Perhaps my question is irrelevant since the documentation info you provided states that there hasn't been any evidence of an increase in benifit past a dosage of 200mg. I guess I was just wondering about dosages in the higher range.

Neurosci Lett. 1999 Nov 19;275(3):215-8.

A stereological study on the neuroprotective actions of acute modafinil treatment on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced nigral lesions of the male black mouse.

Aguirre JA, Cintra A, Hillion J, Narvaez JA, Jansson A, Antonelli T, Ferraro L, Rambert FA, Fuxe K.

Department of Physiology, School of Medicine, Malaga, Spain.

The effect of an acute administration of the vigilance-promoting drug modafinil ((+/-)(diphenyl-methyl)-sulfinyl-2 acetamide; Modiodal) on the nigrostriatal dopamine system was studied after damage induced by MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) by means of immunohistochemistry for tyrosine hydroxylase (TH) and a stereological method. MPTP (40 mg/kg) reduced from 24,380 +/- 902 to 13,501 +/- 522 and from 37,868 +/- 3300 to 20,568 +/- 1270, respectively, the number of TH immunoreactive (IR) and non-TH IR nigral neurons. Co-administration of Modafinil restored to normal the number of these neuronal populations. MPTP treatment induced also a reduction in the volume of TH IR neurons, which was counteracted by Modafinil administration. The data provide morphological evidence, based on unbiased stereological analysis, for a potential neuroprotective role of Modafinil, not only in dopaminergic neurons, but also with a similar magnitude in the non-DA nerve cell population of the substantia nigra after MPTP lesion.  These results suggest that Modafinil has a neuroprotective role in the substantia nigra via a still undefined mechanism in which a crucial role of DA uptake blockade should be excluded. Modafinil may therefore have a therapeutic potential in neurodegenerative processes such as those occurring in Parkinson's disease.
PMID: 10580713 [PubMed - indexed for MEDLINE]

Expert Opin Pharmacother. 2006 May;7(7):837-48.

Neuroprotective agents in schizophrenia and affective disorders.

Krebs M, Leopold K, Hinzpeter A, Schaefer M.

Department of Psychiatry and Psychotherapy, Charite-Universitatsmedizin Berlin, Campus Charite Mitte, Schumannstr. 20/21, D-10117 Berlin, Germany. Michael.Krebs@charite.de

With the exception of dementia, the use of neuroprotective agents in psychiatric disorders is not yet well established. However, recent data from brain imaging studies and clinical trials support the view that neurodegenerative mechanisms may play a role in the pathophysiology of schizophrenia and affective disorders. Further evidence for the use of neuroprotective agents can be drawn from the findings that second-generation antipsychotics, mood stabilizers and antidepressants have been shown to have neuroprotective effects in vitro and in vivo. Neuroprotective agents as add-on therapies (e.g., modafinil, erythropoietin, glycine, D-serine, memantine and celecoxib) are currently being evaluated in schizophrenia and related disorders. This paper reviews the current options for neuroprotective treatment approaches focusing on schizophrenia and affective disorders.PMID: 16634707 [PubMed - in process]

Acta Pharmacol Sin. 2004 Mar;25(3):301-5.

Neuroprotective mechanism of modafinil on Parkinson disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

Xiao YL, Fu JM, Dong Z, Yang JQ, Zeng FX, Zhu LX, He BC.

Department of Pharmacology, Chongqing Medical University, Chongqing 400016, China. fjmin@21cn.com

