Fact Sheet
Update on BMAA
In 2003, the hypothesis was raised that a causal link existed
between exposure to the non-protein amino acid BMAA
(beta-amino-L-alanine - produced by some species of
cyanobacteria) and a number of human neurodegenerative
diseases including Alzheimer’s Disease, ALS (amyotrophic
lateral sclerosis; also known as motor neurone disease or
MND), and Parkinson’s Disease (1). This theory evolved from
a chain of evidence dating back to the 1950s when research
was undertaken into the possible environmental causes
for elevated frequencies of ALS and Parkinson’s Disease
among the indigenous people on the Pacific island of Guam.
Studies of the traditional diet led to a search for neurotoxic
compounds in native trees of the Cycad family, resulting in
the identification of BMAA in 1967. BMAA is an amino acid
that is not normally found in proteins. A number of such nonprotein amino acids have been identified in plants, and have
been hypothesised to play a role in defences against grazing
by herbivores and/or to act as signalling compounds in plant
metabolism.
BMAA in flour made from the seed of cycad trees on
the island was initially postulated as the causative agent
of neurological diseases in Guam, but this theory was
abandoned when animal studies failed to demonstrate
neurotoxic effects except at exposures hugely in excess
of possible human consumption levels. In addition, there
was no recognised mechanism by which a water-soluble
compound such as BMAA could accumulate in the body, and
therefore chronic accumulation of BMAA to reach toxic levels
did not appear to be feasible.
Decades later, researchers at the Institute of Ethnobotany
in Hawaii reported that BMAA could bioaccumulate in the
Guam food chain, leading to high levels of human exposure
through traditional consumption of flying foxes (large bats)
which feed on cycad seeds (2). It was suggested that BMAA
could be erroneously incorporated into protein, forming a
persistent endogenous reservoir from which BMAA could
be released during protein metabolism, and thus providing
a mechanism to explain chronic effects. This hypothesis
was supported by small studies demonstrating detection
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of BMAA in the brains of people who had died from
neurological diseases, but not in those who had died from
non-neurological causes.
It was also reported that BMAA was synthesised by Nostoc
cyanobacteria living in a symbiotic association with cycad
roots, rather than being produced directly by the trees. A
subsequent survey of cyanobacterial strains from several
countries showed the presence of BMAA in a wide range
of free-living and symbiotic cyanobacteria, including some
species which occur in freshwater bodies used as drinking
water sources (3). Cyanobacteria are a major component
of both freshwater and marine food chains, so this finding
opened the possibility that BMAA exposure through food
and water might be widespread in human populations,
rather than being confined to the few locations where Cycads
are currently found. The resultant media publicity largely
accepted this preliminary hypothesis as established fact and
speculated that exposure to BMAA in drinking or recreational
water could be a major cause of neurological diseases in the
community.
Since 2003, more than 200 papers on BMAA have been
published but definitive evidence of the involvement of
BMAA in human neurological disease has not yet been
demonstrated. A substantial proportion of the publications
have not contributed any new data, but have simply
reiterated the hypothesis and in some cases extended the
scope of conjecture. There have been a number of studies
on the toxicological effects of BMAA in vitro and in vivo. A
range of adverse effects on neurological and other cell types
have been reported, but in the absence of information on
dietary BMAA intake, absorption via the digestive system and
resultant concentrations in body tissues, it is not possible
to determine how relevant these effects are to actual
human exposure levels. Despite the postulated importance
of bioaccumulation of BMAA through the food chain to
reach levels high enough to cause toxic effects in the Guam
scenario, there have been few reports of testing for BMAA
in fish, shellfish or crustaceans, which might be expected to
form a major route of human exposure to this substance.
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 Epidemiological evidence has been sought by re-examining
past studies of apparent geographic clusters of ALS in an
effort to establish links with exposure to cyanobacterial
blooms or consumption of fish, but the lack of systematic
records limits the quality of such retrospective analyses, and
no conclusions could be drawn.

including interactions with known neurotoxicants, and
measuring BMAA levels in dietary supplements derived from
cyanobacteria to assess levels of public exposure. This study
will definitively establish whether BMAA is incorporated into
proteins and the outcomes will determine whether further
testing is undertaken by the NTP.

