and tolerance by using modafinil less than necessary. Assuming monoamines are being depleted and/or receptors are being altered, perhaps intermittent “breaks” may allow the brain to restore the drug-induced depletion prior to the next dosage.
- Modafinil Vacation: Another strategy similar to the “as needed” strategy is to take modafinil vacations. This means you may want to avoid using modafinil for an extended period during which you won’t need to maintain peak alertness and/or cognitive function. For example, if you were to go on a 7-day vacation where high-performance cognition isn’t necessary, refraining from modafinil may refresh your neurochemistry. You could also take mini-modafinil-vacations on weekends. This may prevent the occurrence of neurophysiologic desensitization to the effects of modafinil.
- Diet: One thing that all modafinil users should be doing is eating a healthy diet. A healthy diet ensures that your brain is getting the amino acids it needs to synthesize neurotransmitters. If you aren’t giving your brain the right amount of healthy fats, proteins, carbohydrates, and nutrient-dense food (e.g. oysters), your brain may be unable to replenish lost neurotransmitters from modafinil.
- Supplements: Certain supplements when co-administered with modafinil may prevent modafinil tolerance and/or offset some of the potentially detrimental neurophysiologic implications associated with modafinil usage. Exact recommendations cannot be made, as optimal supplements may be subject to individual variation based on deficiencies. That said, if you are lacking in any particular vitamins, cofactors, fatty acids, etc. – consider that ingesting optimal amounts may mitigate long-term risks of modafinil.
- Minimize energy expenditure: Just because modafinil gives you an energy boost doesn’t mean you should automatically take up marathon running as a hobby. While mild, low-grade exercise may be helpful while taking modafinil, high-intensity training may be a poor choice. The modafinil will already be taxing your nervous system and adrenals to a significant extent. If you throw in heavy weight training, long distance running, or overtraining – expect to pay the cost later.
- Reduce stress: Stress is known to sap energy over a long-term via numerous mechanisms. Stress may alter your hormone levels, neurotransmitter concentrations, brain function, and impair sleep. Certain mechanisms of stress may synergize with those of modafinil, possibly leading to quicker-than-necessary depletion of neurotransmitter stores. Take the time to engage in stress reduction such as with the emWave2, meditation, and/or breathing exercises.
Have you noticed long-term effects from modafinil?
If you’ve taken modafinil for a long-term, discuss whether (in your anecdotal experience), you’ve noticed any long-term effects in the comments section below. If you’ve experienced unwanted long-term effects from modafinil, mention what they were and their perceived severity (on a scale from 1 to 10). Note whether you’ve taken any steps to proactively reduce these long-term effects and whether your efforts have been successful.
To help others better understand your situation, mention how regularly you use modafinil, the total duration over which you’ve used it, and your daily dosage. Also share whether you developed tolerance to a dosage, have adjusted your dosage, and whether you take holidays from modafinil (e.g. use on an “as needed” basis). (Feel free to also share anecdotes if you’ve used the related drug armodafinil a.k.a. Nuvigil).
Did you find any long-term effects to be beneficial that could be maintained and/or reaped even after discontinuing modafinil? Did you find any long-term effects to be detrimental and/or disconcerting that lingered even after stopping and/or discontinuing modafinil? Realize that according to currently available scientific literature, modafinil is regarded as yielding minimal unfavorable long-term effects.
However, one should be cautious when interpreting this data. The studies may not be of long-enough term to gauge the full extent of modafinil’s long-term effects. Additionally, cognitive implications of long-term modafinil usage haven’t even been researched. Therefore, if you are using modafinil regularly over a long-term, it is necessary to remain cautiously optimistic in regards to the hypothetical long-term effects. (You may even want to continuously evaluate yourself with cognitive assays randomly during “breaks” or modafinil vacations to determine whether your function has dipped below a pre-modafinil baseline).
Stay updated with the latest scientific research and be cognizant of any new findings regarding the implications of long-term modafinil usage. Although there’s no such thing as a biological free lunch, modafinil may be bargain (especially when compared to amphetamines) over the long-term. That said, even one serious adverse long-term effect may trump the perceived bargain.