AIM: To observe the neuroprotective mechanism of modafinil on Parkinson disease (PD) models induced by 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP). METHODS: The model of PD was induced by intraperitoneally injecting MPTP into C57BL/6J mice for 4 d. Modafinil (i.p., 50 or 100 mg/kg(-1)/d(-1)) was administered at 30 min following MPTP for 4 d and for another 10 d continuously. The contents of dopamine (DA), noradrenaline (NA), 5-hydroxytryptamine (5-HT), gamma-aminobutyric acid (GABA), glutamine (Glu) in the striatum, and the contents of GABA, Glu, malondialdehyde (MDA), and glutathione (GSH) in the substantia nigra (SN) of model mice were determined. RESULTS: Modafinil (50 and 100 mg/kg) prevented against the decrease of the contents of DA, 5-HT, and NA in the striatum and GSH, GABA in the SN induced by MPTP, but reduced the increase of MDA in the SN and GABA in the striatum induced by MPTP. Modafinil preferentially inhibited striatal GABA release, but it did not change the increase of nigrostriatal Glu release induced by MPTP. CONCLUSION: The anti-oxidation and the modulation of nigrostriatal GABA and striatal NA and 5-HT release contributed to the neuroprotective effects of modafinil on PD induced by MPTP.
PMID: 15000882 [PubMed - indexed for MEDLINE]

Behav Pharmacol. 2006 Sep;17(5-6):453-62.
Neuroprotective effects of modafinil in a marmoset Parkinson model: behavioral and neurochemical aspects.

van Vliet SA, Vanwersch RA, Jongsma MJ, van der Gugten J, Olivier B, Philippens IH.
aDepartment of Diagnosis and Therapy, TNO Defence, Security and Safety, Rijswijk bDepartment of Psychopharmacology, Utrecht Institute of Pharmaceutical Sciences and Rudolf Magnus Institute of Neurosciences, Utrecht University, Utrecht, The Netherlands.

The vigilance-enhancing agent modafinil has neuroprotective properties: it prevents striatal ischemic injury, nigrostriatal pathway deterioration after partial transsection and intoxication with 1-methyl-1,2,3,6-tetrahydropyridine. The present study determines the protective effects of modafinil in the marmoset 1-methyl-1,2,3,6-tetrahydropyridine Parkinson model on behavior and on monoamine levels. Twelve marmoset monkeys were treated with a total dose of 6 mg/kg 1-methyl-1,2,3,6-tetrahydropyridine. Simultaneously, six animals received a daily oral dose of modafinil (100 mg/kg) and six animals received vehicle for 27 days. Behavior was observed daily and the locomotor activity, hand-eye coordination, small fast movements, anxiety-related behavior and startle response of the animals were tested twice a week for 3 weeks. Modafinil largely prevented the 1-methyl-1,2,3,6-tetrahydropyridine-induced change in observed behavior, locomotor activity, hand-eye coordination and small fast movements, whereas the vehicle could not prevent the devastating effects of 1-methyl-1,2,3,6-tetrahydropyridine. Dopamine levels in the striatum of the vehicle+1-methyl-1,2,3,6-tetrahydropyridine-treated animals were reduced to 5% of control levels, whereas the dopamine levels of the modafinil+1-methyl-1,2,3,6-tetrahydropyridine-treated animals were reduced to 41% of control levels. The present data suggest that modafinil prevents decrease of movement-related behavior and dopamine levels after 1-methyl-1,2,3,6-tetrahydropyridine intoxication and can be an efficaceous pharmacological intervention in the treatment of Parkinson's disease.

PMID: 16940766 [PubMed - in process]

I've read anywhere from 100mg 1x daily, to 400mg 1x daily is a good dosage for Modafinil. I know people react differently to different things, so with that aside, what do you find to be the optimal dosage for you personally?

Also, are you able to get to sleep at night on that dosage?

