Cola – Cola (Colae semen)
|Latin name of the genus:||Cola|
|Latin name of herbal substance:||Colae semen|
|Botanical name of plant:||Cola nitida (vent.) schott et endl. and its varieties and cola acuminata (p. beauv.) schott et endl.|
|English common name of herbal substance:||Cola|
Latin name of the genus: Cola
Latin name of herbal substance: Colae semen
Botanical name of plant: Cola nitida (Vent.) Schott et Endl. and its varieties and Cola acuminata (P. Beauv.) Schott et Endl.
English common name of herbal substance: Cola
- 1. Introduction
- 2. Historical data on medicinal use
- 3. Non-Clinical Data
- 3.4. Overall conclusions on non-clinical data
- 4. Clinical Data
- 4.1. Clinical Pharmacology
- 4.2. Clinical Efficacy
- 4.2.1. Dose response studies
- 4.2.2. Clinical studies (case studies and clinical trials)
- 4.2.3. Clinical studies in special populations (e.g. elderly and children)
- 4.3. Overall conclusions on clinical pharmacology and efficacy
- 5. Clinical Safety/Pharmacovigilance
- 6. Overall conclusions
1.1. Description of the herbal substance(s), herbal preparation(s) or combinations thereof
According to the European Pharmacopoeia, Colae semen is the whole or fragmented dried seeds, freed from the testa, of Cola nitida (Vent.) Schott et Endl. (C. vera K. Schum.) and its varieties, as well as of Cola acuminata (P. Beauv.) Schott et Endl. (Sterculia acuminata P. Beauv.). Content: minimum 1.5 % of caffeine (dried drug) (Ph. Eur. 7.0).
Cola seed consists of the endosperm freed from the testa of various Cola species Schott et Endlicher, particularly C. nitida (Ventenat), belonging to the family of the Sterculiaceae. The drug contains at least 1.5% methylxanthine (caffeine, theobromine) (Blumenthal, 1998).
According to Bruneton, the French Pharmacopoeia (10th Ed.) indicates that the part to be used is the seed, devoid of tegument and dried, of C. acuminata (Bruneton, 1998).
According to the definition of the British Herbal Pharmacopoeia 1974, Cola (syn. Cola nuts, Cola seeds) consists of the dried cotyledons of Cola nitida A. Chev. and of C. acuminata Schott & Endl. with a caffeine content not less than 1.25% (British Herbal Pharmacopoeia 1974). In the British Herbal Pharmacopoeia 1996 the definition is as follows: dried cotyledons of C. nitida (Vent.) Schott et Endl. or C. acuminata (Beauv.) Schott et Endl (British Herbal Pharmacopoeia 1996).
The fruits comprise two to six lignified, voluminous
The seeds, incorrectly called Cola nuts, comprise two cotyledons (C. nitida) or
Macroscopical description: Reddish brown,
Microscopical description: Outer layer of
Odour and taste: Cola seeds have no odour. The herbal substance has a bitter, astringent taste when fresh. After drying, the taste becomes milder and faintly aromatic, with an odour suggestive of nutmeg.
Botanical characteristics of Cola seeds:
The Cola genus comprises about 140 species and the most commonly consumed are C. acuminata and C. nitida. (Bruneton, 1998) Other species frequently used in commerce include C. verticillata and C. anomala (Blumenthal, 2000).
The early records did not distinguish between the two commercial species, C. nitida and C. acuminata. The major centres for C. nitida were Sierra Leone, Benin, Ghana and Ivory Coast. By the middle of the
20th century the cultivation of the species had spread westwards to the southern border of Senegal and Gambia, eastwards into Zaire and also overseas to the Caribbean islands, especially Jamaica. C. acuminata has its original area of distribution stretching from Nigeria to Gabon and it has been extensively planted in other parts of West Africa (Adeyeye, 1994).
Synonyms of Cola (according to Seitz, 1992):
•Cola nitida (Vent.) Schott et Endl.: C. vera K. Schum., Sterculia nitida Vent., C. acuminata var. latifolia Schum.
•Cola acuminata (P. Beauv.) Schott et Endl.: Sterculia acuminata P. Beauv., C. pseudoacuminata Engl.
Phytochemical characteristics of Cola seeds:
Cola seeds contain purine bases chiefly represented by caffeine, ranging from 1.5 to 3.2% (2.5% on average in the dried drug) (Bruneton, 1998), traces of theobromine, which ranges from 0.02 to 0.08% and theophylline (Morton, 1992). The composition of C. nitida and C. acuminata seeds differ only quantitatively. The purine alkaloid content of C. nitida is higher (Seitz, 1992).
