The range of dietary supplements available to the consumer has been increasing, and nutraceuticals are an expanding sector of this market. They are being studied not only for use in diet supplementation but also for development as drugs for the treatment of a huge range of major diseases including cancer and Alzheimer’s disease. Stephen De Felice of the Foundation for Innovation in Medicine was the first to use the term, defining a nutraceutical as a “food, or parts of a food, that provide medical or health benefits, including the prevention and treatment of disease”.

1. Adverse Effects and
Toxicity of
Nutraceuticals
Prepared by,
Himanshu Vasanta Suryawanshi
2021T14M
Mtech Food Technology
CFT, VNMKV, Parbhani

2. Focus of Discussion
1. Introduction
2. General Adverse Effects
3. Drug Interactions
4. Problems with Formulated Products
5. Most Common Nutraceuticals
• Carnitine and Acetyl-L-Carnitine
• Isoflavones
• Proanthocyanidins
• Melatonin
• β-carotene
• Glucosamine
6. Adverse effects – At a glance
7. Conclusions

3. Introduction
• Nutraceuticals are one of the expanding
sectors in the market.
• Studied for use in diet supplementation as
well as for development as drugs for the
treatment of a huge range of major diseases.
• Stephen De Felice of the Foundation for
Innovation in Medicine (FIM) was the first to
use the term.
• He defined nutraceutical as “food, or parts of
a food, that provide medical or health
benefits, including the prevention and
treatment of disease”.

4. Differences
Side Effects Adverse Effects
Therapeutic and harmful Harmful and undesirable
Expected by the doctor Not expected by the doctor
Do not hinder the main effect Hinder the treatment and
lead to more complications
Mild and self-resolving More severe and life
threatening
Toxicity
The degree to which a
substance (a toxin or poison)
can harm humans or animals
Occurs when person has
accumulated too much drug
in bloodstream
Occurs when dose given is too
high so that liver or kidney
unable to remove from the
bloodstream
Pharmacokinetics – study of what the body does to drug.
Pharmacodynamics – study of what the drug does to body.

5. General Adverse Effects
Nutraceuticals are frequently involved in basic metabolic
pathways in the body and, as such, are closely involved in
the metabolism of these nutrients.
• Availability of one nutrient may impair or enhance
the action of another in the immune system.
• Decreased absorption of any prescription drug may
occur with concomitant dosing with certain
nutraceuticals.
• Increased antibiotic and antimicrobial resistance
caused by certain nutraceuticals, certain products
shows interaction with antibiotics.
• Interference in normal mechanism of nutraceutical.

6. Drug Interactions
© REVIEWS IN FOOD AND NUTRITION TOXICITY by Victor R. Preedy and Ronald R. Watson

7. Special care should be taken
1. With prescription drugs.
2. With certain opium derivatives.
India being the world’s largest manufacturer for legal
opium pharmaceutical industry.
3. With foods high in Tyramine.
(Cured, smoked, or processed meat; hot dogs,
sauerkraut, bacon, pepperoni, pickles (cucumber)).
Tyramine tighten blood vessels and increases blood
pressure by triggering nerve cells to release
norepinephrine.

8. Problems with Formulated Products
• A formulated product is composed of at least
two ingredients which are selected,
processed and combined in a specific way
to obtain well-defined target properties,
functionality and performance. It can exist in
liquid, semisolid or powder form.
• May be formulated differently, leads to
variations between products of different
manufacturers.
• e.g, L-tryptophan formulated with 3-
phenylamino alanine causes sub-chronic
toxicity.

9. Carnitine and Acetyl-L-Carnitine
• Synthesized from lysine and methionine
in liver, kidney and brain.
• Used for Alzheimer’s disease, HIV, chronic
fatigue syndrome, CVD diseases.
Forms of carnitine:

10. Functions
1. Transfer of long-chain fatty acids across the
inner mitochondrial membrane.
© Hussain Biology

11. 2. Facilitation of ketogenesis.
(Metabolic pathway that produces ketone bodies,
which provide alternative pathway form of energy)
CPT-1 Acetyl
CoA
Acetoacety
l- CoA
ACAT or
Thiolase
HMG-CoA
HMG-CoA
synthase Acetoacet
ate
HMG
CoA
lyase
Acetone
Beta hydroxy
butyrate
Non enzymatic
decarboxylation
Beta hydroxy
butyrate
dehydrogenas
e
Acetoacet
ate
Beta hydroxy
butyrate
dehydrogenase
Acetyl
CoA
Carnitine
palmitoyl
transferase
Citric acid
cycle
Oxidative
phosphorylation
β-ketoacyl CoA
transferase
22 ATP
https://www.ncbi.nlm.nih.gov/b/ooks/NBK493179

12. 3. Shuttling of acyl-CoA products of peroxisomal
α-oxidation to mitochondrial matrix of the
liver.