I am a modafinil user and would be interested to as to long term affects but I think at the moment it is very hard to tell.
I take a daily dose of 200 mg, everyone is different. The dose at which it works on you is the best dose to take and you will notice it, its not to say that if you need twice as much you are potentially putting yourself at twice a high risk of toxicity, it’s probably due to your body being more efficient at getting rid of it. As for whether this drug is neuroprotective there is no real way of telling from any of the published articles. The ones quoted above are based on a compound called MPTP, well known in heroin addicts of California in 1982 who got sold a duff batch which later showed to contain this nasty chemical which totally destroyed dopamine cells in their striatal cells causing irreversible Parkinson’s like symptoms on all these poor young fellars. Advice firstly, don’t buy dodgy drugs! From the reports above it seems highly likely that modafinil effects the dopaminergic system. I say this because MPTP depleted killed off these guys dopamine cells by being taken up by a specific dopamine transporter (DAT) and wrecking the mitochondria inside (the powerhouse of the cell). This to me suggests that modafinil has had these protective effects by being a similar shaped molecule to this compound competing it out and getting and preventing its affects (this is my guess, I have not had access to the journal so it could be wrong).
So if modafinil is acting in a similar way to dopamine what does this mean in terms of adverse long term affects. As mentioned depletion of dopamine is the cause behind Parkinson’s disease ie rigidity. I notice with myself that I am more active whilst taking it, concurring with the expected opposite to parkinsons like symptoms. On the other hand excess dopamine is thought to be the cause behind schizophrenia, indeed most antipsychotic drugs block dopamine. This does not mean that buy taking it long term you are likely to develop it since it is mainly caused buy genetics. Merely this suggests that some of the reasons why dopamine causes schizophrenia may also affect a modafinil user, enhanced sensory responses and vigllance. Dopamine is a modulator and can enhance any active stimulus going through your brain.
I feel I am willing to take the risk by taking this drug, it improves my life and there may well turn out to be positive benefits long term but equally negative affects can not be rulled out. I trust the FDA, they license it at the moment for long term use in a couple of conditions so they can not be too wooried about it.

Im 6'2" 180 pounds, Male


100MG/day is fine

I did, 500MG on the first day, then continued with 100mg

The provigil will kick in within an hour or two, and the 'full on' effects last like 8 hours, but it's possible to maintain it for up to 40 hours with relative ease. This drug turned my brain into a sponge, what happens to you as a result of that, depends on what that sponge is exposed to. If you have a decent amount of willpower, you should be fine.

Life Extension Magazine has an article about some of their questionable decisions

http://www.lef.org/magazine/mag2001/may200...son2_1.html



I mean, why would you promote cheap and natural dietary supplements (i.e. folic acid) to prevent disease before it occurs - not at all lucrative - when you can make all the money you ever dreamed of by just treating health problems after they occur; thanks to your friends in the multi-billion dollar drug industry?

Consumer Reports (May 2004) and the “Dirty Dozen” unsafe herbs still readily available

· “CONSUMER REPORTS has identified a dozen (supplements) that … are too dangerous to be on the market. Yet they are.” Introductory paragraph in red ink.

· Factors contributing to unsafe supplements on the market.

· “ ‘The standards for demonstrating a supplement is hazardous are so high that it can take the FDA years to build a case,’ said Bruce Silverglade, legal director of the Center for Science in the Public Interest, a Washington D.C., consumer advocacy group”(pg. 12).

· “The FDA’s supplement division is understaffed and underfunded, with about 60 people and a budget of only 10 million “dollars)…” (pp. 12-13).

· “…Overwhelming opposition from Congress and industry forced it to back down” when the FDA first tried to regulate ephedra in 1997 (pg. 13).

· The public assumes a greater degree of government regulation than exists – in a 2002 Harris Poll of 1010 adults, 59% of respondents believed that supplements must be approved by a government agency before they can be sold to the public, 68% thought the government requires warning labels on supplements with regard to potential dangers, and 55% thought that supplement manufacturers could not make safety claims without solid scientific support.

Overview of Data and Eligibility for a Qualified Health Claim

A health claim characterizes the relationship between a substance and a disease or health-related condition (21 CFR 101.14(a)(1)).  The substance must be associated with a disease or health-related condition for which the general U.S. population, or an identified U.S. population subgroup is at risk (21 CFR 101.14(b)(1)).  Health claims characterize the relationship between the substance and a reduction in risk of contracting a particular disease.[2]  In a review of a qualified health claim, the agency first identifies the substance and disease or health-related condition that is the subject of the proposed claim and the population to which the claim is targeted.[3]  FDA considers the data and information provided in the petition, in addition to other written data and information available to the agency, to determine whether the data and information could support a relationship between the substance and the disease or health-related condition.[4] 

The agency then separates individual reports of human studies from other types of data and information.  FDA focuses its review on reports of human intervention and observational studies.[5] 

