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The Use of Melatonin in the Treatment of Hypertension
By Susan T. Marcolina, MD, FACP, Dr. Marcolina is a board-certified internist and geriatrician in Issaquah, WA; she reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study.
Hypertension is a risk factor for cardiovascular and cerebrovascular disease, two of the top three causes of mortality for adults in the United States.1 It stands to reason that successfully controlled blood pressure (BP) can mitigate risk for both conditions. Despite the array of antihypertensive drugs available and widespread implementation of lifestyle modifications such as the DASH diet, optimal BP control remains elusive for most hypertensive patients.2,3
There is mounting evidence, however, from ambulatory blood pressure monitoring (ABPM) in clinical studies, highlighting that loss of the diurnal pattern of BP may be an important factor that impacts development of cardiovascular complications in hypertensive patients. Therefore, the use of melatonin may provide an additional novel approach to BP control for a subset of patients who exhibit disturbed circadian organization.
Central Pacemaker Function
Endogenous circadian rhythms in mammals are regulated by the suprachiasmatic nucleus (SCN) of the hypothalamus, which acts via the sympathetic and parasympathetic nervous systems and imposes a 24-hour time table to many biological functions, including production of the hormone melatonin in the pineal gland. In general, humans are diurnal creatures, programmed to be out when the sun is shining and asleep in bed at night. As the body's clock, the SCN is synchronized with the outside world via afferent input of light signals, which access the SCN via the optic nerves. When light from the sun or other bright light source shines in the eyes, nerve pathways to the SCN switch the clock to the "off" phase, turning off melatonin production by the pineal gland. As ocular light inputs decrease, the body's clock turns "on" and the pineal gland recommences melatonin production, which is then released into the bloodstream to reach all body cells.4
Melatonin and Cardiovascular Health
The cardiovascular system has a distinct daily activity cycle entrained by the SCN at least in part via the effects of melatonin. At nighttime, the heart rate slows and BP drops an average of about 10% of the daytime systolic and diastolic BP levels (normal "dipper" profile [DIP]). BP and pulse rate reach the low point of the 24-hour cycle at the same time melatonin levels peak around 02:00-03:00. At the cellular level, the calcium pump becomes more active at this time.
With the dawn, heart rate increases, BP rises, and calcium levels build up within the cells. While these changes prepare for the activity of the day, they also increase the risk that a heart attack or stroke will occur during this time period. Muller et al have noted that the highest vulnerability for a cardiac emergency occurs between the hours of 06:00 and 12:00, with the greatest risk occurring around 09:00. This "heart attack vulnerability period" occurs around the time melatonin levels reach a daytime low.5
Normal daily rhythmicity in BP, e.g., higher BP levels during the daytime and a decrease during the nighttime, represents an anticipatory adaptation to higher demands during an active phase of a daily cycle. This regular cycle of BP is important especially in hypertensive patients because nocturnal hypertension (mean nighttime systolic BP greater than 125 mmHg) is an independent risk factor for cardiovascular morbidity and mortality.6,7
A study by Bruegger et al linked melatonin levels to heart health. They compared nighttime melatonin levels from a group of 10 healthy volunteers and 15 patients with established coronary artery disease that were matched for age and sex. The healthy patients produced five times as much nocturnal melatonin as those with heart disease.8
Blood Pressure Profile: Dipper vs. Non-dipper
A "non-dipper" (NDIP) BP profile refers to patients whose nocturnal decrease of mean BP is less than 10% of the mean daytime blood pressure level. Such patients with impaired nocturnal BP reduction have a higher risk of renal, cardiac, cerebral, and vascular tissue damage.9,10
A blunting of the fall in nocturnal BP is the most consistent change associated with incipient diabetic neuropathy, defined by microalbuminuria in normotensive adults with Type 1 diabetes mellitus. However, this type of NDIP profile may also occur in normotensive young adults with Type 1 diabetes in the absence of microalbuminuria, suggesting that the circadian BP abnormality can precede renal disease and overt hypertension.11
Although most hypertensive patients can be readily categorized as DIP or NDIP, nearly 30% show fluctuation between the two.12
Jonas et al studied 16 elderly patients (mean age 68 years) with essential hypertension, most of whom were treated with one or more antihypertensives including calcium channel blockers, ACE inhibitors, beta blockers, and diuretics.13 These patients were defined as DIP or NDIP according to ABPM results. Levels of the main melatonin metabolite, 6-sulfatoxymelatonin (6-STM), were determined by ELISA in two separate urine collections, one in the daytime and one during the night. During the night, mean arterial pressure decreased by 10.3 mmHg in the DIP group and increased by 7.5 mmHg in the NDIP group. Although daytime urinary 6-STM levels were comparable between the DIP and NDIP patients, nocturnal urinary 6-STM levels of the NDIP patients were not significantly different from the daytime levels.
