International Journal of Clinical Medicine, 2013, 4, 1-7 Published Online October 2013 (
The Role of 5-Aminolevulinic Acid (5-ALA) and Sleep*
Michael H. Perez1#, Terry T. Shintani1, Beatriz L. Rodriguez2, James Davis1, Rosanne C. Harrigan1
1Department of Complementary and Alternative Medicine, University of Hawaii, John A. Burns School of Medicine, Honolulu, USA;
2Department of Geriatric Medicine, University of Hawaii, John A. Burns School of Medicine, Honolulu, USA.
Received August 3rd, 2013; revised August 30th, 2013; accepted September 20th, 2013
Copyright © 2013 Michael H. Perez et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Objective: To determine if there is a relationship between the administration of the dietary supplement containing
5-Aminolevulinic Acid (5-ALA) and sleep. Methods: A double-blind, randomized parallel-group study was conducted.
It was a 4-month study of 40 participants between the ages of 40 and 70. Males and females were recruited equally.
There were 20 in each group who had existing sleep disorders. The tool used to measure participant sleep improvement
included the Pittsburgh Insomnia Rating Scale-20 Question (PIRS-20). Improved sleep is reflected when the total
PIRS-20 score is lower. Results: Improvement in sleep in the group taking 50 mg 5-ALA, compared to controls, was
significant. The mean change, from baseline through week 6, was 5.67 units less on the sleep scale than the control
group with a p value of 0.001. The mean change from week 6 to week 10 when the participant was no longer taking the
supplement was 4.55 units higher than the control group with a p value of 0.062, which is of borderline significance.
Conclusions: There is a relationship between the administration of dietary supplements containing 5-ALA and sleep.
The results of this study suggest that 5-ALA is associated with improved sleep. The mechanism for sleep improvement
needs to be explored. Further research is warranted.
Keywords: Insomnia; Heme; Energy; Metabolism; 5-Aminolevulinic Acid; Sleep
1. Introduction
According to the United States Centers for Disease Con-
trol, “Insufficient sleep is associated with a number of
chronic diseases and conditions—such as diabetes, car-
diovascular disease, obesity, and depression—which
threaten our nation’s health” [1]. However, most sleep
remedies can cause other problems such as drowsiness
that can increase the risk of motor vehicle and machinery
related accidents. They can even contribute to depression
and sleep disorders. Thus, there is great value in finding
a natural sleep-aid that does not cause drowsiness or
other negative side effects.
5-Aminolevulinic Acid (5-ALA) is a naturally occur-
ring substance and is the basic building block of both
heme and chlorophyll. During a previous trial of the oral
administration of 5-ALA, some preliminary reports from
participants suggested that 5-ALA might improve sleep.
The purpose of this investigation is to determine if a rela-
tionship exists between the administration of dietary sup-
plements containing 5-ALA and sleep.
2. Background
5-Aminolevulinic Acid is a natural non-alpha amino acid.
5-ALA is a delta amino acid and is not a component of
protein. It is found in many common foods and fer-
mented products such as green pepper, bananas, baker’s
yeast, vinegar, etc. (see Table 1).
5-ALA is synthesized in the mitochondria. It is a
building block of protoporphyrin and a precursor of both
chlorophyll and heme. 5-ALA has been associated with
the origin of life.
The structure of 5-ALA is described in Figure 1. In
the prophyrin synthesis pathway, 5-ALA is the first
compound. In mammals, this pathway leads to the syn-
thesis of heme and in plants, where chlorophyll is syn-
thesized. Heme plays a role in oxygen transport and cel-
lular energy production [2]. Cellular energy generation
uses membrane-localized heme-based electron transfer
chains for adenosine-5’-triphosphate (ATP) synthesis
*Conflicts of Interests: The authors declare that they have no conflicts
of interest.
Financial Support: The Supplement Sleep and Mood Study’s were
funded by SBI Pharmaceuticals Co., Ltd. The authors were partially
supported by grants from the National Institute on Minority Health and
Health Disparities U54MD007584 and G12MD007601 from the Na-
tional Institutes of Health.