In a systematic analysis of different Cola accessions the caffeine and theobromine content of C. acuminata was determined as
The tannin content of Cola seeds is
The total phenolic content of 0.1 M HCl extract of Cola seed was determined as 49.36±2.75 and 31.36±4.83, respectively in C. nitida and C. acuminata (expressed in mg equivalent of chlorogenic acid per g of fresh weight). Catechin was the major compound and represented 48.93±2.5% and 51.18±2.2% of total soluble phenols (Boudjeko, 2009).
White and pink Cola acuminata seed (90% methanol extract) contains 3.37 and 4.17 mg/100 g fresh weight total phenol, respectively. The same value for white, pink and red C. nitida semen was 4.45, 6- 12 and 9.09 (Odebode, 1996).
Phenolic compounds identified from 90% methanol Cola extract using authentic phenolic compounds as reference, Solvent B.A.W.(4:1:5) were as follows:
In a systematic analysis of different Cola accessions the total polyphenol content of C. acuminata was determined as
Two condensed proanthocyanidins have been isolated from the fresh fruit of C. acuminata (Adeyeye, 1994).
Caffeine forms a molecular association with the catechin derivates, and therefore, the proportions of free and combined caffeine vary depending on whether the drug is fresh, dry, or stabilized (Bruneton, 1998). It has been suggested that the differences in the stimulatory action between fresh and dried seeds may be due to the formation of a
It is also considered that, in fresh Cola seeds, an unstable complex occurs as colatin and caffeine glycosides. This complex oxidises and hydrolyses to form
The major elements of Colae semen were Ca
Three secondary amines (dimethylamine, pyrrolidine and piperidine) and four primary amines (methylamine, ethylamine, isobutylamine and isopentylamine) were detected in one or more Cola seed varieties. C. acuminata contained the highest average amounts of dimethylamine (4 mg/kg), pyrrolidine (7.4 mg/kg) and ethylamine (13 mg/kg). Piperidine and isobutylamine were not detected. Methylamine content was 1.2 mg/kg, isopentylamine was 0.4 mg/kg (Atawodi, 1995).
Thiamine and other
Cola seed is good source of protein
Proximate composition (%) of C. acuminata (Adeyeye, 1994):
Amino acid composition (mg/g crude protein) (Adeyeye, 2007):
•Herbal preparation(s) See sections 1.2, 2.2 and 2.3.
•Combinations of herbal substance(s) and/or herbal preparation(s) including a description of vitamin(s) and/or mineral(s) as ingredients of traditional combination herbal medicinal products assessed, where applicable.
1.2. Information about products on the market in the Member States
Regulatory status overview
MA: Marketing Authorisation TRAD: Traditional Use Registration
Other TRAD: Other national Traditional systems of registration Other: If known, it should be specified or otherwise add ’Not Known’
Note: this regulatory overview is not legally binding and does not necessarily reflect the legal status of the products in the MSs concerned.
The following herbal substances/preparations are in the list of ingredients that may be used in food supplements updated on 1 April 2009 with the following indications:
Although Embryo Colae and Extractum colae siccum are not present in the current list of authorised products in Poland, there is one combination product described in Polish Pharmacopoeia VI and authorised in Poland, Guttae Cardiaceae cum Colae Extractum Fluidum, containing: Convallariae tinctura titrata 27 parts; Crataegi tinctura 20 parts; Valerianae tinctura 20 parts; Colae extractum fluidum 14 parts; Ethanolum (608 g/l) ad. 100 parts.
Also authorised is the following combination product containing herbal components and caffeine: Crataegi cum Valerianae tinctura
One registered product containing Colae semen as single ingredient and 2 multicomponent products.
Preparation: powdered herbal substance as registered product.
Since when is on the market: 24/10/1994.
Pharmaceutical form: capsule (330 mg Colae semen/capsule).
Posology: 2 or 3 capsules 2 times a day.
Indication: tonic, fatigue, asthenia.
1.2. Search and assessment methodology
Handbooks as well as publications (PubMed, SciFinder, Web of Science, ToxNet) were used as sources. Keywords: Cola acuminata, Colae semen.
2. Historical data on medicinal use
Cola seeds are therapeutically and industrially important because of their polyphenol and caffeine contents. Without Cola seeds, traditional hospitality, cultural and social ceremonies are considered incomplete in Nigeria and many West African countries (Atawodi, 1995).
In Africa, Cola seeds are traditionally used as masticatory agents for their stimulating effect. It has been claimed by Cola seed consumers that Cola seeds suppress hunger, thirst and sleep. It is also said that Cola seeds strengthen dental gums and suppress gout and related diseases. Some of the seeds are used as a source of dye. The Cola pod is used in making jams and preservatives as well as fertilizer and feeding stuff for animals. The pod husk, mixed with certain ingredients, is used in traditional concoctions to reduce pain. The following products are obtainable from Cola testa: decaffeinated powder and Cola chocolate; caffeine used in pharmaceutical and food preparations; tannins, food colours and dyes; fertilizer and feeding stuff (Adeyeye, 1994).