13. Why/When do we need carnitine
supplementation?
Because of Drug-induced carnitine deficiency has been
linked with the drugs sodium valproate, isotretinoin,
and pivampicillin.
1. Sodium Valproate:
Interferes with carnitine and forms valproyl-CoA
and valproyl carnitine.
2. Isotretinoin:
Adverse effects like myalgia, weakness, and
hypotension because of the carnitine deficiency,
may cause liver dysfunction, as liver is the site
for the synthesis of carnitine. © Andrea Penaloza, Soheil Zahir, and Mireille Gris

14. 3. Pivampicillin:
Cleavage of pivalic acid in intestine by esterases and
forms esters with carnitine and excreted in urine as
pivaloyl carnitine.
Prolonged treatment with pivampicillin leads to
decrease in circulating carnitine levels.

15. Adverse effects and Toxicity
i. Pungent skin odor to ADHD childrens due to
the formation of trimethylamine.
ii. Fishy odor or urine odor to Rett syndrome
girls.
iii. Gastrointestinal effects like nausea,
vomiting, diarrhea by carnitine as well as
acetyl-l-carnitine.
iv. Diarrhea and Fish odor syndrome when
ODd (5 g/d) by an adult.
v. Aggression, agitation and transient
seizure activity by acetyl-l-carnitine.
vi. Carnitine is promoted as ergogenic aid
because of vasodilatory properties.

16. vii. D-carnitine
D isomers when taken interferes with normal
function of L-isomer.
When administered there may be depletion in
L-carnitine in cardiac and skeletal muscle thus
cause arrhythmia and muscle weakness.
Banned in US.
Dosage
• Healthy children and adults do not need to
consume carnitine from food or
supplements.
• FDA approved carnitine for only carnitine
deficient peoples and recommended less
than 3 grams a day.

17. Isoflavones
• A phytoestrogen that occur naturally in conjugated
and unconjugated forms.
• e.g, Tofu contains high levels of glycoside conjugates
daidzein and genistein. Miso have ≈90% conjugated
daidzein and genistein.
• Binding of isoflavones to estrogens seems to have an
antiestrogenic effects premenopausally, but, estrogen
receptors acts as agonists postmenopausally.

18. Functions
1. Activate estrogen receptors.
Isoflavones are structurally similar to 17-β-estrdiol, which
activates estrogen receptors (ERα and ERβ).
2. Inhibits the activity of growth promoting
steroid hormones.
Inhibits progesterone 5 α reductase as it converts
testosterone into dihydrotestosterone (DHT).
© Advanced Bio-Resource Research Center, Kyungpook National University, Daegu 41566, Korea
© Jillian Levy, CHHC

19. 3. Inhibits Angiogenesis.
Genestein which has anticarcinogenic
property blocks the growth of blood vessels
that support tumor growth.
4. Inhibits ATP hydrolyzing DNA topoisomerase.
Topoisomerases helps DNA to wound and to prevent over
wound.
Topoisomerase I cuts only single strand. No need of ATP.
Topoisomerase II cuts doble stranded, needs 2 ATP.

20. Toxicity
Phytoestrogens have properties like teratogenic,
mutagenic and carcinogenic.
1. Teratogenic:
• Infertility syndrome: Ewes grazing on pastures of
Trifolium subterranean containing isoflavone
precursor formononetin. Metabolism of this
compound leads to the formation of equol (weak
estrogen). This equol gets absorbed, achieves high
blood concentrations which result in permanent
damage of reproductive organs of ewe.
• Veno-occlusive liver disease: In feline’s liver
because of their inability to deactivate unconjugated
isoflavones by conjugating with glucuronic acid.