#Corresponding author.
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The Role of 5-Aminolevulinic Acid (5-ALA) and Sleep
Table 1. Common foods that contain 5-ALA.
FOOD 5-ALA content
Spinach 0.18 mg/kg
Green pepper 0.23 mg/kg
Tomato 0.13 mg/kg
Shitake mushroom 0.60 mg/kg
Potato 0.12 mg/kg
Banana 0.40 mg/kg
Squid 0.50 mg/kg
Octopus 1.00 mg/kg
Shochu lees 70 mg/kg
Sake lees 9 - 26 mg/kg
Baker’s yeast 140 mg/kg
Wine 1.4 - 2.2 mg/L
Vinegar 0.1 - 5 mg/L
Sweet sake 0.4 - 6 mg/L
Sake for cooking 0.3 - 13 mg/L
Sake 0.9 - 4.5 mg/L
Soy sauce 0.3 mg/L
Figure 1. Molecular formula: C5H9NO3, average mass:
131.130005 Da, monoisotopic mass: 131.057999 Da [19].
which is used for metabolic energy.
Increased presence of glucose in the cell results in de-
creased 5-ALA production [3]. At the same time, de-
creased heme production occurs with aging. This results
in decreased heme enzyme activity. A decline in the mi-
tochondrial electron transfer system follows, with de-
creased basal metabolism. This may result in physical
energy decline and possibly depression and sleep distur-
bance. Understanding the relationship between 5-ALA,
heme and energy production might provide evidence that
explains why 5-ALA may have a relationship with sleep.
2.1. Sleep and 5-ALA
In a previous study conducted to examine the relation-
ship between 5-ALA and pre-diabetes, a questionnaire
covering a wide range of measures of health was admin-
istered. The study placed participants on the 5-ALA sup-
plement up to 50 mg per day for a period of 12 Weeks.
During the course of this study, some interesting results
relating to sleep patterns emerged. Table 2 provides a
summary of the survey results pertaining to sleep in some
of the participants.
These data support the hypothesis that 5-ALA may be
related to improved sleep. The fact that sleep patterns
improved while on the 50 mg supplement, and then re-
turned to previous patterns when the supplement was
stopped, provide strong rationale for this pilot investiga-
2.2. Hypothesis Related to Sleep
There are several possible mechanisms hypothesized for
the improvement in sleep. Five-ALA may have an impact
on increasing the energy of all cells. In one study in-
volving test mice, researchers found that the regular ad-
ministration of 5-ALA appeared to raise serotonin levels
in the brain [4]. This may explain the improvements in
sleep patterns.
Another possible hypothesis is that 5-ALA helps each
cell’s metabolism, such that its own circadian rhythms
are better defined. One may also speculate that 5-ALA
may support hormonal regulation, including melatonin
production, in the pineal gland—which may result in
better sleep and corticosteroid production in the adrenal
glands. This may also assist in dealing with stress which
may reduce a potential cause of sleep disruption.
3. Methods
3.1. Design
This was a double-blind, randomized parallel-group
comparison study. The intervention group was placed on
50 mg/day of 5-ALA with 57.4 mg of Sodium Ferrous
Citrate (SFC), and the comparison group was placed on a
placebo (see Table 3). The capsules were administered
daily for 6 weeks. Participants were assessed at Baseline,
week 3 and week 6 and re-assessed at week 4 when no
longer taking the supplement. The study staff was blind-
ed to the intervention group.
3.2. Sample
40 participants were randomized to the following 2 study
groups: Control Group—20 participants, and Interven-
tion Group—20 participants. A table of randomized
numbers was used to assign the participants.
3.3. Procedures
Recruitment. Advertisements were prepared for the
newspaper, TV and radio. Postcards were mass mailed to
geographical locations in Hawaii to recruit participants.
Flyers and newspaper ads were distributed and local
MD’s and organizations were contacted.