In Trinidad and Tobago, C. acuminata is used for childbirth and fertility and unspecified female problems and to treat diabetes and hypertension (Lans, 2007) (Lans, 2006).
C. acuminata is used as a masticatory when fresh, while the dried seeds are used for beverages and pharmaceutical purposes in Europe and North Africa (Adeyeye, 2007).
The dried seed is utilised in African
Cola seeds have also been used in African traditional medicine for the treatment of various ailments including parasitic diseases.
The seeds are also used in treatment of sexual impotence and erectile dysfunction in Western Uganda. They have been in use for centuries in treating or managing conditions of the male reproductive organs. C. acuminata is frequently utilised and is already under sale for treating these conditions. The preparation from the fruit can involve roasting, pounding or chewing and the mode of administration is oral in tea, porridge or milk as a beverage
C. acuminata fruits are mixed with other plants in Benin to treat primary and secondary sterility. The fruits are also said to be diuretic and laxative when administrated orally
In Nigeria Cola seed is commonly used against emesis gravidarum and migraine (Seitz, 1992).
Dried Cola seeds are shipped all over the world for pharmaceutical use, for extraction of caffeine, for the preparation of dry or aqueous extracts or concentrates to be used as flavourings in carbonated soft drinks, particularly with extracts of
Cola seeds are also used in liqueurs, ice creams, confectionery and baked goods. In Europe, they are used mainly in flavouring various beverages, mineral waters, wine and pharmaceutical products (Morton, 1992). Cola seed is on the Generally Recognized as Safe (GRAS) list for food additives in the United States without any limitation (FDA, 2010).
Cola seed is approved for food uses by the Council of Europe, the Flavour and Extract Manufacturers’ Association and the International Organisation of Flavour Industries (Burdock, 2009).
Specifications for Cola seed extract for use as an ingredient for addition to food have not been published by any relevant authoritative body. Herbal preparations of Cola seed extract for medicinal use are typically standardised on the methylxanthine content, usually
The Council of Europe has classified Cola seed extract as ‘Category 4’, which is defined as ”plants, animals and other organisms, and parts of these or products thereof, and preparations derived there from, not normally consumed as food items, herbs or spices in Europe, which contain defined ’active principles’ or ’other chemical components’ requiring limits on use levels” (Burdock, 2009).
Certain chemical constituents of Cola seeds have also been approved in pure form for use in foodstuff. Caffeine is regulated by FDA as GRAS for use in
Both caffeine and theobromine have been approved by the European Commission as flavouring substances for use in or on foodstuff (Burdock, 2009).
Caffeine is also regulated as a drug by FDA, specially as the only active ingredient approved for use in
According to Adeyeye, Soreat (1971) had proposed a combination of naturally occurring amino acids (essential and
2.1. Information on period of medicinal use in the Community
See sections 1.2, 2.2 and 2.3.
2.2. Information on traditional/current indications and specified substances/preparations
There is evidence that
In Europe, the dried seeds have been used as strong stimulant, in addition to use for the treatment of migraine, neuralgia, diarrhoea, and as a stimulant or cardiotonic, for loss of appetite, and as an antidepressant and for melancholy
Literature data support the traditional use of Cola seed as medicinal product. Several monographs (Commission E, British Herbal Compendium, British Herbal Pharmacopoeia) have described Cola seed as a medicinal product for the treatment of mental and physical fatigue and for some other indications (Blumenthal 2000) (Bradley 1992) (British Herbal Pharmacopoeia 1996).
In the British Herbal Pharmacopoeia 1974, published in 1971, and British Herbal Compendium Volume 1, published in 1992, the following preparations of Cola seeds are listed (British Herbal Pharmacopoeia 1974):
•Liquid extract (1:1, 60% ethanol)
•Tincture (1:5, 60% ethanol)
The indications of the listed preparations are as follows: depressive states, melancholia, atony, exhaustion, dysentery, atonic diarrhoea, anorexia migraine. A specific indication is also given: depressive states associated with general muscular weakness (British Herbal Pharmacopoeia 1974). In the British Herbal Compendium Volume 1, the indications are
In the Commission E monograph published in 1991, the following herbal preparations are included:
•Cola nut (powdered)
•Extract (Erg.B.6) (extracting solvent 90% ethanol v/v, caffeine+theobromine content mininum 12%)
•Liquid extract (Erg.B.6) (percolate with 70% ethanol v/v, caffeine+theobromine content minimum 1.2%)
•Tincture (Erg.B.6) (DER 1:5, 70% ethanol, caffeine+theobromine content minimum 0.25%)
•Cola wine (Erg.B.6) (Cola liquid extract, Xeres wine, sugar sirup 50:850:100)
The approved indication for the herbal preparations listed above is mental and physical fatigue (Blumenthal, 1998).
