Melatonin, Jet Lag, and the Nanny State

For those of you who travel frequently to the United States, you'll notice you're able to obtain melatonin very easily. But in Australia it’s a very different matter. Here, you need a prescription – and then you need to find a compounding pharmacy that will sell you melatonin at an exorbitant price. This is because of the decision of the Therapeutic Goods Administration (TGA) in Australia, which I’ll discuss in a minute.

In my posts I don’t normally use this many references, but today I have a point to make, so expect a long reference list. Way back in the 1980s, more than 30 years ago, 17 healthy volunteers were flown from London to San Francisco and the effect of melatonin was examined, and found to be safe and effective (Arendt et al. 1987), and its use for jet lag was advised by the lead author in the prestigious medical journal The Lancet 30 years ago (Arendt & Aldhous 1988), with the optimal dose of melatonin was found to be 5.0 milligrams around 20 years ago (Suhner et al. 1998)

Jet lag testing got brutal. Twenty people were flown from Auckland to London and back (that’s 12 hours’ time zone difference: as bad as it can ever get!) finding that melatonin was useful for jet lag (Petrie et al. 1989). Similarly, 37 volunteers were flown from France to the United States with 8 milligrams of melatonin as a one-off dose, again finding that melatonin was safe and effective in the management of jet lag (Claustrat et al. 1992).

The number of participants in clinical trials was ramped up, with 52 international cabin crew tested for melatonin and jet lag, finding that “melatonin may have potential benefits for international aircrew” (Petrie et al. 1993). However, in a study of 31 participants flying from London to Eastern Australia, subjects who “after arrival, followed a busy schedule which resulted in frequent and erratic exposure to daylight, melatonin had no benefit in alleviating jet-lag or the components of jet-lag” (Edwards et al. 2000).

In terms of safety, melatonin alone much less likely to cause side effects than in combination with zolpidem (Stilnox, Ambien), which is hardly surprising (Suhner et al. 2001).

A Cochrane Collaboration systematic review in 2002 found that “melatonin is remarkably effective in preventing or reducing jet lag, and occasional short-term use appears to be safe. It should be recommended to adult travellers flying across five or more time zones, particularly in an easterly direction”, with the only cautions requiring possible further investigation were for people with epilepsy, and a possible interaction with warfarin (Herxheimer & Petrie 2002), and in 2004 melatonin was found to be useful in a study of 27 subjects who flew across seven time zones east from Texas to France (Beaumont et al. 2004).

Reviews of melatonin use of found it to be safe and effective for jet lag, and this research continues until the current day (Emens & Burgess 2018; Ferracioli-Oda, Qawasmi & Bloch 2013; Srinivasan et al. 2008).

Melatonin has also been used for shift workers with “social jet lag” (Arendt et al. 1997; Brown et al. 2009; Burgess, Sharkey & Eastman 2002), insomnia (Sletten et al. 2018), delayed sleep phase syndrome (Williams et al. 2016), and some sleep problems of the elderly (Arendt & Skene 2005), and melatonin has even been used in children (Zhdanova, Wurtman & Wagstaff 1999).

You’ll recognise the name Josephine Arendt from many of the references, who is one of the leading researchers in the therapeutic use of melatonin. Years later she’s still referring to the benefits of melatonin for jet lag (Arendt 2009), so there's quite a substantial body of work around this treatment.

And this is just a limited selection of the references about melatonin.

Yet the TGA only allow less than 1 milligram for homeopathic use (Therapeutic Goods Administration 2017). My opinion on homeopathy is that it is nonsense, and homeopathic anything is useless. What disturbs me, however, is that Australian consumers can go out and buy homeopathic melatonin, thinking that they're getting the real thing, but that’s the subject for another post.

But of course if you travel to the United States or Canada, you can buy melatonin in health stores. That’s right, health stores – not even pharmacies (or drugstores as they are called over there).

Here's the problem. For starters, melatonin if off patent – WAY off patent, so there's no real interest from major drug companies to put this product through clinical trials, as they won’t have exclusive rights to it. If melatonin was given the resources that a patented drug was given (some years ago I worked on the Viagra clinical trials, so I know the sort of resources that are out there), then the stand of the TGA would be effectively challenged.

So it seems that the system is broken: here is a safe effective drug that can’t get to market. And because Australian business is so heavily reliant on international partnerships, often with North America or Europe, Australia is lagging behind.

I’ll leave the final word to two scientists who are both well known in the field of sleep medicine, who wrote in the British Medical Journal that much more can be for jet lag. Specifically regarding melatonin, they write “no pharmaceutical company wants to pay for the toxicological studies and the data assembly required to obtain a product licence because it cannot have exclusivity. It seems that many people and organisations, including governments and armed forces, would benefit from the use of melatonin to reduce jet lag. If use of the drug is in the public interest then public funds should be used to get it properly tested and licensed. A finance initiative is urgently needed to solve the problem and might best begin with a cost benefit assessment” (Herxheimer & Waterhouse 2003)

That’s my rant for the day on melatonin. I hope you got something out of reading it, and as always, happy travels!

References:

Arendt, J 2009, 'Managing jet lag: Some of the problems and possible new solutions', Sleep Medicine Reviews, vol. 13, no. 4, pp. 249-56.