In addition to individual reports of human studies, the agency also considers other types of data and information in its review, such as meta-analyses,[6] review articles,[7] and animal and in vitro studies.  These other types of data and information may be useful to assist the agency in understanding the scientific issues about the substance, the disease or health-related condition, or both, but can not by themselves support a health claim relationship.  Reports that discuss a number of different studies, such as meta-analyses and review articles, do not provide sufficient information on the individual studies reviewed for FDA to determine critical elements such as the study population characteristics and the composition of the products used.  Similarly, the lack of detailed information on studies summarized in review articles and meta-analyses prevents FDA from determining whether the studies are flawed in critical elements such as design, conduct of studies, and data analysis.  FDA must be able to review the critical elements of a study to determine whether any scientific conclusions can be drawn from it.  Therefore, FDA uses meta-analyses, review articles, and similar publications[8] to identify reports of additional studies that may be useful to the health claim review and as background about the substance-disease relationship.  If additional studies are identified, the agency evaluates them individually.

FDA uses animal and in vitro studies as background information regarding mechanisms of action that might be involved in any relationship between the substance and the disease.  The physiology of animals is different than that of humans.  In vitro studies are conducted in an artificial environment and cannot account for a multitude of normal physiological processes such as digestion, absorption, distribution, and metabolism that affect how humans respond to the consumption of foods and dietary substances (Institute of Medicine, National Academies of Science, 2005).  Animal and in vitro studies can be used to generate hypotheses or to explore a mechanism of action but cannot adequately support a relationship between the substance and the disease.

FDA evaluates the individual reports of human studies to determine whether any scientific conclusions can be drawn from each study.  The absence of critical factors such as a control group or a statistical analysis means that scientific conclusions cannot be drawn from the study (Spilker et al., 1991, Federal Judicial Center, 2000).  Studies from which FDA cannot draw any scientific conclusions do not support the health claim relationship, and these are eliminated from further review.

Because health claims involve reducing the risk of a disease in people who do not already have the disease that is the subject of the claim, FDA considers evidence from studies in individuals diagnosed with the disease that is the subject of the health claim only if it is scientifically appropriate to extrapolate to individuals who do not have the disease.  That is, the available scientific evidence must demonstrate that: (1) the mechanism(s) for the mitigation or treatment effects measured in the diseased populations are the same as the mechanism(s) for risk reduction effects in non-diseased populations; and (2) the substance affects these mechanisms in the same way in both diseased people and healthy people.  If such evidence is not available, the agency cannot draw any scientific conclusions from studies that use diseased subjects to evaluate the substance-disease relationship.

Next, FDA rates the remaining human intervention and observational studies for methodological quality.  This quality rating is based on several criteria related to study design (e.g., use of a placebo control versus a non-placebo controlled group), data collection (e.g., type of dietary assessment method), the quality of the statistical analysis, the type of outcome measured (e.g., disease incidence versus validated surrogate endpoint), and study population characteristics other than relevance to the U.S. population (e.g., selection bias and whether  important  information about the study subjects--e.g., age, smoker vs. non-smoker was gathered and reported).  For example, if the scientific study adequately addressed all or most of the above criteria, it would receive a high methodological quality rating.  Moderate or low quality ratings would be given based on the extent of the deficiencies or uncertainties in the quality criteria.  Studies that are so deficient that scientific conclusions cannot be drawn from them cannot be used to support the health claim relationship, and these are eliminated from further review.

Finally, FDA evaluates the results of the remaining studies.  The agency then rates the strength of the total body of publicly available evidence.[9]  The agency conducts this rating evaluation by considering the study type (e.g., intervention, prospective cohort, case-control, cross-sectional), study category , the methodological quality rating previously assigned, the quantity of evidence (number of the various types of studies and sample sizes), whether the body of scientific evidence supports a health claim relationship for  the U.S. population or target subgroup, whether study results supporting the proposed claim have been replicated[10], and the overall consistency[11] of the total body of evidence.[12]  Based on the totality of the scientific evidence, FDA determines whether such evidence is credible to support the substance/disease relationship, and, if so, determines the ranking that reflects the level of comfort among qualified scientists that such a relationship is scientifically valid.

