by Fiona Taylor

The snowdrop is a delicate white flower often associated with springtime. The Mecklenburgh Square Garden contains a few discrete shaws of snowdrops, consisting of at least two species, thought to be Galanthus nivalis L and G. elwesii Hook.f. Although threatened in its native regions the snowdrop still delights gardeners and despite the bulbs being poisonous the alkaloids extracted from snowdrops are currently used to alleviate the symptoms of Alzheimer’s disease.

Popular history and contemporary use

The snowdrop is a characteristic early spring flowering plant, the Latin name of the genus is Galanthus from the Greek gala (milk) and anthos (flower), there are at least 20 species within the genus. The snowdrop is an iconic flower of early spring and is one of the earliest flowers to be seen in gardens and countryside throughout Britain. It fact most species come into flower at the very end of winter before the vernal equinox, although some species (e.g. G. regina eolgae) flower from the autumn onwards. Snowdrops are believed not to be native to the British Isles and it has been suggested they may have been bought here by the Romans or possibly introduced as late as the early 16th century. They are indigenous to Europe, Asia Minor and the Caucasus. They have frequently featured in poetry and literature as symbols of spring and purity such Walter de la Mare’s poem ‘The Snowdrop’ or Alfred Lord Tennyson’s poem of the same name. In Hans Christian Anderson’s story also titled ‘The Snowdrop’ the snowdrop flowers whilst there is still snow on the ground, it is picked and sent in a love letter, only to be forgotten but the ending is happy when it is finally used as a bookmark in a book of poetry. In contrast, in English folklore the snowdrop often features as a sign of bad luck, and should not to be brought into the house. Contemporary use of the term ‘snowdrop’ is listed in the Oxford dictionary of Modern slang since 1944 as an American military policeman, based upon the white helmets they wear.

The Snowdrop

by Alfred Lord Tennyson

Many, many welcomes,

February fair-maid!

Ever as of old time,

Solitary firstling,

Coming in the cold time,

Prophet of the gay time,

Prophet of the May time,

Prophet of the roses,

Many, many welcomes,

Biological Characteristics and Identification

Snowdrops are in the Amaryllidaceae, sub group Amaryllidoideae, which also includes daffodils and amaryllis. Wild snowdrops grow in temperate deciduous woodlands, and are one of the first plants to emerge and flower usually at the end of winter taking advantage of the lack of tree canopy to capture sunlight for photosynthesis and growth. Due to their rapid vegetative growth and flowering the seeds are relatively immature at dispersal.

Snowdrops are bulbous perennial herbaceous plants, with characteristic two or three linear leaves and a solitary erect, leafless scape bearing a single small bell shaped flower consisting of two rings (whorls) of white ‘petals’. Doublet flowers are a feature of some varieties ( e.g. G. nivalis ‘Flore Pleno’). The smaller inner ring, enclosing six stamens usually has green markings within the white background. The markings on the inner ring tend to vary by species and can be absent altogether, although they can vary within species. The markings although usually green, can occasionally be more yellow and vary from dots to dashes to U or V shapes around the tip of the petal, as viewed from the outer side. When viewed within the ring the green marking form lines of green going down to the centre of the flower towards the stamens. The green markings are thought to attract and guide pollinators and it has been suggested than the chlorophyll within the green areas may provide the developing seeds with photo-assimilates (Aschan and Pfanz 2006). The ovary is three- celled and the seed is whitish with a small fleshy tail called the elaiosome. In Galanthus and other species the elaiosome, contains substances which are adapted to the nutritional needs of ants and it is postulated that by attracting ants the dispersal of seeds is promoted (Fischer, et al 2008). The seeds have little desiccation tolerance (Newton, et al 2013). Snowdrops spread by both bulb offsets and dispersal of seeds.

Snowdrops usually have two leaves which emerge from the bulb and can vary from grey-green to bright grass-green, they are generally slender narrow, but some species have a more broad leaf,. The arrangement of leaves relative to each other (vernation) can be of three types; applanate (flat to each other), supervolute (one clasped tightly around the other) or explicative (flat against each other but leaf edge folded back). This characteristic once was used to distinguish between species but has been found to be unreliable.

