Report of Morinda citrifolia chronic toxicity not applicable to commercial noni juice

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Report of Morinda citrifolia chronic toxicity not applicable to commercial noni juice
Brett J. West
Research and Development, Morinda, Inc, 737 East 1180 South, American Fork, UT 84003
Email: brett_west@morinda.com
DOI: 10.1016/j.yrtph.2017.03.014
© 2017. This manuscript version is made available under the CC-BY-NC-ND 4.0
license http://creativecommons.org/licenses/by-nc-nd/4.0/

Letter to the Editor
In a recent issue of this journal, a chronic oral toxicity test of Morinda citrifolia fruit and
leaf extracts was reported (Mohamad Shalan et al., 2017). Within this report, the authors claim
that results of their study provide supporting evidence to a presumed causal link between noni
juice ingestion and liver injury, that was suggested in previously published case reports.
However, the authors’ claim is not supported by their study, due to shortcomings in the
experimental design, and is not consistent with existing data.
Mohamad Shalan et al. explain that the controversial outcomes in the literature, including
7 cases of hepatotoxicity in patients that had been consuming noni preparations, were the
justification for conducting their study, as there were other significant confounding factors in
each case which could been the causes of liver injury (Brown, 2012). However, the noni fruit
extract evaluated by them was not representative of typical commercial noni juice products,
especially those identified in the case reports. In preparing the test material, it appears that the
authors gave no consideration to the type of noni preparations described in the case reports.
Instead, they prepared an aqueous extract from dried whole noni fruit, with the seeds and skin
included. In four of the case reports cited, the exact brand of product was known and disclosed
(Stadlbauer et al., 2008). The product associated with three of the cases was identified as
Tahitian Noni® Juice. This particular brand of noni juice is made from noni fruit puree, where
the skin and seeds have been removed, and is free of anthraquinones (Westendorf et al., 2007;
Deng et al., 2009; Deng et al., 2010; Bussman et al., 2013). The unidentified noni products
associated with two of the other cases are also likely to have been free of seeds, skin, and
anthraquinones, as these cases occurred in Austria and Germany. At that time only Tahitian
Noni® Juice, or a substantially equivalent brand, had been approved for sale in those countries.

In the most recent case cited, chemical analysis of identified product revealed that it contained no
anthraquinones and < 1% noni fruit juice, with the patient having ingested no more than 6 mL in
total (West and Deng, 2011). In all of these cases, significant confounding factors
As the test material prepared by Mohamad Shalan et al. contained substances not present
in the noni juice products described in the case reports, their study does not provide any
additional support for a link between noni juice ingestion and the reported liver injury.
Additionally, their argument that anthraquinones were likely the causative agents is also not
supported because these simply were not present in the noni juice products available to most of
the patients in these case reports.
Another deficiency of the study is the number of animals. The authors reported
following an Organization for Economic Cooperation and Development protocol, OECD 452.
However, OECD 452 calls for including 20 animals per gender for each dose group evaluated
(OECD, 2009). The authors included only five female ICR mice per dose group, citing budget
limitations. While this limitation is understandable, it precludes a thorough statistical evaluation
that is called for by OECD 452. The influence of such a shortcoming is further seen in the
clinical chemistry measurements, where only 3 animals per group where used for the analyses.
The standard deviations of aspartate aminotransferase (AST) and alanine aminotransferase
measurements are so large in the noni fruit extract high dose group that they prevent any
meaningful comparison to the controls. This high variability undermines the authors suggestion
that the data provides evidence of a dose-response. Further, the declining alkaline phosphatase
values seen in the test groups do not support a liver injury conclusion.
The authors report that hepatocellular necrosis was observed in the noni fruit extract
groups and that two animals died, one during week 9 and the other at 13 weeks. While the

occurrence of these observations is not in question, their significance is. As noted above, the
number of animals in each dose group is much smaller than required by OECD 452. One reason
for including larger numbers of animals in each group is to control for potential skewing of
outcomes by spontaneous diseases that are unrelated to treatment, such as the all-too-common
mouse hepatitis virus (Pritchett-Corning et al., 2009). The inadequate sample size is further
highlighted by the fact that the conclusions of Mohamad Shalan et al. do not agree with those
previously reported in other studies of M. citrifolia fruit. Although these other repeat dose
studies in rodents were not carried out for 6 months, they did extend for the same amount of time
(13 weeks) within which the deaths were reported to occur and the presumed hepatotoxicity
began to develop. One of these studies even evaluated an aqueous extract of whole noni fruit
from Malaysia, similar to the test material prepared by Mohamad Shalan et al., but at much
higher doses. This 13-week oral toxicity test of the extract, at 2000 and 5000 mg/kg body weight
(b.w.), in Sprague-Dawley (SD) rats did not produce mortality or liver injury (Rosly et al., 2011),
with the high dose being 25 times greater than that evaluated by Mohamad Shalan et al. The
group sizes in the Rosly et al. study were 20 (10 males and 10 females).
More relevant to the noni preparations associated with the case reports are the findings of
a 13-week oral toxicity test of freeze-dried noni fruit puree in SD rats, with a high dose of 6.86
g/kg b.w., wherein no mortality or toxicity was observed (West et al., 2009). No deaths or liver
injury occurred in two 13-week oral toxicity studies involving consecutively higher doses of
Tahitian Noni® Juice up to 80 mL/kg b.w. (West et al., 2006a). Additionally, an 18-week study
of 10% noni juice in drinking water (approximately equivalent to 10 mL noni juice/kg b.w. per
day) provided no evidence of liver injury in female SD rats, even when they had been exposed
concurrently to carbon tetrachloride (Wang et al., 2008).

Nine and a half years of post-market surveillance of Tahitian Noni® Juice revealed that
more than 80 million bottles were sold, with 304 health related complaints received from
consumers during this time (European Food Safety Authority, 2006). This is approximately one
health related complaint for every 250,000 bottles sold. The complaints were catalogued
regardless of the authenticity of the reported event, an actual diagnosis by a physician, or receipt
of valid medical records. Aside from the case reports already cited, no other cases of liver injury
were reported by these consumers. Considering this, and a documented history of noni fruit as
part of the diet of aboriginal populations of the Pacific region (West et al., 2006b), it seems
unlikely that typical commercial noni juice is directly toxic to the liver.

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