Thus, it appears that diminished nocturnal melatonin secretion, as seen with the NDIP profile, attenuates nocturnal BP reduction in hypertensive patients.
Melatonin: The Chemical Signal for Darkness, Rest, and Recuperation
Melatonin is produced by the pineal gland from the essential amino acid tryptophan and is chemically known as N-acetyl-5 methoxytryptamine. Intrapineal tryptophan is initially converted to serotonin, which is subsequently modified enzymatically into the regulatory hormone melatonin.
Melatonin has been found in every animal and plant from humans to one-celled algae. In all of these living organisms, it is identical in both its molecular structure and the circadian rhythm of its production cycle. Humans produce 5-10 times more melatonin at night than during the day, a cycle that is found in diurnal animals as well. In a healthy adult, daytime melatonin values average around 10 ng/mL, whereas they peak at nighttime to average values of 60 ng/mL. Exposure to light at night is a powerful suppressant of melatonin production.14,15
Serum melatonin has a short half-life and is rapidly metabolized, primarily via hepatic pathways. Measurement of 6-STM excreted in urine reflects pineal function. Urinary 6-STM levels are highly correlated with plasma melatonin levels. In particular, peak plasma nocturnal melatonin levels have correlated well with morning levels of urinary melatonin.16,17
Melatonin and its metabolites are powerful antioxidants and free radical scavengers. Because melatonin is fat- and water-soluble, it can penetrate the blood-brain barrier. This property likely contributes to its salutary cardiovascular and cerebrovascular benefits.18,19
Proposed Mechanisms of Melatonin's Antihypertensive Effect
The effect of melatonin on diurnal BP changes may be explained by its effects on the sympathetic nervous system. During non-REM sleep, BP usually decreases due to reduced sympathetic activity and a reciprocal increase in vagal tone, which leads to a reduction in cardiac output and peripheral resistance.20 Hojo et al and Kohara et al demonstrated that patients with an NDIP profile had impaired cardiovascular relaxation with altered sympathetic-vagal balance, resulting in reduced nocturnal sympathetic suppression and sustained adrenergic tone during sleep.21,22 Oral melatonin suppresses sympathetic activity.23 Therefore, if administered prior to bedtime, it is possible that melatonin may contribute to nocturnal suppression of the sympathetic nervous system, a factor which underlies the nocturnal BP dip.