There are currently at least 20 identified species of wild snowdrop, the twentieth addition to the species list was as recently as 2012, named Galanthus panjutinii from Western Transcaucasia (Dimitry, et al 2012). Modern molecular phylogenetic analysis has placed the 20 species within 7 clades, a clade being a group with common ancestral descent (Ronsted, et al 2013). Appendix 1 provides a comparison of Galanthus species and the clades that were assigned to them by Ronsted et al, following DNA analysis. It is difficult to identify different species by eye due to variable and inconsistent morphological characteristics. There are hundreds of cultivars of snowdrop species, both natural hybrids and those commercially bred.

Pests and Diseases

The snowdrop is generally a hardy plant but can suffer from pests or fungal infection. Narcissus flies lay their eggs near or on dormant bulbs, the emerging larvae feed on the bulbs. It is sometimes recommended to plant the bulbs in shady locations where they seem less affected by the flies. There are two fungi that often infect snowdrops in the UK. Botrytis galanthia, grows as a grey fluffy mould on the plant whereas, Stagonospora curtisii, known as Red Fire or Red Blotch creates bright red or brownish spots or streaks on any part of the plant. The spores of both fungi can spread from plant to plant and lie dormant in the soil. If affected by either fungus, fungicides may help if treated early. It is recommended to move non infected bulbs to fresh soil.

Conservation

G.nivalis is the most common and widely distributed species in contrast to the very rare G. trojanus found in one small area of western Turkey. Turkey has the greatest number of snowdrop species. Collection of Galanthus species has become very popular by aptly named galanthophiles due to their simple beauty and early flowering. However this surge in interest has created a huge trade in wild-collected bulbs from Turkey and neighbouring countries. This has resulted in Galanthus being placed on Appendix II of CITES (Convention on International Trade in Endangered Species) in 1990. The Cites Appendix II “includes species not necessarily threatened with extinction, but in which trade must be controlled in order to avoid utilisation incompatible with their survival”. This limits and makes illegal the export of wild-collected Galanthus unless by authorised permit (https://www.cites.org).

Phytochemistry

The Amaryllidaceae are well known for the interesting isoquinoline alkaloids they produce with varied pharmacological activities. Alkaloids are thought to provide chemical defences against herbivores, predators and microorganisms. However, Amaryllidaceae alkaloids are also frequently found to have other useful biological properties. Galanthus, as a member of the Amaryllidaceae have their fair share of interesting and diverse alkaloids. The composition of alkaloids (different chemotypes) varies between species, although factors that affect this diversity remain unclear. It may be that environmental factors play a part in this diversity, as well as/or genetic factors. Also a study by Berkov, et al (2008) found that different parts of the plants had different alkaloids profile, and this varied between the two species studied. They reported a total of 37 alkaloids detected in the two species studied with only 5 in common. In G. elwesii they found predominantly homolycorine-type alkaloids in the roots, bulbs and leaves, whereas the flowers contained mainly tyramine-type. In G. nivalis however they report the leaves containing predominantly lycorine-type, bulbs tazettine-type and roots both types, whereas the flowers contained haemanthamine-type alkaloids. The key alkaloid types discovered thus far from the genus Galanthus are listed in the table 1 along with their biochemical derivation and pharmacological properties

Table 1.

Different Alkaloid Types identified in Galanthus species and their pharmacological properties.

Alkaloid type	Derived from:	Biological and Pharmacological Activities
Norbelladine	L-phenylallanine and L-Tyrosine	Anti-inflammatory (Cox enzymes inhibitor,and suppress NF-B)
Lycorine type	ortho-para’ oxidative coupling of Norbelladine	Inhibitor of cell cycle in plants,algae and yeasts. antiviral, anti fungal,anti-protozoan, anti-inflammatory, insect antifeedant,
Homolycorine type	Lycorine	Cytotoxic, antiretroviral, hypotentive, anti-fungal, insect antifeedant
Galanthamine type	para-ortho’’ oxidative coupling of Norbelladine	Increase levels of Acetylcholine, by inhibiting AChE and modulating nACh receptor. can cross blood brain barrier
Haemanthamine type	para-para’ oxidative coupling of Norbelladine	Inducer of programmed cell death, antimalarial, hypotentive effects, antiretroviral, antibacterial
Narciclasine type	Haemanthamine	Retroviral activity, DNA topoisomerase reactive, anti-protozoan
Graciline type	Haemanthamine
Tazettine type	Haemanthamine	Cytotoxic
Plicamine type	Tazettine

Compiled mainly from data in The Genus Galanthus: A Source of Bioactive Compounds by Berkov et. al. (2012).

