Spirulina did not Ameliorate Idiopathic Chronic Fatigue in four N-of-1 Randomized
Cristian Baicus1,2* and Anda Baicus3
1 Department of Internal Medicine, Spitalul Colentina, Soseaua Stefan cel Mare 19-21, sect. 2,
020125 Bucharest, Romania
2 Clinical Research Unit RECIF (Réseau d’Epidémiologie Clinique International
Francophone), Bucharest, Romania
3 I. Cantacuzino National Institute of Microbiology, Bucharest, Romania
Idiopathic chronic fatigue is an exclusion diagnosis established when no chronic disease is
found. Spirulina platensis is an alga with a rich content of proteins, vitamins, minerals and
amino acids and is considered as a bioactive additive with multiple effects, among them being
effects against fatigue. However, despite the worldwide utilization of Spirulina, there are only
a few quality studies with it and none concerning fatigue. The Nof- 1 randomized trials are
made on one patient, and by this kind of study the efficacy of a treatment on that particular
patient can be assessed. A series of four N-of-1 double-blind, randomized trials were
performed on four physicians who complained of chronic fatigue. Each patient was his own
control and received three pairs of treatments comprising 4 weeks of spirulina and 4 weeks of
placebo. Spirulina platensis was administered in a dose of 3 g/day. For each pair, the order of
treatments was randomized. Outcome measures were severity
of fatigue measured on a 10-point scale.
The scores of fatigue were not significantly different between spirulina and placebo.
Spirulina administered in a dose of 3 g/day did not ameliorate fatigue more than the placebo
in any of the four subjects, and possibly it has no effect on chronic fatigue. Copyright © 2007
John Wiley & Sons, Ltd.
Keywords: spirulina; N-of-1 trial; single-case research; randomization; double-blind.
The term spirulina refers to a large number of cyanobacteria, or blue-green algae, which are a
rich source of nutrients, containing up to 70% protein, B-complex vitamins, phycocyanin,
chlorophyll, betacarotene, vitamin E and numerous minerals (Cifferi, 1983). Spirulina has
been said to possess a variety of medical uses. However, these uses have not been thoroughly
studied in humans, and there is limited scientific evidence about safety or effectiveness.
Scientists have studied spirulina for the following health problems: high cholesterol (Ionov
and Basova, 2003; Samuels et al., 2002), diabetes (Mani et al., 2000), oral leucoplakia
(Mathew et al., 1995), chronic viral hepatitis (Baicus and Tanasescu, 2002) and malnutrition
(Branger et al., 2003).
Fatigue is a common complaint, which may account for up to 37% of patients presenting to
family physicians with general weakness or tiredness for any length of time (Okkes et al.,
2002). One of the indications of Spirulina, claimed by numerous manufacturers, is idiopathic
chronic fatigue. Because of the lack of evidence and based on mixed anecdotal reports, it was
decided to perform N-of-1 trials on four of our colleagues who complained of chronic fatigue.
One of them was a resident who had taken spirulina previously for fatigue and had reported
The N-of-1 trials are randomized controlled trials (RCTs) in individual patients. Built on the
work of experimental psychologists with single-case or singlesubject research, they maintain
the methodological safeguards provided by RCTs (Portney and Watkins, 1993; Guyatt et al.,
1986). Because they determine the best care for the particular patient of interest, without
issues of external validity, they were situated recently at the top of the hierarchy of strength of
evidence for treatment decisions, above systematic reviews of randomized trials (Guyatt et al.,
Each subject received three pairs of treatments starting in March 2004. Each pair consisted of
a 4 week period of Spirulina platensis treatment (1 g t.i.d.) and a 4 week period of placebo
treatment (Fig. 1). For each pair of treatments the order of spirulina and placebo was
randomized. The random sequence was prepared in advance by one of the investigators for
each subject separately. Only that investigator (who did not participate in the assessment of
the subjects) was aware of the sequence of treatments. Identical capsules of similar colour,
smell and taste were used to ensure blinding. Washout periods were interpolated between the
periods of treatment in order to avoid the carry-over effects. Because no information, either in
the literature or in the package insert, was found concerning the amount of time necessary for
the full effect and/or cessation of action once stopped, durations were chosen that were
considered long enough for the treatment (1 month) and for the wash-out (2 weeks).
To eliminate carry-over effects, fatigue was measured only during the second half (weeks 3
and 4) of the ‘treatment’ periods.
The measured outcome was fatigue, self-evaluated by every subject on a ten-point scale (0 –
severe fatigue, 10 – no fatigue). Because subjects 1 and 2 complained of matinal (wake-up),
and postprandial fatigue, respectively, they evaluated their type of fatigue. The others
evaluated fatigue for the whole day. Every subject kept a diary where he marked the score
daily, during the second half of each ‘treatment’ period (either spirulina or placebo). Because
the single case design was used, all outcome measures were analysed for each patient
separately. The subjects recorded 14 scores for every ‘treatment’ period, for which the mean
score was calculated. At the end of the trial, there were three pairs of mean scores (Table 1)
which were analysed, as indicated by other authors (Sackett et al., 1991; Guyatt et al., 2002b),
with a Student’s paired t-test. GraphPad InStat 3.06 for Windows was utilized for statistics
(GraphPad Software, Inc., San Diego California USA, www.graphpad.com). The difference
was considered significant when p < 0.05.
