Hypothesized Treatment for Migraines Using Low Doses of Tryptophan, Niacin,Calcium,Caffeine,And Acetylsalicylic Acid

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Medical Hypotheses (2001) 56(1), 91Ð94 © 2001 Harcourt Publishers Ltd doi: 10.1054/mehy.2000.1117, available online at http://www.idealibrary.com on Hypothesized treatment for migraines using low doses of tryptophan, niacin, calcium, caffeine, and acetylsalicylic acid

A. Gedye

Psychologist, Independent Consultant, Point Grey, Vancouver, British Columbia, Canada

Summary The author hypothesized that existing agents known to influence serotonin blood level, vascular tone, and inflammatory reactions might terminate migraines. The author presented the rationale for using five different agents therapeutically and avoiding two other agents during a migraine. The proposed treatment is to use low doses of tryptophan, niacin, calcium, caffeine, and acetylsalicylic acid (ASA) soon after migraine symptoms are noticed and to avoid during a migraine high-potassium food and magnesium supplements. Preliminary results from 12 migraine patients indicated that 9 of 12 (75%) had significant benefit from this approach. Using these five agents together is a novel combination and a new idea for treating migraines. © 2001 Harcourt Publishers Ltd

INTRODUCTION and in some but not all migraines; (d) an increasing release of histamine still rising 24 hours after onset (1). Migraine attacks can have debilitating effects that last Histamine is a powerful vasodilator (12). Migraine medic- many hours or a few days. Most affected individuals have ations that contain substances that enhance serotonergic a family history of migraines (14), and more women have functioning might be expected to alleviate sequelae migraines than men (about 18% vs. 6%) (17). Migraines caused by falling serotonin blood levels. Migraine medic- have been classified according to the appearance of ations that contain substances that affect blood vessel neurological symptoms in relation to the headache tone, such as vasoconstriction, can be expected to allevi- (14). Various treatments are available, but some risk a ate the migraine feature of vasodilatation and/or irregu- vicious cycle of rebound headaches or serious adverse larities of vascular tone. Some migraine medications effects (4,8). individually influence only 1 or 2 of the first 3 physiologic features listed above. Some medications influence THE HYPOTHESIS all 3 physiologic features, such as sumatriptan/Imitrex (8). Unfortunately, sumatriptan causes rebound head- Physiologic events occurring during migraine attacks aches in about 40% of migraine patients and, in rare include but are not limited to the following: (a) falling cases, causes serious cardiac effects (8). blood levels of serotonin (1,2); (b) vascular dilatation (6,7); The author hypothesized that agents known to influ- (c), inflammatory response in intracranial structures (18), ence these 3 physiologic features – falling blood level of serotonin, vascular dilatation, and inflammatory response Received 21 January 2000 – might be useful in treating migraines. The rationale for Accepted 28 February 2000 this hypothesis follows. Published online 8 December 2000

Correspondence to: A. Gedye PhD, PO Box 39081 Point Grey, Vancouver, 1. To reverse a falling blood level of serotonin, a low dose British Columbia, Canada V6R 4P1 of the serotonin precursor L-tryptophan can be used (9).