CONFLICT OF INTEREST

Prudent stewardship of public funds that support research programs requires that appropriate steps be taken to ensure high quality results. Therefore, recipient organizations must establish safeguards to prevent employees, consultants, or members of governing bodies from using their positions for purposes that are, or give the appearance of being, motivated by a desire for private financial gain for themselves or others such as those with whom they have family, business, or other ties. Therefore, each institution receiving PHS funds must have written policy guidelines on conflict of interest and avoidance thereof. These guidelines should reflect state and local laws and must cover financial interests, gifts, gratuities and favors, nepotism, and other areas such as political participation and bribery. These rules must also indicate how outside activities, relationships, and financial interests are reviewed by the responsible and objective institution official(s).

In addition, the institution has the responsibility for maintaining objectivity in research by ensuring that the design, conduct, or reporting of research will not be biased by any conflicting financial interest of investigators responsible for the research in accord with the provisions of PHS regulations 42 CFR Part 50, Subpart F, and 45 CFR Part 94. (/grants/guide/notice-files/not95-179.html). See also (http://grants.nih.gov/grants/policy/coifaq.htm) for frequently asked questions about research investigator financial conflict of interest and Part II of the NIH Grants Policy Statement (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part4.htm#_Toc54600065). For information on the workshop on conflict of interest, held on the NIH campus on September 30, 2002, see the Conflict of Interest Workshop Summary (MS Word or PDF).

Institutions which identify research investigator financial conflicts of interest are required to report the conflicts to the NIH Grants Management Officer (GMO) at the NIH Institute or Center (I/C) which funds or will fund the project. Questions should be directed to I/C GMO's at the address shown on NIH notices of grant awards.

I don't think the FDA are necessarily the real problem.

They might be easiest to point the finger at...

The facts are: the USFDA is a very small task force with a very limited budget that acts on laws passed through US legislation. All it would probably take to get the FDA to change its policies on allowing more preventative treatments and NIH funding on research on aging and cognition enhancement is a big enough lobby and pressure from elected officials' constituencies.



The FDA implements particularly high standards of evidence, as is discussed here.



Thank you Opales for finding the link from which I quoted data above.

Also, I don't necessarily believe everything (or anything?) I read...and I tend to take an even closer look at evidence when it is presented by companies and/or individuals who have a conflict of interest in selling substances they advocate the use of. I myself have engaged in sales of products that I advocated the use of; and unfortunately the payoff for selling products for which there is no peer reviewed evidence to support their purported uses was quite low; not to mention risky! You can read more about the role of conflict of interest in medicine by clicking here. The reason why the individual I referenced was charged criminally was due to the fact that he did not seem to disclose a conflict of interest. Many companies and individuals (some highly accredited, such as Dr. Sinclair) do seem to have a conflict of interest in some of their research...however, when a researcher openly discloses a conflict of interest, they disclose a potential bias and the individual(s) evaluating the data -- let's suppose the FDA in this case -- can prudently take that factor into account. The reason the individual in question was fined so heavily was due to the fact he was also an NIH researcher (therefore he solicits public funds -- i.e. -- US tax dollars):

Do you know if there's a huge crash if you stay awake for say, 40 hours?

What about when you do go to bed? Do you need extra hours of sleep in order for your body to recouperate after staying awake that long?

Also, is the quality of sleep better, worse, or the same when taking modafinil?

By the way, I definitely agree with you about your brain turning into a sponge.  [lol]

CONFLICT OF INTEREST

Prudent stewardship of public funds that support research programs requires that appropriate steps be taken to ensure high quality results. Therefore, recipient organizations must establish safeguards to prevent employees, consultants, or members of governing bodies from using their positions for purposes that are, or give the appearance of being, motivated by a desire for private financial gain for themselves or others such as those with whom they have family, business, or other ties. Therefore, each institution receiving PHS funds must have written policy guidelines on conflict of interest and avoidance thereof. These guidelines should reflect state and local laws and must cover financial interests, gifts, gratuities and favors, nepotism, and other areas such as political participation and bribery. These rules must also indicate how outside activities, relationships, and financial interests are reviewed by the responsible and objective institution official(s).