2.3. Specified strength/posology/route of administration/duration of use for relevant preparations and indications
In the British Herbal Pharmacopoeia 1974 (British Herbal Pharmacopoeia 1974) and British Herbal Compendium Volume 1 (Bradley, 1992), the following posologies are listed for the different preparations:
•Liquid extract (1:1, 60% ethanol):
•Tincture (1:5, 60% ethanol):
In the Commission E monograph (Blumenthal, 1998), the following posologies (daily dose) are contained:
•Dry extract (Erg.B.6):
•Liquid extract (Erg.B.6):
•Cola wine (Erg.B.6):
The available marketing status overview shows that only one monocomponent Cola seed product exists on the European market as a medicinal product. However, several other medicinal products containing Cola seed are marketed in combination with other herbal ingredients. There are also products marketed as foods or food supplements.
The following herbal substances and herbal preparations have been on the European market for a period of 30 years and are included in the monograph on traditional use:
•Powdered herbal substance
•Powdered herbal substance as herbal tea (decoction)
•Liquid extract (1:1, 60% ethanol)
•Tincture (1:5, 60% ethanol)
Based on the confirmed traditional use and the plausible effects, and taking into account the Community herbal monograph on Mate folium, the following uses are considered appropriate for traditional use: symptoms of temporary fatigue and sensation of weakness.
Caffeine is a mild stimulant and has diuretic properties and this is the main basis of the use of Cola seed. Cola extracts are also astringent and
The pharmacodynamic properties of Cola seed may be interpreted on the basis of its caffeine content. Caffeine itself is sometimes given in conjunction with other analgesics to produce stronger and quicker
Caffeine increases the free fatty acid and glucose level in plasma. The underlying mechanistic basis for these effects is generally regarded to be a selective blockade of adenosine receptors via competitive inhibition, which are present in brain, blood vessels, kidneys, heart, gastrointestinal tract and respiratory passageways (Burdock, 2009). From a therapeutic point of view, the most important effect of Cola is the central nervous system stimulatory activity, due to its caffeine content.
The following actions were confirmed in animal experiments for Cola seed: analeptic; stimulates production of gastric acid; lipolytic and increases motility. Compared to other methylxanthines, caffeine is a weaker diuretic and positively chronotropic (Blumenthal, 2000).
Central nervous system effects
Scotto (1987) conducted a behavioural study of rats exposed for two weeks to either fresh Cola seed (i.e., nuts) extract (C. nitida) or pure caffeine. The fresh Cola seed extract employed in the study was standardized to contain 6.2% caffeine, 0.9% theobromine, and 15% catechine. Male
Vaille (1993) evaluated the effects of Cola seed extract on electroencephalogram readings in male
(20 mg/kg/day), or Cola seed extract (320 mg/kg/day, containing caffeine equal to 20 mg/kg/day), via oral gavage, for 15 consecutive days. Test article administration commenced ten days after surgical implantation of five recording electrodes into the skull of each animal. EEG recordings were taken prior to any treatment (baseline), at 1 hour after dosing on days 1, 5, 10, and 15 of treatment, and also on the seventh day following treatment cessation. A frequency analysis was also conducted on five rats from each group on the 12th day of treatment. The authors conclude that the effects of Cola seed extract on cortical activity are consistent with what is known from the literature of the corticostimulatory effects of caffeine on EEG patterns, with the caffeine and the Cola seed extract patterns being largely similar. The differences are mainly characterised by a broadening and increase in complexity of the spectral patterns of Cola seed
Ajarem (1990) studied locomotion behaviour in male mice following intraperitoneal injection of Cola seed extract (C. nitida). The extract consisted of the clear supernatant drawn off from a suspension of a paste of ground fresh Cola seeds in normal (0.9%) saline, left undisturbed overnight. Male Swiss- Webster mice (6/dose group) were injected intraperitoneally with 0, 2.5, 5, or 10 mg/kg body weight of this supernatant extract, adjusted to a uniform dose volume of 0.1 ml. No analysis or control of any chemical constituents of this extract was conducted. At defined intervals following dosing of 15, 30, 60, or 120 minutes, the animals were placed in an enclosed arena for behavioural observations. These observations were 300 s in duration each and consisted of quantification of the number of floor grid squares crossed, rearing behaviour, duration of locomotion, and immobility. The report does not state whether all six animals of each dose group were subjected to observation at each observation interval. The author concluded that while the
The comparative effects of chronic [28 days] consumption of Cola seed and its active constituent, caffeine diets on locomotor behaviour and body weights in mice were investigated by Umoren. Thirty adult Swiss white mice
rodent chow, mice in the Cola
and body weight change were also measured. Daily food intake in the Cola seed and
The effectiveness of certain antioxidant substances (among them Cola extracts) in the protection of red cells from oxidation and degradation with respect to their window times of survival has been analysed using
The ethanol extracts from Cola seeds exhibited a considerably high trypanocidal activity (Kubata, 2005).