Four N-of-1 randomized trials were made on four physicians (a specialist and three residents)
who complained of idiopathic chronic fatigue. The subjects had no organic disease and did
not fulfil the criteria for depression or chronic fatigue syndrome. They did not take any
concomitant medication. Their ages were 40, 31, 29 and 28 and they were three men and a
woman. All the subjects completed the 36 week trial. None of the subjects reported any side
The fatigue scores are summarized for every patient as box-plot graphs in Figs 2–5. As can be
seen by visual inspection, there did not appear to be a difference between spirulina and
placebo in any of the four patients.
The mean scores for the treatment periods are given in Table 1. No significant difference
between spirulina and placebo concerning the fatigue score (p > 0.05, Table 1) was found.
As a result, the resident who used to take spirulina before the trial discontinued its use.
Spirulina platensis administered in a dose of 3 g/day did not ameliorate fatigue more than
placebo in any of the four subjects. Spirulina is produced and sold worldwide. In Romania it
is both produced locally and imported, and it is expensive.
Spirulina is a nutritive supplement which, based on theory and tradition, is supposed to have
multiple beneficial effects. However, most have not been proven by quality clinical studies,
the great majority of the studies being of grade C of evidence (unclear scientific evidence for
this use) and even grade D (fair scientific evidence against this use).
One of the unproven indications of spirulina is idiopathic chronic fatigue, and we proceeded
to this series of four N-of-1 randomized trials, at the end of which it was concluded that, in
the four subjects, spirulina did not ameliorate fatigue.
There is no other study concerning the utilization of spirulina in idiopathic chronic fatigue. In
fact, this is one of the indications for N-of-1 studies (Sackett et al., 1991): without any
previous valid research, the effectiveness of spirulina in chronic fatigue was in doubt.
Spirulina was not efficient for the treatment of idiopathic chronic fatigue in our subjects.
However, it might be efficient in other patients. Apart from this study, there is no valid proof
that spirulina might be efficient for chronic fatigue in any subject. In order to demonstrate
this, the producers should conduct RCTs.
Hofigal SA Bucharest furnished the medication and placebo.
Baicus C, Tanasescu C. 2002. In chronic viral hepatitis, the treatment with spiruline for one
month has no effect on the aminotransferases. Rom J Intern Med 40: 89–94.
Branger B, Cadudal JL, Delobel M et al. 2003. Spiruline as a food supplement in case of
infant malnutrition in Burkina- Faso [Article in French]. Arch Pediatr 10: 424–431.
Cifferi O. 1983. Spirulina, the edible microorganism. Microbiol Rev 47: 551–578.
Guyatt G, Haynes B, Jaeschke R et al. 2002a. Introduction: the philosophy of evidence-based
medicine. In User’s Guides to the Medical Literature. A Manual for Evidence-based
Medicine, Guyatt G, Rennie D (eds). American Medical Association Press: Chicago; 2–12.
Guyatt G, Jaeschke R, McGinn T. 2002b. Therapy and validity. N of 1 randomized controlled
trials. In User’s Guides to the
Medical Literature. A Manual for Evidence-based Medicine, Guyatt G, Rennie D (eds).
American Medical Association Press: Chicago; 275–290.
Guyatt GH, Sackett D, Taylor DW et al. 1986. Determining optimal therapy – randomized
trials in individual patients. N Engl J Med 314: 889–892.
Ionov VA, Basova MM. 2003. Use of blue-green micro-seaweed Spirulina platensis for the
correction of lipid and hemostatic disturbances in patients with ischemic heart disease. Vopr
Pitan 72: 28–31.
Mani UV, Desai S, Iyer U. 2000. Studies on the long-term effect of spirulina supplementation
on serum lipid profile and glycated proteins in NIDDM patients. J Nutraceut 2: 25–32.
Mathew B, Sankaranarayanan R, Nair PP et al. 1995. Evaluation of chemoprevention of oral
cancer with Spirulina fusiformis. Nutr Cancer 24: 197–202.
Okkes IM, Oskam SK, Lamberts H. 2002. The probability of specific diagnoses for patients
presenting with common symptoms to Dutch family physicians. J Fam Pract 51: 31– 36.
Portney LG, Watkins M. 1993. Single-case experimental designs. In Foundations of Clinical
Research. Applications to Practice.
Appleton and Lange: Norwalk; 191–232.
Sackett D, Haynes B, Guyatt G, Tugwell P. 1991. Clinical Epidemiology. A Basic Science for
Clinical Medicine, 2nd edn. Little, Brown: Boston; 223–238.
Samuels R, Mani UV, Iyer UM, Nayak US. 2002. Hypocholesterolemic effect of spirulina in
patients with hyperlipidemic nephrotic syndrome. J Med Food 5: 91–96.
Figure 1. Study design
Figure 2. Fatigue scores evolution in patient 1.
Figure 3. Fatigue scores evolution in patient 2
Figure 4. Fatigue scores evolution in patient 3.
Figure 5. Fatigue scores evolution in patient 4.
Table 1. Results of the N-of-1 RCT of spirulina in four subjects with asthenia