Melatonin

Additional information

Melatonin is approved for use in sleep disorders [1]. However, as it has anxiolytic effects it has been studied on other indications.

Pharmacokinetics and dosing

In the EPAR its stated that a 3-4- fold increase in Cmax is apparent for women compared to men [1, 2]. A five-fold variability in Cmax between different members of the same sex has also been observed. No pharmacodynamic differences between males and females were found despite differences in blood levels [1].

Effects

No data on sex differences in the effect of melatonin have been found in the pivotal studies on melatonin treatment for insomnia.

In a Dutch study, children (n=59) with long-term melatonin treatment for chronic idiopathic childhood sleep onset insomnia were evaluated regarding the effect on sleep, puberty and mental health using questionnaires in [3]. Mean Strength and Difficulties Questionnaire (SDQ) score (22 boys, 25 girls aged 8-13), mean Children’s Sleep Habits Questionnaire (CSHQ) score and Tanner Stages standard deviation scores (16 boys, 30 girls) were not statistically different from published scores of the general Dutch population of the same age and sex [2].

In a randomized controlled trial (n=73), the effect of melatonin (24 men, 12 women) as premedication compared to placebo (23 men, 14 women) in wisdom teeth extraction was studied. After adjusting for patient’s sex, women on melatonin had a significantly faster rate of reduction of VAS (visual analogue scale) pain and anxiety scores over time compared to the placebo group [3].

A clinical study (142 boys, 108 girls) investigating melatonin as an alternative to sedation in children (age 1 month to 13.7 years, with an average of 2.3 years) undergoing brainstem audiometry showed no differences between the sexes. 123 of 142 boys (86.6%) compared to 93 of 108 girls (86.1%) were successfully investigated during melatonin-induced sleep [4].

The effects of a standard dose (5 mg for men and 3 mg for women) of melatonin on the body temperature rhythms of elite biathletes (8 men, 4 women) after an eastward trans-meridian flight to an international competition was measured. The results indicate different effects on body temperature rhythms in men compared to women with a potential need for personalized dosing schedules to avoid undesirable consequences [5].

Adverse effects

No studies with a clinically relevant sex analysis regarding adverse effects of melatonin have been found.

Reproductive health issues

It should be noted that patients on estrogens (e.g. contraceptive or hormone replacement therapy), which increase melatonin levels by inhibiting its metabolism by CYP1A1 and CYP1A2 [1]. The clinical relevance of this is unclear. Regarding drug-drug interactions aspects, please consult Janusmed Interactions (in Swedish, Janusmed interaktioner)

Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).

Other information

A register-based study (during 2006-2013) investigating the use of melatonin in Swedish children and adolescents 0-19 years old (4296 boys, 3093 girls) with regard to age, sex, and medication for ADHD showed that more boys than girls used melatonin regularly. In the age groups 5-9 and 10-14 years, the incidence was higher among boys, but in the age group 15-19 years, the incidence was higher among girls. Regular users of melatonin were most common among boys 10-14 years. In 2013, 65% of boys and 49% of girls, using melatonin regularly, also used medication for ADHD regularly. This could indicate that boys and girls partly are prescribed melatonin for different reasons [6].

In a study assessing if melatonin is helpful in stopping the long-term use of hypnotics (16 men, 22 women)), the influence of sex was investigated as one of the secondary objectives. No statistical difference between men and women regarding definite stoppers (6 men, 9 women) and non-stoppers (10 men, 13 women) could be shown [7].