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Clinical Safety of a High Dose of Enriched Phycocyanin Aqueous Extract from Arthrospira (Spirulina) platensis --Part 2

- May 09, 2018 -

Clinical Safety of a High Dose of Enriched Phycocyanin  Aqueous Extract from Arthrospira (Spirulina) platensis: Results from a Randomized, Double-Blind, Placebo-Controlled Study with a Focus on Anticoagulant Activity and Platelet Activation 

Part 2

Gitte S. Jensen,0,1 Cassandra Drapeau,2 Miki Lenninger,1 and Kathleen F. Benson1

1NIS Labs, Klamath Falls, Oregon, USA.

2Cerule LLC, Klamath Falls, Oregon, USA.

0Corresponding author.


The goal for this study was to evaluate safety regarding anticoagulant activity and platelet activation during daily consumption of an aqueous cyanophyta extract (ACE), containing a high dose of phycocyanin. Using a randomized, double-blind, placebo-controlled study design, 24 men and women were enrolled after informed consent, and consumed either ACE (2.3 g/day) or placebo daily for 2 weeks. The ACE dose was equivalent to ∼1 g phycocyanin per day, chosen based on the highest dose Generally Recognized as Safe (GRAS) by the U.S. Food and Drug Administration. Consuming ACE did not alter markers for platelet activation (P-selectin expression) or serum P-selectin levels. No changes were seen for activated partial thromboplastin time, thrombin clotting time, or fibrinogen activity. Serum levels of aspartate transaminase (AST) showed a significant reduction after 2 weeks of ACE consumption (P < .001), in contrast to placebo where no changes were seen; the difference in AST levels between the two groups was significant at 2 weeks (P < .02). Reduced levels of alanine transaminase (ALT) were also seen in the group consuming ACE (P < .08). Previous studies showed reduction of chronic pain when consuming 1 g ACE per day. The higher dose of 2.3 g/day in this study was associated with significant reduction of chronic pain at rest and when physically active (P < .05). Consumption of ACE showed safety regarding markers pertaining to anticoagulant activity and platelet activation status, in conjunction with rapid and robust relief of chronic pain. Reduction in AST and ALT suggested improvement in liver function and metabolism.

Key Words: :  phycocyanin, anticoagulant activity, blood pressure, chronic pain, liver enzymes, platelet, P-selectin



The activation status of blood platelets plays an intricate role in blood coagulation. Due to the well-documented COX-2 inhibiting effects of phycocyanin,3–5 and therefore a potential role for interfering with platelet function,28–30 it was a central part of this study to evaluate various markers pertaining to platelet function and activation status (Fig. 2). During the 2-week study, no changes were seen in platelet numbers in subjects consuming a high dose of 2.3 g/day of the phycocyanin-enriched extract (Fig. 2A). A small but statistically significant reduction in mean platelet volume was seen in the group consuming ACE (P < .02) (Fig. 2B). No differences were seen between the placebo and ACE groups pertaining to platelet aggregation or platelet P-selectin expression, or serum levels of soluble P-selectin (Fig. 2C, D).


FIG.2 Phycocyanin Parameters pertaining to platelet numbers.jpg 

FIG. 2.

Parameters pertaining to platelet numbers (A) platelet count, (B) mean platelet volume and activation status, (C) platelet P-selectin expression, and (D) soluble P-selectin are shown as the group averages ± standard error of the mean. Consumption of ACE was associated with a miniscule but statistically significant reduction in platelet mean volume (*P < .02) and a mild reduction in serum levels of soluble P-selectin (*P < .06).


Clotting markers

Plasma was tested at baseline and after 2 weeks of consuming 2.3 g/day of the phycocyanin-enriched ACE (Table 5). There were no changes in aPTT or thrombin clotting time between the two groups. There was a mild but statistically insignificant increase in fibrinogen activity in the group consuming ACE, in contrast to the group consuming placebo.


Table 5. Phycocyanin Blood Clotting Markers.jpg 


Other observations

Data were collected regarding subjective observations from study participants, including gastrointestinal discomfort, since this could be a potential concern due to the COX-2 inhibiting properties of phycocyanin. There were no reports of gastrointestinal discomfort above what was normal for each study participant. Questions were also asked pertaining to bruising, gum health, and nose bleeds. One person consuming ACE reported mild bruising during the study, and three people consuming ACE, who did not normally notice bleeding gums, reported mild incidents of bleeding gums in association with brushing their teeth during the study.

Female pre-/perimenopausal study participants were asked about symptoms associated with menstrual discomfort as well as bleeding duration and intensity. However, there were only two pre-/perimenopausal female volunteers enrolled in the study, and both volunteers were in the placebo group. Thus, this study did not include systematic data collection on menstrual discomfort or bleeding intensity.

Reduction of chronic pain

To perform the safety evaluation in a study population that reflects the typical consumer of ACE, the study was conducted in a population with a long history of chronic pain but not diagnosed with a specific joint disease. Based on previous data on pain relief when consuming 1 g ACE per day, it is not surprising that a robust decrease in pain scores was seen in the ACE group in this study, where study participants were consuming 2.3 g/day (Fig. 3). Each individual's anatomical areas for chronic pain were identified before study start, based on the degree with which the pain interfered with daily living. Pain scores were collected for primary and secondary pain complaints at rest and when physically active. Pain scores for primary pain at rest and when active were similar between the two groups at baseline, but were statistically significant after 2 weeks (P < .05). The reduction in primary pain scores within the ACE group was highly significant (P < .01).