In addition, there has been controversy in the literature
about the reliability of different BMAA assay methods, and
a direct comparison of three detection methods indicated
that use of highly selective assay methods produced
BMAA estimates 10 to 100-fold lower than the more
commonly used but less selective techniques (4). Similarly, a
commercially marketed ELISA kit for water testing was also
found to produce overestimates of BMAA and false positive
results. A recent review concluded there is serious doubt as
to whether BMAA was identified correctly in some studies
because of poor analytical methods, or because inadequate
reporting of analyses made it impossible to verify the results
(5). This has thrown doubt on the results of surveys showing
BMAA production to be common among cyanobacteria,
and there have been conflicting reports from groups using
different assay methods on BMAA occurrence in human brain
tissues. Advancement of the science on this issue will require
development and use of selective, inter-laboratory validated
methods and detailed reporting of the analytical work to
ensure that results are accepted as reliable.

The study of risk factors for neurological diseases is difficult
because of the long time frames involved, and there is
increasing evidence that subtle neurological changes may
occur years or even decades before disease symptoms
become apparent. Risks from exposures to BMAA or other
postulated environmental toxins (e.g. pesticides, heavy
metals) may relate to cumulative exposure over many years
or exposure at critical time periods for the neurological
system (perhaps even in utero). The picture is further
complicated by the possible role of variations in genetic
susceptibility in the population, and the potential for
interactions between different environmental factors.

A new epidemiological study conducted by the French
National Research Agency is investigating possible links
between ALS and BMAA (6). The project is focusing on
ten counties in three regions of France and will include
all ALS cases diagnosed between 1 January 2003 and 31
December 2011. The study will collect information on
exposures and behaviours from both ALS cases and healthy
controls, examine clinical samples for the presence of
BMAA, and sample for cyanobacteria and test their BMAA
content. BMAA analysis will be conducted using liquid
chromatography (LC) coupled to tandem mass spectrometry
(LC-MS/MS), which is recognised as a specific and accurate
analytical methodology. Exposures to other suspected
occupational and environmental risks factors for neurological
disease will also be assessed. The three year study, which
began in early 2012, should provide high quality data
to either confirm or refute the involvement of BMAA in
development of ALS.
In addition, an extensive study of BMAA metabolism is
currently being undertaken by the US National Toxicology
Program (NTP). This study, performed in rats and mice of
both genders, is evaluating the fate of radioactively labelled
BMAA administered by single and multiple oral doses, and by
intravenous injection. The study will assess the disposition of
BMAA in various body tissues, seek to identify metabolites
of BMAA and track elimination via urine, faeces and exhaled
breath. The effect of fasting and other dietary variations
will be examined to test the hypothesis that BMAA may be
released during protein catabolism. Other proposed work
includes an examination of the biological activity of BMAA,
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At present the evidence on BMAA is not sufficient to
conclude whether this compound is a contributing factor to
human neurological disease. There is also uncertainty about
how common BMAA production is among cyanobacterial
species, and insufficient information to characterise
current human exposure levels and determine the relative
importance of drinking water, recreational water, food
or other sources. Research studies currently underway
should help to resolve some of the major uncertainties that
currently limit understanding of the significance of BMAA to
human health.
References
1.

Biomagnification of cyanobacterial neurotoxins and
neurodegenerative disease among the Chamorro
people of Guam. Cox PA., Banack SA, et al. (2003). PNAS
100(23): 13380-3.

2.

Cycad neurotoxins, consumption of flying foxes, and
ALS-PDC disease in Guam. Cox PA and Sacks OW. (2002)
Neurology 58 956-959.

3.

Diverse taxa of cyanobacteria produce beta-Nmethylamino-L-alanine, a neurotoxic amino acid. Cox PA,
Banack SA, et al. (2005). PNAS 102(14): 5074-8.

4.

A comparative study on three analytical methods for the
determination of the neurotoxin BMAA in cyanobacteria.
Faassen EJ, et al. (2012) PLoS ONE 7(5).

5.

Presence of the neurotoxin BMAA in aquatic ecosystems:
what do we really know? Faassen EJ, (2014) Toxins 6,
1109-1138; doi:10.3390/toxins6031109

6.

Searching for a link between the L-BMAA neurotoxin
and amyotrophic lateral sclerosis: a study protocol
of the French BMAALS programme. Delzor A,
Couratier P,Boumédiène F, et al. (2014) BMJ Open
2014;4:e005528. doi:10.1136/bmjopen-2014-005528

This fact sheet is an update based on the information
provided in Health Stream issue 72, January 2014.
March 2015 Page 2