21. 2. Carcinogenic and Mutagenic:
• Breast cancer: Due to increase in number of
epithelial cells in the S-phase of cell phase.
As soy proteins have estrogen agonist effects on breast.
• Leukemia in infants: particularly ALL. By
chromosomal translocations involving MLL gene.
Isoflavones (genestein and diadzein) have been identified as
substances that cause DNA cleavage in the MLL breakpoint
cluster region (BCR).
Only 200μm of diadzein produced 50% MLL gene cleavage.
• Neuronal apoptosis: from high doses of genistein
(around 50μm).
© National Cancer Institute (US)

22. Adverse effects
1. Loss of appetite, pedal edema, abdominal tenderness –
from single dose of daidzein, genistein and glycitein to
healthy men.
2. Pancreatitis, acute pancreatitis, leucopenia,
hypophosphatemia.
• Genistein inhibits phosphate reabsorption and
increases phosphorous excretion by kidney.
• Also changes phosphorous deposition in the bone.
• Low phosphorous over an extended period of time
may inhibit bone formation.
3. In women, pedal edema, nausea, breast tenderness.
Because of estrogenic effect of isoflavones and HRT
(Hormone replacement therapy) in menopause women.
Dosage:
North American Menopause
Society recommends dose of
50mg/day.
For postmenopausal women :
900mg/day

23. Proanthocyanidins:
• Isoflavones and proanthocyanidins
(condensed tannins) are a subgroup of
bioflavonoids.
• Naturally occur in flowers, fruits, vegetables,
bark.
• Based on Flavanol (flavan-3-ol) ring.
Catechin – trans – green tea
Epicatechin – cis – cacao beans, green tea
Epigallocatechin – green tea
Gallocatechin – green tea
+
catechin epicatechin
proanthocyanidin

24. Toxicity and Adverse effects
1. Prooxidation: high levels of antioxidants.
Three factors can influence the function of
an antioxidant transforming it to a
prooxidant:
• Presence of metal ions
• Concentration of the antioxidant in matrix
environments
• Redox potential
2. Cardiovascular damage and atherosclerosis.
(On high dosage)
3. Esophageal cancer
By consuming some tannin rich foods like
betel nuts and herbal teas.

25. t
4. Toxic to erythrocytes, hepatocytes and
kidney.
o In very high doses of catechin i.e,
100mg/100g body weight.
o In combination with iron, it may affect
fatty acid metabolism.
5. Male infertility:
o Epicatechin–(4-β-8) may be used as
contraceptive drug for men.
o But on high doses it shows strong
inhibitory effect on sperm motility.
Dosage:
Preferred: 100-300 mg/day.
Low doses of 30-100 mg/day has
antioxidant properties whereas,
high doses of 1000 mg/day shows
prooxidant effects.

26. Melatonin
• It is a hormone produced by pineal glands in
darkness but not in bright light.
• Derivative of serotonin – also plays role in
sleeping and body’s day-night orientation.
• Principle: Receptors found in nucleus
situated above optic chiasma, these react with
melatonin and thus becomes synchronized to
the day-night rhythm on the release of
melatonin.

27. As melatonin is proposed to control circadian
rhythms thus it has been used for –
• Jet lag
• Sleep disorders
• Aging
• Antioxidant properties
• Cancer
• Enhanced immunity and reproduction
In US and India, melatonin is available without
prescription, whereas in Europe this cannot be
sold OTC (over the counter).
The lowest dose available in OTC preparation
(0.3mg) produces levels that are comparable
with natural nocturnal melatonin.

28. During the synthesis of melatonin, which derives
from L-tryptophan, the metabolite L-kynurenine,
along with others, are found in the metabolic
pathway. This compound has been reported to have
a convulsant effect, and another metabolite,
quinolinic acid, has been reported to be a neurotoxin
that has neuroexcitatory activity at the level of the N-
methyl D-aspartate receptor. © Simon P Jones
https://www.ch.ic.ac.uk/local/projects/s_thipayang/synth.html

29. Adverse effects
1. Neurobehavioral performance tasks: on
giving 5mg of melatonin to young healthy
childrens.
2. Fever, dizziness, gastrointestinal disorders,
headaches, pigmentation, ankle edema,
hepatic pain, thrombosis, and hyperglycaemia
in type 1 diabetes patients receiving
treatment, tolerance and fatigue – to the
patients of circadian rhythm disorders using a
dose of 5mg melatonin every evening (before
melatonin production).