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The Role of 5-Aminolevulinic Acid (5-ALA) and Sleep
Copyright © 2013 SciRes. IJCM
Table 2. Results of pilot investigation related to sleep.
Sleep at
Week 0 (first day to start 5-ALA)
Sleep at
Week 12 (12 wks 5-ALA intake)
Sleep at
Week 16 (4 wks post 5-ALA)
# 4 6.5 hours, wakes up several times 7.25 hours, mostly continuous sleep Pattern reverting to waking up several
times at night & less restful sleep
# 138
8.0 hours sleep and does not take a “nap”
during the day, “Moderate” energy
7.5 hours of continuous sleep, able to take a 10 min. “nap”
during the day, now reports having “Normal” energy Feels “tired”, “no energy”, “sleepy”
Table 3. Ingredients of control and intervention supple-
Control Intervention
5-ALA Phosphate 0 mg 50 mg
Sodium Ferrous
Citrate (SFC) 0 mg 57.4 mg
(6.08 mg as Fe)
Other Ingredients Alpha starch,
Silicon dioxide
Alpha starch,
Silicon dioxide
Inclusion Criteria. Both males and females were
equally recruited. Participants were given questionnaires,
and those who were between 40 and 70 years, who self-
reported having insomnia or difficulty sleeping, were
Exclusion Criteria. Those at a body weight of <110 or
>250 lbs were excluded. Those who were taking any sup-
plements or medications for sleep were also excluded.
Those with a history of porphyria were not able to par-
ticipate, as 5-ALA may cause adverse effects on porphy-
ria patients as it affects porphyrin metabolism. Those
with a history of hemochromatosis were excluded, as
sodium ferrous citrate (SFC) may cause adverse effects
on hemochromatosis patients which have defects in iron
metabolism. Those with a history of hepatitis were also
excluded, as SFC may cause an allergic reaction in this
population. Those with active liver disease and iron sen-
sitivity were also excluded. Women who were pregnant,
breastfeeding, and those participating in another clinical
study were excluded. Those with ferritin levels elevated
above 125% of normal on screening were excluded.
3.4. Measures
3.4.1. Sleep Study Questionnaire
Sleep was measured using a lifestyle questionnaire and
the Pittsburgh Insomnia Rating Scale—20 Questions
(PIRS-20), along with a daily study diary to monitor con-
sistent sleeping or mood patterns.
3.4.2. Lifestyle Questionnaire
Leisure-time physical activity and general health was
measured using a standardized Lifestyle Questionnaire.
The questionnaire covered: Medical history, occurrence
of allergy, use of medical drugs and/or health food,
drinking, smoking habits, etc.
3.4.3. PIRS-20
The PIRS-20 sleep scale is copyrighted by the University
of Pittsburgh [5]. In order for the design feature to be a
valid sleep scale, questions were used in the original
format. The PIRS-20 uses repeated measures to validate
answers. A lower score indicates better sleep: Scale—0
(good sleep) to 60 (bad sleep) [5].
3.4.4. Clin i c al E xami nations
The examinations recorded participant body weight,
Body Mass Index (BMI), seated/resting systolic and dia-
stolic blood pressure and waist circumference.
3.4.5. Laboratory Tests
These tests measured baseline Complete Blood Count
(CBC) and ferritin levels. Venous blood was obtained
and all analyses were conducted using standardized and
certified procedures by Diagnostic Laboratory Services
(DLS). Samples for selected tests were stored by DLS at
appropriate temperatures for assay testing. The same
digital scale was used for weighing patients at each site
throughout the study. Height was measured in the stand-
ing position and measured to within the nearest millime-
ter without shoes. A stadiometer fitted with a vertical
backboard, fixed floorboard, and a movable headboard
was utilized. BMI was determined as weight (kg) divided
by height squared (m2). Waist circumference was meas-
ured using a tension-controlled measuring tape while the
subject is standing. Abdominal obesity is defined as a
WC 88 cm in women and 102 cm in men. Blood
pressure was measured with a digital sphygmomanome-
ter while patients are in a sitting position. The same arm
was used to obtain all readings over the course of the
study, unless contraindicated. Sitting systolic and dia-
stolic blood pressures were estimated by averaging 2
replicate measurements obtained 1 to 2 minutes apart.