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A 1 gram dose of tryptophan would be the upper limit of tryptophan-niacin-calcium-caffeine-ASA for treating mi- per intake because single doses higher than 1 gram graines. approach a ‘loading dose’ of tryptophan. Loading Vasodilatation can be caused by histamine (12). doses activate the enzyme tryptophan pyrrolase which Research by Anthony and Lance (1) indicated that some, routes tryptophan down the kynurenine pathway not all, migraines involve a strong release of histamine away from conversion to serotonin (9). Loading doses which is still increasing 24 hours after the onset of the of tryptophan such as 2 grams per intake actually migraine. Therefore, the author reasoned that in episodes lower serotonin levels (3,9). where the 5-component approach had little or no effect, 2. To facilitate tryptophan’s conversion to serotonin it could be because that particular migraine involved a instead of conversion to kynurenines and nicotinic strong histamine release and an anti-histamine would be acid, niacin (also called nicotinic acid) is effective therapeutic. The author reasoned that a non-sedating because it is a feedback regulator for the kynurenine histamine type 1 blocker might be useful as an add-on pathway of tryptophan metabolism, and it reduces the treatment if the other 5 components were ineffective. amount of tryptophan converted to kynurenines (15). Niacin can cause flushing of the skin which is CONDITIONS LIKELY TO RENDER THE harmless (19). PROPOSED TREATMENT INEFFECTIVE 3. To restore serotonin’s influence in regulating blood vessel tone, reversing the falling blood level of 1. Abnormally low serum iron (ferritin) is a condition serotonin is required; acetylsalicylic acid can displace likely to render this treatment ineffective. Iron is a tryptophan from binding proteins, thereby freeing up co-factor in the enzymatic conversion of tryptophan more tryptophan for serotonin synthesis (5, p 61). to the serotonin precursor 5-hydroxytryptophan, so Using acetylsalicylic acid at the same time as niacin insufficient iron would mean less tryptophan can be helps reduce the flushing response (21). routed toward conversion to serotonin. Increasing 4. To reduce vasodilatation, agents with vasoconstricting serotonin is a crucial part of this treatment. properties such as caffeine (16) or calcium (12, p 192) 2. Delaying taking the treatment by 1–2 hours after are potentially useful. noticing migraine symptoms would likely diminish its 5. To reduce the inflammatory response, a prostaglandin efficacy. blocker such as acetylsalicylic acid (ASA) can be useful 3. Patients who frequently use medication that causes (4). (The prostaglandin blocker naproxen/Anaprox medication-induced rebound migraines or could be considered as an alternative anti- withdrawal-induced migraines would likely not inflammatory agent (4).) benefit from this approach. The modest effects of low 6. To reduce further vasodilatation, one can avoid during doses of components found in common foods (a a migraine the consumption of food and drink that are vitamin, mineral, amino acid, caffeine) plus a standard high in potassium, a mineral that causes dose of ASA would be comparatively weak against vasodilatation (12, p 192). powerful addictive agents like codeine or barbiturates 7. Given that the mineral magnesium has vasodilating which can cause withdrawal-induced migraines. effects (12, p 192), one can also avoid taking Therefore, this ‘relatively benign’ approach is unlikely magnesium supplements during a migraine. to be effective in people with frequent medication- induced migraines related to frequent use of certain In brief, the author hypothesized that taking low doses migraine medications. of tryptophan, niacin, calcium, caffeine, and ASA together would be useful in treating migraines. AN APPLICATION OF THE HYPOTHESIS The 5 agents being proposed have been in use with humans for decades or much longer, but there are As an illustration of the application of this hypothesis, no reports of the 5 being combined therapeutically. Nu- results are presented on 8 women and 4 men who tried merous migraine medications mimic the effects of this approach for 10 migraines. They were kept naive serotonin (11). ASA alone has been used for migraines about the main components, but their physicians were (11) and it can block plasma extravasation which is aware of all treatment agents. The known safety of the associated with migraine pain (10). Another anti- components, lack of serious side effects especially at low inflammatory drug, naproxen, has also been used alone to doses, and ethical considerations were discussed with all treat migraines (20). ASA and/or caffeine are common co- involved. Consent was obtained from participants and agents in currently available migraine medication. Niacin their physicians. alone has been mentioned anecdotally for migraines The hypothesized treatment involved the following (13, p 60). This is the first report proposing a combination steps. Step 1 was to take the 5 components soon after