30. 3. Autoimmune hepatitis – after giving
melatonin therapy for insomnia.
4. Timing of puberty – long day length
experienced in the postnatal period.
© REVIEWS IN FOOD AND NUTRITION TOXICITY by Victor R. Preedy and Ronald R. Watson

31. Toxic effects and drug
interactions
1. Melatonin + nifedipine – increases blood
pressure and heart rate of patients.
2. Melatonin + anti-inflammatory drugs –
gastric ulcers – produce these effects when
given in morning than evening.
3. Rhythmic variations in milk – when
melatonin crosses the placenta in pregnant
womens.
4. Harmful effects when entered in water
supply.

32. β-Carotene
• A carotenoid available in fruits and vegetables.
• Which then converted into retinol (Vitamin A)
by the action of dioxygenase.
• Vitamin A is a fat soluble vitamin found in
foods of animal origin.
• As a nutraceutical, used for lung cancer.
β-carotene
Retinal
Retinol
dioxygenase
alcohol dehydrogenase

33. a
Toxic effects
1. Lung cancer:
β-carotene induces lung cancer in smokers.
It has a powerful booster effect on phase I
carcinogen-bioactivating enzymes
(cytochrome 450) including activations of
polycyclic aromatic hydrocarbons (PAH).
Induction was associated with generation of
oxidative stress. Thus β-carotene recognized
as co-carcinogen.
More specifically β-carotene has the effects
on later tumor rather than new ones.

34. Drug interactions
1. Alcohol –
It interferes with β-carotene, which later
interferes with the conversion to retinol.
Alcohol + carotene hepatic injury
Also cause pulmonary cancer; when
pulmonary cells exposed to high oxygen
concentration, β-carotene loses its
antioxidant activity and shows prooxidant
activity.

35. 2. Acetaldehyde – a toxic metabolite of
ethanol in Hep G2 cells.
when β-carotene inhibits the activity of
mitochondria in human liver tumor cells and
when it is given with acetaldehyde, the effect
is enhanced.

36. 3. α-tocopherol –
Decreases plasma and hepatic levels of α-
tocopherol, this is because β-carotene
alters the binding sites of α-tocopherol by
competing for the same binding sites on
lipoprotein molecules.
Vitamin A packaged into lipoproteins esp.,
LDL and transported to different sites
within the body including liver.
Without LDL, β-carotene cannot process
into retinoids.
Dosage:
• Safe upper limit – 7mg/day
• Average intake for male –
2.4mg/day
• Average intake for female –
2.1mg/day
• RDA 750μg of retinol i.e.,
4.5mg of β-carotene

37. Glucosamine
• Synthesized from glucose and glutamic acid.
• It is found naturally in the body at cartilages,
tendons and ligaments.
• It is a precursor of articular cartilage
glycosaminoglycan (disaccharide units).
• Not found within the diet.
• Used for osteoarthritis patients as 1500mg
in divided doses.

38. Adverse effects
Diabetes – occurs when too much of glucose in
blood.
Glucosamine affects insulin secretion, because it
accelerates the hexosamine pathway flux
independently of glucose.
Thus may cause glucose toxicity by an increased
flux and induce reduction in insulin secretion.
© Neha M. Akella, Lorela Ciraku, Mauricio J Reginato

39. Adverse effects – at a glance
 Minor effects:
 Mild to moderate effects:
Nutraceutical Effect
Glucosamine or chondroitin Gastrointestinal upsets
Pycnogenol (pine bark extract) Gastrointestinal upsets
Nutraceutical Effect
S-adenosyl methionine (SAM-e) Gastrointestinal upsets, psychiatric
and CVDs
Carnitine Gastrointestinal upsets and depress
thyroid hormone.

40. 10
Cont.
Nutraceutical Effect
α-lipolic acid (ALA) Allergic skin reaction and
hypoglycaemia
trans-10, cis-12 conjugated linoleic
acid
Liver hypertrophy and lipodystrophy
Melatonin Prooxidant effects
Shark cartilage Hepatitis
Coenzyme Q10 Depressed glucose levels
1,4-Butanediol – γ-hydroxybutyrate Coma

41. Conclusions
1. Carnitine, soy isoflavones, proanthocyanidins, and β-carotene
are safely ingested on a daily basis by most people; however, if they are to
be promoted as nutritional supplements or developed as drugs, further
investigations must be made concerning the toxicity of these plant
derivatives.
2. Melatonin and glucosamine are normal components of human
metabolism and also may appear safe in initial considerations but at
unusual dosages and in chronic administration, they may be shown to
exhibit further side effects.
3. Very little information of melatonin but still in some parts it is sold as
OTC, thus should be banned or should not sell OTC because of its toxic
effects.

42. Thank you