When possible, the same nurse or study coordinator
measured waist circumference at each visit to ensure
consistency. Results from the lab were reviewed by the
medical staff/physician within three business days of
receiving the results. There was follow-up activity by
contacting the participant and the participant’s physician,
as appropriate.
3.5. Study Schedule
Participants took the supplement from time of enrollment.
The measurements occurred at baseline, week 3, week 6
and week 10. At week 10, participants were no longer
The Role of 5-Aminolevulinic Acid (5-ALA) and Sleep
taking the supplement (see Table 4).
3.6. Efficacy Measures
A significant difference between sleep and related meas-
ures of sleep quality during the examination period be-
tween the treatment groups was the major outcome
measure. A significant difference in sleep scores between
the treatment group and control group at the end of ad-
ministration is desired and reflective of affirming the
Adverse events data were assessed every two weeks to
identify statistically or clinically significant differences
between the control group and intervention group, and
assessments of whether or not changes to the protocol
were needed. If statistically or clinically significant dif-
ferences in serious adverse events among the placebo and
the intervention group were found that indicated that
there was a greater risk than benefit for study participants,
the study could have ended.
Participants were advised to contact the PI or Co-PI
immediately if they had any concerns. If any abnormal
findings were identified, and reported the participant
would have been removed from the investigation, if war-
3.7. Statistical Analysis
Variables monitored as part of the evaluation were as-
sessed by comparing the intervention group to the control
group. Two-sample t-tests were used to assess statistical
significance at baseline and follow-up exams between the
control and intervention groups. Baseline data were
summarized as means and standard deviations with dif-
ferences among the randomized groups tested for sig-
nificance using t-tests and chi-squares. To measure the
possible differences in rates of change in sleep scores
across follow-up time between the 5-ALA treatment and
the control group, an additional analysis was imple-
mented. This consisted of estimating differences in
slopes using a linear regression model. Mixed linear
models were fit using the proc mixed procedure in SAS
9.2 [6]. The regression models included an indicator
variable identifying treatment groups, a variable for
weeks of follow-up, and interaction terms between the
indicator variables and follow-up time. Results were
summarized as the difference in slopes comparing the
intervention groups to the control group. Results were
also presented graphically to illustrate the estimated dif-
ferences in slopes for the study groups. All significant
tests were two-sided. Differences were considered sig-
nificant if the p values were 0.05.
4. Results
Of the 40 participants in the Sleep study, refer to Tab le 5 ,
the mean age for the control group was 54.7 years and
for the intervention group 56.3 years. Seventy percent of
the participants were female in the control group opposed
to 65% female in the intervention group. The analysis of
variance (ANOVA) was used to test statistical signifi-
cance for age by supplement, the p value was .494 and it
is not significant. A Fishers exact test was used to deter-
mine statistical significance of race by supplement. The p
value was 0.905 and it is not significant. A Fishers exact
test was used to determine statistical significance of
gender by supplement. The p value was 1 and it is not
significant. No significant differences were identified
between the groups related to the demographic charac-
The PIRS-20 scale shows sleep improvement when the
score is lowered. The control group (see Figure 2) and
the slight change in sleep improvement could be attrib-
uted as a random result from baseline to week 3. As
week 3 to week 6 show no response in either direction.
On week 10, when no longer taking the supplement,
there was no change. The 5-ALA 50 mg group (see Fig-
ure 3), the PIRS-20 score declined from baseline to week
3 and again on week 6. Week 10, when no longer taking
the supplement, the response begins to return to baseline.
This is the expected outcome.
Table 4. Sleep study sche dule .