Arendt, J & Aldhous, M 1988, 'Further evaluation of the treatment of jet lag by melatonin: a double blind crossover study', Annual Review of Chronopharmacology, vol. 5, pp. 53-5.

Arendt, J, Aldhous, M, English, J, Marks, V, Arendt, J, Marks, M & Folkard, S 1987, 'Some effects of jet-lag and their alleviation by melatonin', Ergonomics, vol. 30, no. 9, pp. 1379-93.

Arendt, J & Skene, DJ 2005, 'Melatonin as a chronobiotic', Sleep Medicine Reviews, vol. 9, no. 1, pp. 25-39.

Arendt, J, Skene, DJ, Middleton, B, Lockley, SW & Deacon, S 1997, 'Efficacy of melatonin treatment in jet lag, shift work, and blindness', Journal of Biological Rhythms, vol. 12, no. 6, pp. 604-17.

Australian Government Department of Health 2017, 3.2 Melatonin, Therapeutic Goods Administration.

Beaumont, M, Batéjat, D, Piérard, C, Beers, PV, Denis, JB, Coste, O, Doireau, P, Chauffard, F, French, J & Lagarde, D 2004, 'Caffeine or melatonin effects on sleep and sleepiness after rapid eastward transmeridian travel', Journal of Applied Physiology, vol. 96, no. 1, pp. 50-8.

Brown, GM, Pandi-Perumal, SR, Trakht, I & Cardinali, DP 2009, 'Melatonin and its relevance to jet lag', Travel Medicine and Infectious Disease, vol. 7, no. 2, pp. 69-81.

Burgess, HJ, Sharkey, KM & Eastman, CI 2002, 'Bright light, dark and melatonin can promote circadian adaptation in night shift workers', Sleep Medicine Reviews, vol. 6, no. 5, pp. 407-20.

Claustrat, B, Brun, J, David, M, Sassolas, G & Chazot, G 1992, 'Melatonin and jet lag: confirmatory result using a simplified protocol', Biological Psychiatry, vol. 32, no. 8, pp. 705-11.

Edwards, B, Atkinson, G, Waterhouse, J, Reilly, T, Godfrey, R & Budgett, R 2000, 'Use of melatonin in recovery from jet-lag following an eastward flight across 10 time-zones', Ergonomics, vol. 43, no. 10, pp. 1501-13.

Emens, JS & Burgess, HJ 2018, 'Effect of Light and Melatonin and Other Melatonin Receptor Agonists on Human Circadian Physiology', Sleep Medicine Clinics, p. in press.

Ferracioli-Oda, E, Qawasmi, A & Bloch, MH 2013, 'Meta-Analysis: Melatonin for the Treatment of Primary Sleep Disorders', PloS one, vol. 8, no. 5, p. e63773.

Herxheimer, A & Petrie, KJ 2002, 'Melatonin for the prevention and treatment of jet lag', The Cochrane Library.

Herxheimer, A & Waterhouse, J 2003, 'The prevention and treatment of jet lag: It's been ignored, but much can be done', BMJ : British Medical Journal, vol. 326, no. 7384, pp. 296-7.

Petrie, K, Conaglen, JV, Thompson, L & Chamberlain, K 1989, 'Effect of melatonin on jet lag after long haul flights', British Medical Journal, vol. 298, no. 6675, pp. 705-7.

Petrie, K, Dawson, AG, Thompson, L & Brook, R 1993, 'A double-blind trial of melatonin as a treatment for jet lag in international cabin crew', Biological Psychiatry, vol. 33, no. 7, pp. 526-30.

Sletten, TL, Magee, M, Murray, JM, Gordon, CJ, Lovato, N, Kennaway, DJ, Gwini, SM, Bartlett, DJ, Lockley, SW, Lack, LC, Grunstein, RR, Rajaratnam, SMW & for the Delayed Sleep on Melatonin Study, G 2018, 'Efficacy of melatonin with behavioural sleep-wake scheduling for delayed sleep-wake phase disorder: A double-blind, randomised clinical trial', PLOS Medicine, vol. 15, no. 6, p. e1002587.

Srinivasan, V, Spence, DW, Pandi-Perumal, SR, Trakht, I & Cardinali, DP 2008, 'Jet lag: Therapeutic use of melatonin and possible application of melatonin analogs', Travel Medicine and Infectious Disease, vol. 6, no. 1–2, pp. 17-28.

Suhner, A, Schlagenhauf, P, H?fer, I, Johnson, R, Tschopp, A & Steffen, R 2001, 'Effectiveness and tolerability of melatonin and zolpidem for the alleviation of jet lag', Aviation, Space, and Environmental Medicine, vol. 72, no. 7, pp. 638-46.

Suhner, A, Schlagenhauf, P, Johnson, R, Tschopp, A & Steffen, R 1998, 'Comparative study to determine the optimal melatonin dosage form for the alleviation of jet lag', Chronobiology International, vol. 15, no. 6, pp. 655-66.

Williams, WP, McLin, DE, Dressman, MA & Neubauer, DN 2016, 'Comparative Review of Approved Melatonin Agonists for the Treatment of Circadian Rhythm Sleep‐Wake Disorders', Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy.

Zhdanova, IV, Wurtman, RJ & Wagstaff, J 1999, 'Effects of a low dose of melatonin on sleep in children with Angelman syndrome', Journal of Pediatric Endocrinology and Metabolism, vol. 12, no. 1, pp. 57-68.