In addition, the institution has the responsibility for maintaining objectivity in research by ensuring that the design, conduct, or reporting of research will not be biased by any conflicting financial interest of investigators responsible for the research in accord with the provisions of PHS regulations 42 CFR Part 50, Subpart F, and 45 CFR Part 94. (/grants/guide/notice-files/not95-179.html). See also (http://grants.nih.gov/grants/policy/coifaq.htm) for frequently asked questions about research investigator financial conflict of interest and Part II of the NIH Grants Policy Statement (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part4.htm#_Toc54600065). For information on the workshop on conflict of interest, held on the NIH campus on September 30, 2002, see the Conflict of Interest Workshop Summary (MS Word or PDF).

Institutions which identify research investigator financial conflicts of interest are required to report the conflicts to the NIH Grants Management Officer (GMO) at the NIH Institute or Center (I/C) which funds or will fund the project. Questions should be directed to I/C GMO's at the address shown on NIH notices of grant awards.

For anyone who tries to keep track of which foods provide which health benefits, life seemed a little more complicated this morning. The first major analysis of nutritional research found the science to be every bit as susceptible to sponsor bias as pharmaceuticals. In a paper published online Tuesday in  PloS Medicine researchers from Children's Hospital Boston report that when studies linking beverages to health are funded entirely by industry, the conclusions are four to eight times more likely to support the sponsor's commercial interest than studies with no industry funding. And the implications of the findings, says senior author David Ludwig, are far-reaching. "Whereas conflicts of interest in pharmaceuticals could affect the millions of people taking drugs," he says, "conflicts of interest in nutrition could affect everybody — because everybody eats."

The research analyzes 206 studies on the health effects of juice, milk, and soft drinks — all of them published over the five-year period ending Dec. 31, 2003, and archived in the National Library of Medicine's online database, Medline. Ludwig says his team focused on beverages because they provided a discreet, easily analyzed sample to test the hunch that nutritional science might be skewed by industry dollars. (More studies would be needed to assess the impact of sponsorship on food research, which the study did not address.)

"When a food company sponsors a study, it is much more likely to be positive" about the health effects of the product, said Dr. David Ludwig. He's the study's senior author and director of the Optimal Weight for Life program at Children's Hospital Boston, the pediatric teaching hospital for Harvard Medical School.

Ludwig and his colleagues analyzed 206 articles from medical journals that evaluated the health benefits or effects of soft drinks, juice and milk. The studies were published from 1999 to 2003.

Of the 206 studies, 111 supplied information on funding. To prevent bias in Ludwig's review, one researcher selected the articles for inclusion in the study. Another two researchers who were not told the funding sources classified each study as favorable, not favorable or neutral toward the beverage studied. A fourth researcher who didn't know the conclusions of the study determined the funding source and classified the studies, based on whether they would be beneficial, negative or neutral to the funder's bottom line.

"Everybody brings a point of view to the table, and in the long run, that's probably a good thing," Miller said.

But the authors say this point of view appears to influence results.

They used Medline, a compendium of scientific literature, to identify 538 studies about soda, milk or juice involving people, not animals. They targeted 206 that made a health claim directly related to the drink being studied _ for example, bone fractures related to calcium and milk intake, or immune system benefits from antioxidants in juice.

Of the 206 studies, only 111 gave information on funding: 22 percent were fully funded by industry and 32 percent got some industry money.

One group of reviewers analyzed study conclusions and classified them as favorable, neutral or unfavorable to the beverage in question. Another independent group of reviewers determined whether a study would help, harm or have no effect on the finances of the study sponsor.

Scientific research funded by the soft drinks industry is up to eight times more likely than independent studies to suggest that its products are healthy, according to the first detailed analysis of the topic released on Monday.

A study by doctors in Plos Medicine, an online medical journal, highlighted the potential for considerable bias in articles about soft drinks, fruit juices and milk in leading nutrition journals.

Of the 206 articles in serious academic journals it analysed, more than half of those who disclosed sponsorhip were fully or partly funded by the industry. Those that were industry-sponsored were between four and eight times more likely to draw favourable conclusions.