Study Schedule ScreeningIntervention PeriodIntervention PeriodIntervention PeriodFollow-Up
VISIT SCHEDULE ScreeningWeek 0
(Visit 1)
Week 3
(Visit 2) Week 6
(Visit 3) Week 10
(Visit 4)
Lifestyle Questionnaire & PIRS-20 Questionnaire
Clinical Examinations Including Physiological
Laboratory Tests: CBC and Ferritin Level
Intake of Study Supplements
Filling of Study Diary
Review Participant Concerns
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The Role of 5-Aminolevulinic Acid (5-ALA) and Sleep 5
Table 5. Baseline statistics.
50 mg N = 20 Control N = 20
Mean Age Mean Age
Asian/Filipino 50% 57.9 45% 53.8
Native Hawaiian 20% 53 10% 62
Caucasian 25% 58.8 30% 56.16
Hispanic/Latino 0% 5% 43
African American 5% 63 5% 53
American Indian/
Alaska Native 0% 5% 53
Female 70% 54.9 65% 54.61
Male 30% 59.5 35% 55
Base LineWeek 3Week 6Week 10
Mean 22.45 19.05 19.95 19.95
PIRS-20 Score
Figure 2. The PIRS-20 scale shows sleep improvement when
the score is lowered. The control group and the slight
change in sleep improvement could be attributed as a ran-
dom result from baseline to week 3. As week 3 to week 6
show no response in either direction. On week 10, when no
longer taking the supplement, there was no change.
Base LineWeek 3Week 6Week 10
Mean29.9521.116.1 20.65
PIRS-20 Score
5-ALA 50 mg
Figure 3. The PIRS-20 score declined from baseline to week
3 and again on week 6. Week 10, when no longe r taking the
supplement, the response begins to return to baseline. This
is the expected outcome.
Improvement in sleep in the group taking 50 mg 5-
ALA, compared to controls, was significant. The mean
change, from Baseline through week 6, was 5.67 units
less on the sleep scale than the control group with a p
value of 0.001. The mean change from week 6 to week
10 when the participant was no longer taking the sup-
plement was 4.55 units higher than the control with a p
value of 0.062, which is of borderline significance.
In addition, No clinically significant abnormalities
were observed in the sleep study or any of the previous
studies that could be attributed to the food supplement.
5. Discussion
Insomnia prevalence in the general population is esti-
mated at 30% - 50% [7]. Medications currently used to
treat sleep disorders like diphenhydramine, doxylamine
and antihistamines have negative side effects. Diphenhy-
dramine side effects include: dry mouth, dizziness, pro-
longed drowsiness lasting into the next day and memory
problems [8]. Doxylamine side effects include: asthma,
bronchitis, glaucoma and peptic ulcer or enlarged pros-
tate [9]. Antihistamines can cause dry mouth, urine re-
tention and blurred vision. In addition, all sleep medica-
tions cause drowsiness as a solution for treating sleep
disorders. Remarkable improvement in sleep was re-
ported by several participants in a previously conducted
study investigating the relationship between the dietary
supplement 5-ALA and pre-diabetes. The dietary sup-
plement 5-ALA is suggested as being a potential alterna-
tive approach to improved sleep. Five-ALA creates en-
ergy and may adjust a person’s circadian cycle in order
to allow for better sleep in a natural way, without nega-
tive side effects. For this reason there is a potential inter-
est for natural alternatives for the treatment of sleep dis-
Increased level of glucose in the cell results in de-
creased 5-ALA production. Decreased heme production
occurs during aging, and at age 40 the human body pro-
duces approximately 50 mg/day less [10]. This results in
decreased hemoglobin production with decreased heme
enzyme activity. A decline in the mitochondrial electron
transfer system, the primary cellular energy producer,
follows, with decreased basal metabolism, as well as
physical energy decline [10].
Melatonin plays a role in regulating circadian rhythms
and maintaining physical energy. Melatonin is a chemi-
cal that occurs naturally in the brain. Melatonin allows a
person to become sleepy. Melatonin is naturally pro-
duced during the day-shift phase (see Figure 4).
Endogenous melatonin is produced by the human body.