A new lead
caused rupture of plasma membranes and the release of cell contents, indicative of a necrotic process rather than a programmed cell death. The proanthocyanidin acted against the bloodstream form but not the procyclic form trypanosomes. This new
Cultures of bloodstream form trypanosomes treated with 100 µg/ml of ethanol extract of Cola seed showed dying cells as early as 1 hour after the drug addition. A change in the morphology of drug- treated dying cells during incubation was also observed. The Cola seed ethanol extract (100 µg/ml) exhibited a potent trypanocidal activity that completely inhibited the in vitro growth of bloodstream form T. brucei after 12 hours of exposure.
In the culture of procyclic trypanosomes, the
The results revealed that in vivo Cola seed proanthocyanidin exhibited a trypanostatic rather than a trypanocidal effect. The
Cytotoxic studies on human epidermoid carcinoma (KB
The purpose of the study of Fontenot was to characterise the putative phytoestrogenic compounds present in Cola acuminata for
Investigation of the effect of aqueous extracts of different Cola seeds (C. acuminata, C. nitida subsp. rubra, C. nitida subsp. alba) on the rhythmic activity of mammalian heart and metabolic rate was carried out using male albino rats. Low concentrations of Cola seed extract stimulated the heart by increasing rate and force of contraction as well as metabolic rate. Higher concentrations reduced rate and amplitude of heart beat resulting, at even higher concentrations, in heart failure. The extract was added in increasing quantities of 0.2 ml each time. The calculated doses for animals of different body weights were diluted to the following range of concentrations: 2, 4, 8 and 10 mg/ml. As the concentration of the extracts was increased, the rate of metabolism also increased up to a certain limit. The increase in basal metabolic rate at high concentrations
The use of Cola beverages has been implicated in the pathogenesis of peptic ulcer and in the management of the ulcer. The administration of caffeine to animals causes pathological changes in the gastrointestinal tract and ulcer formation. The exact mechanism by which Cola induces gastric acid secretion is not known. However, there is increasing evidence that cyclic AMP is implicated in gastric acid secretion caused by the alkaloids. The induction of gastric acid secretion by Cola could be entirely due to the presence in Cola of the xanthines or it may involve other gastric secretagogues in Cola not yet identified (Ibu, 1986).
Male and female albino rats of Wistar strain were used for the experiment. The rats were starved for 12 hours before use. The Cola was extracted in normal saline (pH 7). The test animals were divided into 2 groups. One group had the Cola by intravenous injection; the other had the extract by continuous gastric perfusion. The stimulatory dose used was 10 mg/100 g body weight. By perfusing the rats’ stomach with Cola extract, the acid output increased from a mean basal value of 0.88 ± 0.08 mMol/l/h to 1.5 ± 0.77 mMol/l/h. This represents a percentage increase of 69.3%. By intravenous route the acid secretion increased from 1.27 to 2.10 mMol/l/h, which represents an increase of 65.3%. So through the oral route, the stimulation of acid secretion is slightly higher than the intravenous route. This may be due to a direct action of the Cola on the parietal cells in the stomach as no absorption is involved (Ibu, 1986).
Osim (1991) investigated the relative effect on gastric acid secretion in cats of Cola seed extract (Cola nitida alba) and an equivalent dose of caffeine. Cats (15 male and 10 female) were fasted overnight, after which the stomachs were surgically cannulated under anesthesia and perfused with 0.9% saline. The jugular vein was also cannulated for the introduction of blocking drugs. Once stomachs were clear of solids and perfusate was clear, continuous perfusion was maintained with an infusion pump and baseline gastric acid secretion rate was established (control). Test samples (adjusted to pH 7) consisted of a filtrate of 6 g of ground dry Cola seeds and 100 mg of caffeine, both dissolved in 200 ml of 0.9% saline. The infusion rate was maintained at 1 ml/minute. Perfusate samples were collected at 10 minutes intervals for up to 3 hours after dosing and titrated for total acidity. Treatment with Cola
seed extract resulted in a greater than
(0.2 mg/kg body weight) or cimetidine (12 μM/kg body weight), which block, respectively, muscarinic and histaminic receptors. Based on these findings, the authors speculated that caffeine is not the only constituent in Cola seeds acting to stimulate gastric acid secretion, and that the overall response to the extract is mediated, at least in part, via cholinergic and histaminergic pathways. The authors do not discuss whether there might be other etiological factors (e.g. Helicobacter pylori infection) involved in the observed incidence of gastric ulceration (Osim, 1991) (Burdock, 2009).
The study of Solipuram characterized the androgenic and chemopreventative properties of the C. acuminata using androgen receptor positive and negative cell lines. Exposure of prostate cells to the ether extract of C. acuminata resulted in a growth inhibition (GI50) of 15 ppm in LNCaP cells and
3.6 ppm in DU145 cells. The extract elicited a
The oestrous cycles of rats treated with
No data with regard to absorption, distribution, metabolism, elimination are available. According to older studies, the absorption of caffeine is slower from the dry drug than from the
Because caffeine and methylxanthines are principal components of Cola seeds, at least some of the potential toxicities could be due to them. Methylxanthine toxicity has been assessed extensively elsewhere (Eteng, 1997) and is not presented here.