The most medically significant alkaloid obtained from snowdrops is galantamine (or galanthamine) and is a licensed drug for the treatment of Alzheimer’s disease (AD), (Wilkinson 2001). The development of galantamine from snowdrop to modern drug for AD is well documented in a review by Heinrich and Teoh (2004). It was originally isolated in the Soviet Union, during the cold war period of the 1950’s and as such initially was only used in Eastern Europe for the treatment of poliomyelitis (polio). It is said that a Russian pharmacologist discovered the local people in a village at the foot of the Ural mountains using wild Caucasian snowdrops to treat children with poliomyelitis. It was then used for the treatment of other neurological conditions such as myasthenia gravis, muscular dystrophy and trigeminal neuralgia. During the 1980s and into the 1990’s it underwent preclinical and clinical trials in the West and was registered under the name Reminyl in the UK as a prescription only medication in 2000.

The other phytochemical compound of medical, bacteriological and agricultural biotechnological significance is the carbohydrate binding protein known as GNA lectin. This compound was first isolated from Galanthus, and subsequently identified in many other plant species from different families. It is therefore now referred to as GNA-related lectin. It has unique carbohydrate-binding capacity specific to mannose and this feature can be utilised in biomedical research. This compound has been found to have anti-tumour, anti-viral and anti-HIV properties (Li 2009). It has been genetically engineered into wheat (Stoger 1999), rice (Rao 1998), tobacco (Hilder 1995) and potatoes (Birch 1999) to provide insect resistance against Homoptera (aphids), Coleoptera (beetles) and Lepidoptera (butterflies and moths).

Preclinical data / pharmacology

Alkaloids, being derived mainly from ubiquitous amino acids often have diverse biological functions (Table 1). Although Table 1 indicates many potential pharmacological properties of alkaloids from Galanthus spp., in vitro, there is a huge difference between these results and those on animals and so far it is only galantamine that has made it to clinical practise. Galantamine has two modes of action, it is an acetylcholinesterase inhibitor (ChEI) and an allosteric potentiator of nicotinic receptors. AChEI is a chemical or drug that inhibits an enzyme (acetylcholinesterase) from breaking down acetylcholine, an important neurotransmitter in the brain. Its effect on the nicotinic receptors is to modulate activity, as it binds to the receptor in the same way as acetylcholine. Both these modes of actions increases the level of acetylcholine which improves neurotransmission. As the drug is able to pass the blood/brain barrier it has this effect on the neurones within the brain, improving neuroconnectivity and therefore memory, cognition and attention. It is not a cure of AD but can help alleviate some of the symptoms. It is available only through prescription.

Due to galantamine’s effect of increasing acetylcholine it can be used with atropine as an effective treatment for organophosphate poisoning.

Galantamine has also been trialled as an augmentative treatment for children with autism. Ghaleiha, et al (2014) found improved irritability and less lethargy/social withdrawal when the antipsychotic drug risperidone, which is used to treat irritability in children with autism, was administered with galantamine rather than on its own. However, galantamine is not, as yet, registered for other indications such as an augmentative treatment for children with autism.

Toxicology

The snowdrop is not used as a herbal preparation due to its high alkaloid content and, therefore, potentially serious toxicity. Symptoms of Galanthus poisoning include stomach cramps, diarrhoea, dizziness, nausea and vomiting. The bulbs of the plant are particularly toxic. Clinical preparations of Galantamine can also cause gastrointestinal symptoms as undesirable side effects. The most common non-gastrointestinal side effects are dizziness and fainting. Shi, et al (2011) report in clinical trials that at least 5% of patients reported gastrointestinal symptoms and 2% reported dizziness or fainting whilst taking Galantamine compared to a placebo. Galantamine is metabolised by enzymes (cytochrome P450) in the liver, therefore any drugs that inhibit this system can cause increased levels of Galantamine concentration in blood plasma.

Efficacy of galantamine

A Cochrane Review is considered to be an internationally recognised authoritative assessment of primary data in human health care most commonly focusing on the clinical efficacy of a medicine. A Cochrane review on the use of Galantamine for AD and mild cognitive impairment, involving 10 studies and 6805 patients showed a statistically significant positive effect for doses greater than 8mg/day, although they found no evidence of a significant dose-response effect. The studies were for at least 6 months duration, there is no data for long-term benefits. The review found decreased side effects if the dose up to 16mg/day was introduced gradually over four weeks (Loy, 2006). A Cochrane review on the use of Galantamine for vascular cognitive impairment caused by vascular damage only found weak indications that there was an improvement in cognition (Birks, 2006).