Production begins about two hours before bedtime, pro-
vided that the lighting is dim. “This is known as dim-
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The Role of 5-Aminolevulinic Acid (5-ALA) and Sleep
Figure 4. Melatonin plays a role in regulating circadian
rhythms and maintaining physical energy. Melatonin is a
chemical that occurs naturally in the brain. Melatonin al-
lows a person to become sleepy. Melatonin is naturally
produced during the day-shift phase shown in the Phase
Response Curve (PRC). Adapted from Lewy et al. and Khalsa
et al. [12,20].
light melatonin onset, DLMO” [11]. What results is the
phase-advance portion of the phase response curve (PRC)
(Figure 4). This assists with regulation of the sleep-wake
schedule [12].
According to R. L. Sack, et al., circadian rhythm sleep
disorders all involve a problem in the timing of when a
person is asleep and is awake [13]. He proposes a master
circadian clock in the brain called the suprachiasmatic
nucleus (SCN) [14]. The SCN controls the timing of
body rhythms related to temperature and hormone levels
over a cycle that lasts a little longer than 24 hours.
In order for this system to function efficiently, it needs
information from a variety of sources, which include
physical activity, social activities and to experience day
and night. The ganglion cells in the retina collect light
information for the SCN. These cells produce a pigment
called melanopsin and are particularly sensitive to light
[15]. This is true for “non-image visual functions, such as
circadian photo-entrainment and the pupillary light re-
flex” [15]. The major conduit for rod and cone signals to
the brain for non-image visual functions, such as cir-
cadian photo-entrainment and the pupillary light reflex
[15]. Light exposure is needed by the pineal gland to
produce melatonin and the day-phase contributes to me-
latonin production (see Figure 4) [16]. Melatonin allows
a person to be sleepy. “Melatonin is a hormone produced
by the pineal gland that contributes to the reinforcement
of circadian and seasonal rhythms” [17]. It also helps
prepare the body for sleep when melatonin enters phase-
advance and light reduction enters the phase-advance
cycle. Extended or enhanced day-phase activity could
result in increased melatonin during the evening. 5-ALA
could, in fact, enhance day-phase activity, which could
inversely allow a person to experience a better sleep cy-
This is potentially very important as 5-ALA may make
for an ideal sleep-aid that assists in inducing drowsiness
at night and wakefulness during the day as it minimizes
the unwanted side effects related to medications that only
cause drowsiness. It should be noted that this particular
research was not designed to confirm any change in me-
latonin levels in the pineal gland. The methods and de-
sign did not include testing for melatonin production.
Additional studies to evaluate the hypothesis regarding
the clinical significance of the use of 5-ALA and a rela-
tionship with sleep are needed.
6. Conclusions and Recommendations
There appears to be a relationship between the admini-
stration of dietary supplements containing 5-ALA and
sleep. The results of this study suggest that 5-ALA does,
in fact, improve sleep. The mechanism for sleep im-
provement needs to be explored. Further research is war-
ranted to explore the mechanism by which 5-ALA may
play a role in the improvement of sleep.
Current research about 5-ALA and sleep is that 5-ALA
has an indirect relationship with intra-cellular energy
production and an effect on potentially neuroactive sub-
stances such as tryptophan, serotonin, or melatonin. En-
hanced cellular energy production could result in a wide
range of effects from cellular to endocrine to neurologic.
5-ALA as a key component of heme and the cytochrome
system appears to have an impact on increasing the en-
ergy of all cells. Research on cytochrome C oxidase ac-
tivity and ATP levels in mice in response to 5-ALA ap-
pears to confirm this effect [18]. In addition, animal stud-
ies indicate a possible effect on neurotransmitters which
may have an effect on the sleep-wake cycle.
Many sleep medications induce a tolerance and are
recommended only for short-term use. 5-ALA may assist
in the adjustment of a person’s circadian cycle, endocrine
function or neurologic function in order to allow for bet-
ter sleep in a natural way. In doing so, it may provide for
a safer alternative to currently available sleep medication.
Further research is needed to explore this possibility.
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