Melatonin may also have a direct effect on peripheral arteries, causing vasodilation and a decrease in BP, since melatonin receptors have been found in arteries of rodents,24 and melatonin has been shown to modulate rat vascular smooth muscle tone.25 Two melatonin receptor subtypes, Mel 1a and Mel 1b, have been identified in humans. Mel 1a is primarily found in the SCN and the pituitary and cerebral vasculature, whereas Mel 1b is found in the retina. Outside the central nervous system, melatonin binding has been demonstrated in tissues including the coronary vasculature.26
Human Clinical Studies of the Effect of Melatonin on Blood Pressure
Cagnacci et al, in a small placebo-controlled study of 17 young, healthy, early follicular phase women, demonstrated that a single 1 mg oral dose of melatonin administered between 14:00-18:00 significantly decreased systolic (-9.5 ± 2.8 mmHg; P < 0.01), diastolic (-7.5 ± 1.4 mmHg; P < 0.01), and mean (-7.4 ± 1.5 mmHg; P < 0.01) BP, and standing norepinephrine levels (-105.1 ± 43.5 pg/mL, P < 0.02) within 90 minutes compared to placebo.23
Scheer et al performed a randomized, double-blind, placebo-controlled, crossover trial in 16 men with untreated essential hypertension to investigate the influence of acute and repeated (daily for three weeks) oral melatonin on 24-hour ABPM. One hour prior to bedtime, melatonin was taken in a dose of 2.5 mg. Repeated, but not acute, melatonin intake reduced systolic and diastolic BP during sleep by 6 mmHg and 4 mmHg, respectively. No change in heart rate was observed.27
Studies done thus far on the effects of melatonin on BP profiles of hypertensive patients have the drawback of being very small and short term, with the longest study lasting only four weeks.
It is also not clear how melatonin interacts with other antihypertensives. Table 1 lists some common drugs that affect melatonin levels.28-37 Of note is the fact that certain antihypertensives, specifically beta blockers and calcium channel blockers, suppress melatonin. The closer to bedtime these medications are taken, the more likely they are to suppress melatonin secretion and affect nocturnal BP.28 Therefore, taking the necessary antihypertensives early in the morning would minimize effects on the circadian rhythm of BP mediated by melatonin.
Concomitant Use of Melatonin and Conventional Antihypertensives
Lusardi et al performed a double-blind, randomized, placebo-controlled, crossover study of 50 mild-to-moderate essential hypertensive outpatients aged 38-65 (44% female).38 All patients had been stabilized on nifedipine GITS (gastrointestinal transport system) monotherapy with well-controlled BP (< 140/90 mmHg) for three months prior to the study. Patients received 5 mg of immediate-release melatonin or placebo at bedtime for four weeks and then were crossed over. ABPM at the end of each treatment revealed that this dose of melatonin induced a significant increase in systolic and diastolic BP of +6.5 mmHg (P < 0.001) and +4.9 mmHg (P < 0.01), respectively throughout the 24-hour period.
On the other hand, Zeman et al studied 190 patients with primary hypertension previously treated for a minimum of three months with a variety of antihypertensives, including ACE inhibitors, calcium channel blockers, beta blockers, and diuretics.39 NDIPs comprised 36% of the study population. All were monitored via ABPM. In a subgroup of 61 patients, plasma melatonin concentrations were measured in the middle of the dark (02:00) and light (14:00) time periods. Although there were no significant differences in daytime BP between DIPs and NDIPs, nighttime systolic, diastolic, and mean arterial BP measurements were higher in NDIPs than in DIPs (P values of 0.05, 0.001, and 0.001, respectively.) Similarly, daytime melatonin concentrations were low in all patients and did not differ between DIPs and NDIPs. However, there was a lower ratio of night/day melatonin concentrations for hypertensive patients that exhibited the NDIP profile.
Melatonin Dosage for Hypertension
Although generally regarded to be safe for short-term use, melatonin is a hormone with wide-ranging effects in the body, and long-term safety has not been established. Most melatonin supplements are synthetic but chemically identical to the melatonin produced in the body. Melatonin extracted from animal glands is a concern for potential infection with the prion responsible for mad cow disease (bovine spongiform encephalopathy) and variant Creutzfeld-Jakob disease in humans. Supplement companies are required to list the source of the melatonin if plant- or animal-based.