FIG. 3.Phycocyanin Pain scores shown as the group averages – standard error of the mean .jpg 

 FIG. 3.

Pain scores shown as the group averages ± standard error of the mean for (A) primary and (B) secondary pain complaints at rest and when physically active (C, D). Each individual's anatomical areas for chronic pain were identified before study start, based on the degree with which the pain interfered with daily living. Consumption of the ACE was associated with reduced pain scores. Pain scores for primary pain at rest and when active were similar between the two groups at baseline, but were statistically significant after 2 weeks (* <.05). The reduction in primary pain scores within the ACE group was highly significant (##P < .01). Pain scores for secondary pain at rest showed a statistical trend between the two groups ((*)P < .1) as well as within the group consuming ACE ((#)P < .1). The reduction in pain scores for secondary pain when active was statistically significant within the group consuming ACE (#P < .05).



The clinical study reported here is the first to address specific safety concerns about consumption of blue-green algal consumables and extracts thereof, where the content of the light-harvesting pigment phycocyanin has raised questions about potential anticoagulation effects in vivo. Edible blue-green algae include Spirulina and Aphanizomenon species and subspecies, containing the COX-2 inhibitor phycocyanin, as well as additional nonphycocyanin anti-inflammatory compounds.31 Due to the potential of reduced blood coagulation associated with phycocyanin consumption, a previous clinical study collected safety-related data when subjects consumed 1 g ACE per day for 4 weeks. The results showed no changes in standard safety parameters, including platelet numbers and blood chemistry.32 The study presented here involved consumption of 2.3 g ACE per day for 2 weeks and a comprehensive set of tests specifically pertaining to platelet activation and blood coagulation. The dose of 2.3 g ACE per day (equivalent to 1 g phycocyanin) was chosen based on the evaluation by the U.S. Food and Drug Administration where 1 g/day phycocyanin is Generally Recognized as Safe (GRAS).36 Data from this study showed no changes to blood pressure, ECG, blood chemistry, platelet numbers, and activation status as reflected by P-selectin expression. The consumption of ACE did not change aPTT or thrombin clotting time, nor did it reduce normal fibrinogen activity, suggesting that normal blood clotting ability was maintained. Subjective observations by some study participants included one case of increased bruising and three cases of incidents of bleeding gums while consuming ACE. This suggests that daily consumption of high doses of the phycocyanin-rich ACE may have a mild inhibiting effect on the blood clotting system, independent of the clotting factors and markers pertaining to platelet activation included in this study.

A mild but significant reduction in AST and a mild but insignificant reduction in ALT suggested a mild improvement in liver function. Even though the AST and ALT enzyme levels remained within the normal range, the reduction may be of some clinical significance. The effect may possibly be due to PCB uptake on digestive breakdown of phycocyanin, as PCB has been reported to protect liver function.37 A possible mechanism may include the role of Nrf2 in increasing liver enzymes.22

Due to an uneven gender representation in the study, gender-specific analysis is limited to the female population. Interestingly, the average percent of activated platelets in the blood circulation was reduced by 49% in females consuming ACE, in contrast to only 9% in the group of females consuming placebo, further suggesting a broad anti-inflammatory effect of ACE. The average reduction in soluble P-selectin was seen for both genders and was more robust in the male population consuming ACE (16% reduction), compared to the female population consuming ACE (8% reduction).

This study also verified previous documentation of relief of chronic pain associated with consumption of ACE. Based on previous data,32 it was not surprising that rapid and robust pain relief was seen for the higher dose used in this study. We suggest that the pain reduction may be due to the complex effects of phycocyanin in inhibiting COX-2 enzymatic activity, as well as PCB effects on reducing NADPH oxidase and increasing HMOX1 activity as the consumed phycocyanin is digested. Furthermore, the anti-inflammatory effects of the nonphycocyanin fraction include inhibition of lipoxygenase activity and additional anti-inflammatory effects, independent of phycocyanin.31 It is important that the observed relief of chronic pain was associated with a good safety profile pertaining to blood coagulation. Overall, anti-inflammatory effects, such as effects on C-reactive protein and inflammatory cytokines, were not included in this study.

In conclusion, this report adds substantial weight to the safety portfolio for phycocyanin-containing consumables and extracts. This 2-week study, even though short, was an important step in ongoing safety documentation, and based on the lack of safety concerns in a fairly healthy population, it should now be followed by longer studies. Future studies are warranted to expand on this safety documentation, including studies of longer duration and including premenopausal females. Further studies are also warranted for evaluating safety in the training athlete and other populations that may consume high amounts of phycocyanin-rich extracts to reduce pain and accelerate resolution of exercise-induced inflammation.


The study was conducted at NIS Laboratory, an independent contract research laboratory specializing in natural products research. The study was sponsored by Cerule LLC, the manufacturer and distributor of the nutraceutical extract tested in this study.

Author Disclosure Statement

G. S.J., M.L., and K.F.B. are employees at NIS Laboratory, an independent contract research laboratory specializing in natural products research. C.D. is employed by the study sponsor Cerule LLC.


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