Conclusion

There is more to the this spring-time flower than the attractive white bell shaped flowers that are often the first signs of spring poking up through the snow. Whilst it delights the casual observer it excites the more serious plant enthusiast and the plant biochemist alike. The chemicals extracted from the snowdrop are already helping to stave off the mental deterioration that dementia brings and protect crop plants from pests; it is clear that chemical apothecary within the snowdrop has only just begun to be tapped.

DISCLAIMER

This monograph is not intended to advise or recommend plants for medicinal or health use. This information is for educational purposes and should not be considered as a recommendation or an endorsement of any particular treatment. The use or consumption of any such product should be based on the appropriate advice of a health care professional. Snowdrop bulbs are poisonous and are not suitable for human consumption.

All photograhs of snowdrops within this work were taken in Mecklenburgh Square Garden March 2017. The isolated and dissected bulb photograph was from the author’s own garden.

Appendix 1; Species of Galanthus

The native geographical location (including altitude) of each of the 20 species of snowdrop is provided along their flowering period, and leaf morphology.

Species Name	Height of Plant (cm)	Native Location of Plant	Altitude of Wild Plants (m)	Flowering of Wild Plants	Leaves	Special Notes	Clade*
G. nivalis L.	15-20	Western, central and southern Europe	100-1,600	Jan-May	applanate	The most common snowdrop	C
G. reginae-olgae Orph.	approx. 10	Greece,SW Balkan, Corfu, Sicily, Italy (Albanis?)	1000-1,300	Oct-March	narrow applanate	leaves absent or small during flowering	C
G. plicatus M.Bieb.	approx. 25	Central West Black Sea, Crimea, S Russia, N. Turkey, Romania	100-1,350	Feb-April	explicative		C
G. cilicicus Baker	10-18	S. Turkey, Tadrus mountains and Mediterranean sea	500-600	Feb-May	narrow applanate often twisted	Rare	D
G. peshmenii A.P.Davis & C.D.Brickell	9-12	Aegean Islands of kastelorizo & Turkish mainland around Antalya	>0-1,000	Oct-Dec	narrow applanate	leaves absent or small during flowering	D
G. krasnovii Khokhr.	7-27	W. Georgia, NE turkey	1,100-1,700	March-May	super volute broad	rare long bulbs	G
G. rizehensis Stern	8-12	W. Transcaucasus, Georgia, Krasnodar region of Russia	25-1,200	Jan-April	applanate		B
G. lagodechi-anus Kem.-Nat.	approx. 20	E & Central caucasus, Armenia, Azerbaijan	1,800-2,400	Jan-April	applanate narrow		B
G. transcauc-asicus Fomin	4-12	Armenia, Azerbaijan,N. Iran, S caspian Sea	up to 2000	Dec-April	super volute broad		A
G. alpinus Sosn.	approx. 16	Mountains of the Caucasus, TranscaucaN/E Turkey (Iran?)	400-2,200	Feb-May	supervolute		A
G. woronowii Losinsk.	18-20	NE Turkey, W. Caucasus, S. Russia, Georgia	20-1,400	Jan-April	super volute Bright Green		B
G. trojanus A.P.Davis & Özhatay	10-20	NW Turkey	300-500		Wide	Large flower	F
G. panjutinii Zubov & A.P. Davis	18-25	W. Transcaucasia	400-1,800	March-June	super volute narrow Bright Green		G
G. platyphyllus Traub & Moldenke	10-20	Central caucasus, Georgia, Russia	1,200-2,700	April-July	super volute Large		G
G. angustifolis Koss	7-14	N. Caucasus	700-1000		applanate	Rare	A
G. elwesii Hook. F.	9-18	Greece,Ukraine, Balkan, Bulgaria, turkey	800-1,600	Feb-May	super volute broad	Large flower	D
G. koenenianus Lobin, C.D.Brickell & A.P.Davis	5-14	Pontic mountains, N E Turkey	1000-1,700		super volute narrow distinct ribbing underside leaf	Rare Flowers smell of urine / bitter almond	A
G. fosteri Baker	8-16	Central & S Turkey, Syria, Lebanon Jordon (Israel?)	1000-1,600	Jan- April	supervolute		B
G. ikariae Baker	10-15	Aegean Island Andros Naxos Skros, Ikariae	600-900	Jan-April	super volute broad		E

Information mainly compiled from Gardener’s Guide to Snowdrops by Freda Cox (2014)

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