Table 1 Preliminary results from 12 migraine patients using the 5-component approach for 10 attacks Case Age at Age onset Percent of trials Percent of trials No. of trials needing No. of trials with study migraines > 90Ð100% benefit 80Ð100% benefit a repeat dose to end mgr. no benefit F1 28 9 years 90 90 4/10 1/10 F2+ 49 12 80 90 1/10 zero F3+ 54 12 70 70 0 2/10 F4+ 43 late teens 30 30 3/10 2/10 NR F5+ 49 19 50 70 0 zero F6 54 early 20s 90 100 4/10 zero F7 46 25 100 100 1/10 zero F8 62 52 70 80 1/10 2/10 M9+ 47 12 30 60 0 zero M10+ 20 19 80 80 not tried 1/10 M11+ 49 27 20 30 not tried 6/10 NR M12+ 44 29 30 40 not tried 5/10 NR + These patients had 1 or more episodes with benefit that was >25% but <80%. NR = nonresponder. migraine symptoms were noticed. Low doses were used: was effective in 3 of the 6 people who tried it. These pre- 500 mg L-tryptophan; 100 mg niacin; 500 mg calcium liminary findings illustrate a practical application of this carbonate; 64 mg caffeine; 650 mg ASA. (Two tablets of hypothesis. Anacin contain 64 mg caffeine and 650 mg ASA (4). A version with 1000 mg L-tryptophan was also tried, but it did SAFETY CONSIDERATIONS not show a reliable advantage over the 500 mg version.) This can be taken with water or with 1/2 cup of milk to Safety is always a primary consideration. The pharmaco- protect the stomach. Step 2 was to avoid consuming high- logical safety of ASA-caffeine at those doses (Anacin) is potassium food/drink (e.g., bananas, oranges, dried fruit, well established. The safety of vitamin B3/niacin, calcium nuts, tomato juice) and magnesium supplements during a carbonate, and L-tryptophan individually at those low migraine. Step 3 (if needed) was to take a ‘repeat dose’ doses has also been established as these agents are avail- after 4 hours only if benefit had been obtained but later able over the counter or by prescription (L-tryptophan). the migraine symptoms returned after about 4 hours. The proposed treatment is a ‘novel combination’ of 5 Step 4 (optional) was to try a non-sedating anti-histamine components whose safety individually has previously (60 mg terfenadine/Seldane) only if the 5-component been established. The preliminary evidence indicated no approach yielded little or no benefit within 90 minutes. safety concerns and no rebound headaches. (Terfenadine should not be used when taking other medications such as certain antibiotics, antifungal drugs, and CONCLUSION grapefruit juice (4).) For their own comfort, participants were to avoid hot fluids and baths for 1 hour after taking The hypothesized treatment is to use low doses of tryp- the treatment to lessen the minor discomfort from flush- tophan, niacin, calcium, caffeine, and ASA soon after ing caused by niacin. migraine symptoms are noticed and to avoid during a Table 1 shows that 9 of 12 (75%) adults were respon- migraine high-potassium food and magnesium supple- ders to the 5-component approach, obtaining 90–100% ments. The author reasoned that this approach is unlikely relief in about an hour for most or all migraines. With to be effective in patients with low serum iron or patients physician consent, some responders continued to use this who take powerful barbiturate, codeine, or morphine approach for over 2 years, and no one had rebound medication every few days for migraine relief. headaches or adverse events. (Additional details about The proposed migraine treatment may have certain the preliminary study are available from the author.) advantages. It would be relatively inexpensive, which Three of the 12 were nonresponders. One often delayed would make it more accessible to low-income patients. It taking the treatment and she got poor results. Another may have a low risk of serious side effects because the nonresponder had migraines every second day corre- safety of ASA-caffeine together and low doses of niacin, sponding to his taking a codeine-barbiturate medication calcium, and tryptophan used individually has previously (Fiorinal-C) every other day for years. The third nonre- been established. It may have the advantage of not caus- sponder had very atypical migraine symptoms and he ing rebound headaches, as the preliminary evidence sug- had no relatives with migraines, whereas all but one of gests. the other participants had a family history of migraines. Research investigations such as double-blind placebo- When the 5 components gave little or no relief, Step 4 controlled studies are the scientifically acceptable way to

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