There are no studies available to evaluate acute toxicity of Cola seed extracts.
Male Wistar albino rats (12/dose group) were administered distilled water (control) or Cola seed extract (C. nitida) (0.5 ml, equivalent to 57 mg/kg body weight) via oral gavage, every other day, for 18 weeks. The extract consisted of the supernatant obtained when fresh Cola seeds were ground to the consistency of flour and suspended in hot distilled water (100 g/200 ml), then allowed to sit undisturbed at room temperature overnight. No analysis or further characterisation of the extract was undertaken. Food and water were available ad libitum throughout the study duration. Animals were weighed at study initiation and weekly thereafter; animals were also monitored for overt signs of toxicity. At study termination, rats were killed by decapitation and a gross pathological evaluation was performed. Liver, kidneys, brain, testis, and serum were harvested, and homogenates of the organ tissues were prepared. From these homogenates, total protein, RNA, and DNA levels of tissues were assessed, as were
Ajarem and Ahmad (1994) studied the effects of a water extract of fresh Cola seeds (C. nitida) on the
and assessments of pup behaviour, such as locomotion and
Ishidate reported the results of mutagenicity screening of 190 synthetic food additives and 52 food additives derived from natural sources. Among the additives from natural sources that were tested was a substance identified only as ‘Cola extract’. This substance (in physiological saline) was tested for chromosomal aberrations in the Chinese hamster (CHL) fibroblast cell line, at concentrations of up to 16 mg/ml. The results were reported as negative, indicating that the total incidence of cells with aberrations (including gaps) was 4.9% or less (Ishidate, 1984) (Burdock, 2009).
The mutagenicity studies for caffeine have inconclusive results (Genetox, 2010).
There are no studies on carcinogenicity of Cola preparations. However, there has been a concern on the formation of nitrosatable components under certain physiological conditions, because many nitrosamines are powerful carcinogens (see below).
Nitrosatable amines and nitrosatable components formation in C. acuminata
Three secondary amines (dimethylamine, pyrrolidine and piperidine) and four primary amines (methylamine, ethylamine, isobutylamine and isopentylamine) were detected in one or more Cola seed varieties. C. acuminata contained the highest average amounts of dimethylamine (4 mg/kg), pyrrolidine (7.4 mg/kg) and ethylamine (13 mg/kg). Piperidine and isobutylamine were not detected. Methlyamine content was 1.2 mg/kg, isopentylamine was 0.4 mg/kg. Consumption of Cola seeds in habitual chewers generally varies from 50 g to over 200 g fresh seeds per day. On the basis of these figures, average daily exposure to aliphatic amines and, possibly, nitrosamides have been estimated in the following table:
The methylating activity of Cola seeds is the highest ever reported for any fresh plant product that is consumed raw without processing. However the methylating activity was lowest in C. acuminata compared to other types of Cola.
Possible in vivo formation of
considered. The Cola seed is usually chewed throughout life in habitual chewers since it contains caffeine which is an addictive compound. Moreover, most Cola chewers are also cigarette smokers. Therefore, it may be expected that an increased concentration of thiocyanate in the saliva, due to smoking, could catalyse the nitrosation of amines ingested from Cola seeds. Complex interactions might occur in vivo between carcinogens and carcinogenic precursors contained in or generated from both tobacco and Cola seeds (Atawodi, 1995).
3.4. Overall conclusions on
The traditional use of Cola seed for physical and mental tiredness, symptoms of fatigue and sensation of weakness can be explained by the caffeine content. The caffeine content of Cola seed is at
least 1.5% (Ph. Eur. 7.0). The maximum daily dose of Cola seed (9 g) is equivalent to
Although there are many articles on the pharmacokinetics of caffeine, the main active component of Cola, no data are available on that of the herbal substance or the herbal preparations, therefore, no conclusion can be drawn.
4. Clinical Data
4.1. Clinical Pharmacology
For the herbal substance and its preparations, no data are available.
However, the effect of caffeine on mental and physical tiredness has been convincingly confirmed.