The optimal dose of melatonin is not clear, although it has been used in studies for BP control in the range of 0.5-5 mg/d. It is available in controlled- and immediate-release forms. The 2.0 mg controlled-release form has been taken for up to four weeks without adverse effects. Up to 5 mg of the immediate-release form has been taken in clinical studies for 1-4 weeks with some patients reporting side effects of headache, lightheadedness, drowsiness, and weakness.40
Dietary Melatonin Sources
Tart cherries and walnuts are excellent dietary sources of melatonin. Montmorency cherries, which account for the majority of tart cherries produced in the United States, contain 13.5 ng of melatonin per gram of fruit,41 and are available all year in frozen, dried, or juice form. Serving sizes are 1 cup of frozen cherries (134 g), ½ cup dried cherries (60 g), or 8 fluid ounces of juice (240 mL).42 Walnuts provide 2.5-4.5 ng of melatonin per gram of nuts consumed.43 Reiter and colleagues found that feeding chicks a melatonin-rich plant diet increased blood levels of melatonin, indicating that dietary melatonin is absorbed and enters the general circulation, after which it can bind to sites in the brain and other tissues.44
Because tryptophan is an essential amino acid from which melatonin is derived, theoretically another way to boost melatonin levels is to eat foods rich in tryptophan. However, clinical studies demonstrating a bene-ficial effect on BP from dietary tryptophan intake do not exist. Table 2 lists some foods rich in tryptophan.45
L-Tryptophan supplements were banned from public sale in 1989 due to an outbreak of eosinophilia-myalgia syndrome, which was traced to a contaminated product from a single manufacturer. However, 5-hydroxy-L-tryptophan (5-HTP), the immediate precursor in serotonin biosynthesis, has been available as a dietary supplement for almost 20 years and thus far no definitive cases of toxicity have emerged despite world-wide usage.46
Melatonin reduces fertility in women by suppression of the mid-cycle surge of luteinizing hormone secretion and subsequent inhibition of ovulation.47 In clinical studies, morning drowsiness and overall weakness were more frequently reported by patients on melatonin than placebo. Therefore, melatonin should not be used by persons who will drive or operate heavy machinery, it should not be taken during the day in daytime active people, and it should not be used concomitantly with other sedating medications.
Patients with autoimmune disease may respond differently to melatonin and such patients should be carefully monitored. Reiter et al, however, report that melatonin can modulate the immune system in a beneficial way by enhancing natural killer cell activity, inhibiting cytokine production and decreasing inflammation.48 There has been a report of a possible association between melatonin use and exacerbation of Crohn's disease, but the variable natural history of Crohn's disease in any given patient complicates assessment of this potential adverse effect.49
Because melatonin has not been tested in pregnant women and small amounts of melatonin are transmitted through breast milk and might adversely affect infant brain development, it should not be used by pregnant mothers or those who are breastfeeding.40 The use of melatonin in conjunction with calcium channel blockers may cause BP elevation.38 Certain medications such as calcium channel blockers, beta blockers, and aspirin are, however, important for patients with cardiac disease. Taking them early in the day may not only minimize their inhibitory effects on the production of melatonin (which occurs at night), but also may help offset early morning increases in BP and coagulability.50
The lack of nocturnal decline in BP is clinically important because the prognosis for NDIP hypertensive patients is worse than for those with the DIP profile. NDIP and DIP hypertensives differ from each other in their hemodynamic response during sleep and in their physiological response to darkness, as judged by the differential pattern of nocturnal melatonin secretion and autonomic regulation.
The use of melatonin may be a potentially important new strategy for the treatment of primary hypertension with few adverse side effects and possibly several additional benefits. The 5-10 mmHg decline in BP seen with melatonin administered at bedtime is of relevance because a similar decrease in diastolic BP in hypertensive patients is associated with a 20% reduction in cardiovascular mortality.51 However, larger and longer-term trials are necessary to establish which patients would benefit most from the use of melatonin. It will also be important to definitively establish the specific types of antihypertensives with which it can be used.
Larger and longer-term studies are needed to determine whether melatonin can be used, and how much can safely be ingested on a chronic basis, and for how long, to treat essential hypertension. Potential subgroups of hypertensive patients with a NDIP profile as determined by ABPM may especially benefit from the risk reduction offered by treatment of their circadian dysregulation. Lifestyle modifications, such as taking potentially melatonin-suppressing essential medications early in the day and limitation of alcohol and caffeine intake, particularly in the hours prior to bed, may alleviate suppression of endogenous melatonin secretion and improve BP control.
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