The aim of the study of Glaister was to examine the effects of caffeine supplementation on multiple sprint running performance. Using a randomised
Hogervorst carried out a study to examine the effects of ingesting a performance bar, containing caffeine, before and during cycling exercise on physical and cognitive performance.
trained cyclists consumed the products [a performance bar containing 45 g of carbohydrate and 100 mg of caffeine (CAF), an isocaloric noncaffeine performance bar (CHO), or 300 ml of placebo beverage (BEV)] immediately before performing a 2.5 hours exercise at 60% VO2 max followed by a time to exhaustion trial (T2EX) at 75% VO2 max. Additional products were taken after 55 and 115
minutes of exercise. Cognitive function measures (computerised Stroop and Rapid Visual Information Processing tests) were performed before exercise and while cycling after 70 and 140 minutes of exercise and again 5 minutes after completing the T2EX ride. Participants were significantly faster after CAF when compared with CHO on both the computerised complex information processing tests, particularly after 140 minutes and after the T2EX ride (P < 0.001). On the BEV trial, performance was significantly slower than after both other treatments (P < 0.0001). There were no
For the herbal substance and its preparations, no data are available.
Caffeine is rapidly and completely absorbed by the gastrointestinal tract and is readily distributed throughout all tissues of the body. Absorption is complete within approximately 1 hour after ingestion (typically 99% of the ingested dose is absorbed within 45 minutes) and seems to be
10 hours. The toxic range in humans is considered to be above 200 µM. No signiﬁcant splanchnic first- pass effect occurs after oral caffeine ingestion, and it has been estimated that a dose of 1 mg/kg (considered equivalent to one cup of coffee) produces peak plasma concentrations of 5 to 10 µM. Caffeine is sufficiently hydrophobic to pass through all biological membranes and is readily distributed throughout all tissues of the body. The parent compound is extensively metabolised in the liver microsomes to more than 25 derivatives, while considerably less than 5% of the ingested dose is excreted unchanged in the urine. The elimination
4.2. Clinical Efficacy
4.2.1. Dose response studies
For the herbal substance and its preparations, no data are available.
4.2.2. Clinical studies (case studies and clinical trials)
For the herbal substance and its preparations, no data are available.
4.2.3. Clinical studies in special populations (e.g. elderly and children)
For the herbal substance and its preparations no data are available. Use in children and adolescents under 18 years of age is not recommended because data are not sufficient.
4.3. Overall conclusions on clinical pharmacology and efficacy
Although Cola seed has been used for the relief of mental and physical fatigue and some other indications, clinical trials supporting these uses are lacking.
5. Clinical Safety/Pharmacovigilance
5.1.Overview of toxicological/safety data from clinical trials in humans
Although limited biological data are available for Cola seed extract especially, the published data on the major constituents of Cola seed suggest the pharmacological/toxicological properties of Cola seed extract, are roughly equivalent to those of caffeine. Frank developmental/reproductive effects have not been reported and changes in offspring cannot be extrapolated to humans. A ‘no observed effect level’ (NOEL)/’no observable adverse effect level’ (NOAEL) cannot be defined for repeated oral exposure to Cola seed extract from available data. Notwithstanding the foregoing, consumers of the United States have a history of safe consumption of
Based on the data reviewed by Nawrot, it was concluded that for the healthy adult population, moderate daily caffeine intake at a dose level up to 400 mg/day (equivalent to 6 mg/kg body weight/day in a
5.3. Adverse events and serious adverse events and deaths
Contraindications are gastric and duodenal ulcers (Blumenthal, 2000).
There is a preponderance of oral tumours and gastrointestinal malignancies especially in Northern Nigeria, where Cola seed chewing is most common (Atawodi, 1995).
5.4. Laboratory findings
No data for the herbal substance or herbal preparations are available.
5.5. Safety in special populations and situations
Potential for interactions
The potentiation of the action of psychoanaleptic drugs and
Caffeine interactions: Drug interactions and/or related problems of caffeine intake: Monoamine oxidase (MAO) inhibitors, including furazolidone, procarbazine and selegiline (large amounts of caffeine may produce dangerous cardiac arrhythmias or serve hypertension because of the sympathomimetic side effects of caffeine; concurrent use with small amounts of caffeine may produce tachycardia and mild increase in blood pressure) (Thomson Micromedex, 2007)
The potential for Cola seeds and their extracts to interact pharmacologically with a number of drugs included, but not limited to ephedrine, phenelzine, monoamine oxidase inhibitors, adenosine, clozapine, benzodiazepines, propranolol and metoprolol, phenylpropanolamine and quinolone antibiotics has been noted (Burdock, 2009).Overdose
No case of overdose is known in the literature.
Pregnancy and lactation
The American Herbal Products Association includes C. acuminata on its lists of herbs that may cause irritation to the GI tract, that may induce nervous system stimulation, and should not be used in pregnancy unless otherwise directed by a qualified expert (Class 2b) (Burdock, 2009).
Taking Cola seed during pregnancy has no effect on the birth weight or on the size of the head and breast of the newborn (Seitz, 1992). However, no studies are available on the effect of Cola seed consumption in pregnancy. For caffeine, several human studies are available.
Based on available evidence, it is suggested that women of childbearing potential should consume </=300 mg caffeine per day (equivalent to 4.6 mg/kg body weight/day for a
Boylan conducted a prospective longitudinal observational study designed to examine the association of maternal caffeine intake with foetal growth restriction. The study included 2635 low risk pregnant women recruited between 8 and 12 weeks of pregnancy. Investigations quantifying the total caffeine intake from 4 weeks before conception and throughout pregnancy were undertaken with a validated CAT (caffeine assessment tool, a detailed questionnaire,). Caffeine
Bech conducted a randomised double blind controlled trial designed to estimate the effect of reducing caffeine intake during pregnancy on birth weight and length of gestation. The study included 1207 pregnant women drinking at least three cups of coffee (caffeinated or decaffeinated instant coffee) a day, recruited before 20 weeks gestation. Data on birth weight were obtained for 1150 live born singletons and on length of gestation for 1153 live born singletons. No significant differences were found for mean birth weight or mean length of gestation between women in the decaffeinated coffee group (whose mean caffeine intake was 182 mg lower than that of the other group) and women in the caffeinated coffee group. After adjustment for length of gestation, parity,
Weng conducted a
Because of the public health importance of this question, Signorello and MacLaughlin reviewed the results of 15 epidemiologic studies on this topic, with particular attention to the specific methodologic problems that would generate biased findings. These include selection and recall bias, confounding, several issues pertaining to exposure measurement, and the failure to account for foetal karyotype, caffeine metabolism, the timing of foetal demise, and the possibility that an effect of caffeine may be gestational
The amount of caffeine found in breast milk after the consumption of a known amount can vary considerably due to individual differences in absorption and elimination. Peak levels of caffeine are found in breast milk approximately 60 minutes after ingestion. It is estimated that the average dose to breastfed infants after heavy maternal caffeine intake (750 mg/day or
97.5 hours in a neonate, 80 hours in a newborn and 2.6 hours in a
effect on the composition of breast milk. When a woman drinks more than three cups of coffee a day during pregnancy and the early phases of breastfeeding, her breast milk contains
Effect on fertility
There are no data available on the effect of Colae semen on male or female fertility.
However, several articles have been published on the correlation of caffeine intake and fecundability. Taking into account the maximal posology of Colae semen (9 g daily) and the caffeine content of the herbal substance
Leviton and Cowan published a review of the literature relating caffeine consumption by women to their risk of reproductive hazards, published up to 2000 (Leviton, 2002). They concluded that apart from a first report (suffering from several limitations) of a relationship between caffeine consumption and delayed conception, claiming that consumption of as little as 100 mg of caffeine was associated with delayed conception, 11 additional studies were published. Some provide no support for this hypothesis, whereas others show an association in a subsample. The key issue for this outcome is the repeated finding that cigarette smoking appears to place a woman at risk of subfecundity. Residual confounding might explain all the associations reported between coffee/caffeine consumption and subfecundity.
In 2010, an update of this overview was published by Peck et al (Peck, 2010), i.e. the review of the epidemiologic evidence concerning the reproductive health effects of caffeine consumption, between 2000 and 2009. This assessment included articles on fecundability and semen quality as well. Of the nine publications reviewed in order to assess the effect of caffeine consumption on fecundability, one evaluated multiple outcomes associated with fertility treatment, one considered
Time to conception: Exposure measurement errors are a primary concern for the few recent studies addressing time to conception and ovulatory infertility. Potential recall bias and exposure misclassification may explain the modest association reported for coffee and tea consumption and increased time to pregnancy. No support for an association with infertility due to ovulation disorders was provided, but exposure measurement error was likely introduced as a result of the timing of exposure assessments.
Semen quality: Evaluations of semen quality have consistently failed to observe adverse effects associated with caffeine intake. Most of the studies of male reproductive outcomes have suffered from lack of detailed reporting of caffeine exposure assessment, potential exposure misclassification for the relevant etiologic window, no or limited control for confounders, potential selection bias, or restriction to fertile men, which limited the ability to detect
According to the report “Optimizing natural fertility” by the Practice Committee of the American Society for Reproductive Medicine, in collaboration with the Society for Reproductive Endocrinology and
Infertility, moderate caffeine consumption (one to two cups of coffee per day or its equivalent) before pregnancy has no apparent adverse effects on fertility (Practice Committee, 2008).
Taking account the caffeine content of the maximal daily dose of Colae semen, based on the available literature/data, the effect of the caffeine content of cola seeds on fertility cannot be assumed.
5.6. Overall conclusions on clinical safety
Based on empirical and experimental (partly on caffeine) evidence, the use of Cola seed at therapeutic dose is safe. However, due to the lack of data confirming the safety, the use during pregnancy and lactation and in children and adolescents is not recommended.
6. Overall conclusions
Cola seed has been used in traditional medicine for centuries in Africa and at least for 150 years in Europe. There is sufficient data available to establish a Community herbal monograph on the traditional use of Cola nitida and Cola acuminata, semen in an indication suitable for
In the absence of adequate data on genotoxicity, a Community list entry cannot be established.