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Keen on neem?

Posted by apgaylard on August 2, 2010

Neem [Azadirachta indica A. Juss] is a tree of the mahogany family.  Various claims have been made for its health-giving properties.  As the Abha Light organisation seems keen on neem as an anti-malarial, I decided to do a brief review of the literature.  What follows is a commentary based on searching PubMed for ‘neem and malaria’, and doing some additional searches.

I don’t claim that this is exhaustive and I have not been able to locate any information on some of the papers cited*.  For articles behind paywalls, I have only been able to consult the abstract.

A Review

One of the first things that I look for, when I’m researching a new topic, is a review article.  A recent publication by Anyaehie (2009) seemed to provide a good starting point.

This author provides a bit of history around the evidence for the anti-malarial properties of neem.  He notes that, “Extracts from Nigerian neem leaves (Azadirachta indica) have been earlier reported to have anti-malarial activities (Ekanem, 1971)”.  Unfortunately, I cannot locate the reference and he elaborates no further on what the effects might have been.

He does start to discuss methods of extraction – it seems that there has been some controversy here – stating that Udeinya (1993) found, “acetone/water mixture is a more efficient solvent than water alone”.  It appears that neem has been developed into a compound known as IRAB a, “fractionated neem-leaf extract”.

The authors claims that, “Its anti-malarial activity has been reported to be superior to chloroquine (Udeinya et al, 2006), gametocytocidal**.  (Udeinya et al, 2006 and 2008) and schizonticidal*** (Udeinya 2008) against faliciparium malaria parasite.”

This is a little rash.  Udeinya et al, (2006) performed, “in-vitro assays against Plasmodium falciparum“.  So this alleged superiority over chloroquine is not as a treatment in humans, or in an animal model: but in some glassware.  As interesting and potentially useful as neem appears to be, it is a long way from being a viable treatment for humans.

As Udeinya et al, (2006) go on to say, “… If they are found safe and effective in vivo, the neem-leaf fractions may form the basis of new antimalarial drugs that not only cure chloroquine-sensitive and chloroquine-resistant malaria but also markedly reduce transmission.”  So the hurdles of safety and efficacy in people have yet to be cleared.

Udeinya et al, (2008) evaluated IRAB, “for activity against the asexual (trophozoites/schizonts) and the sexual (gametocytes) forms of the malarial parasite, Plasmodium falciparum, in vitro“, again they concluded that, “This extract, if found safe, may provide materials for development of new antimalarial drugs that may be useful both in treatment of malaria as well as the control of its transmission through gametocytes.”

Anyaehie (2009) does add a cautionary note on a potential drug interaction, “Water extracts of neem leaf have been shown to decrease blood levels of chloroquine in rabbits (Nwafor et al, 2003) but this has not been investigated with IRAB. The use in pregnancy has also not been evaluated and thus is not yet recommended.”

This could be a serious issue as chloroquine is still a commonly used anti-malarial.  However, to keep a sense of perspective, this is one study on rabbits not people.  Still, it does raise an issue that needs to be examined.

So, it seems that neem might have some promise as an anti-malarial, but this review highlights that there is, as yet, no evidence to say that it is a safe and effective treatment.  Any use of neem extract to treat malaria is therefore extremely premature.

Tested on animals?

As no trials have been reported for people, are there any studies in animal models that shed some light on the prospects for neem as an anti-malarial treatment?  Lucantoni et al (2010) used, “rodent malaria in vivo model Plasmodium berghei/Anopheles stephensi” and tested NeemAzal® (“a standardized extract of [neem] seed kernels, containing limonoids at a concentration of 57.6%”.) and azadirachtin A (a secondary metabolite present in the seeds of the neem tree) at 34%.

The results indicated that, “NeemAzal® completely blocked P. berghei development in the vector, at an azadirachtin dose of 50 mg/kg mouse body weight.”  Leading the authors to conclude that, “These results and evidence of antiplasmodial activity of neem products accumulated over the last years encourage to convey neem compounds into the drug discovery & development pipeline and to evaluate their potential for the design of novel or improved transmission-blocking remedies.”

So it seems that some of the constituents of neem seeds may have promise as anti-malarial agents.  However, this is evidence for starting a development process, as the authors argue; not for using a leaf extract as a treatment for malaria as Abha Light claim to be doing.

Neem in vitro

Much of the evidence cited for the anti-malarial properties of neem appears to come from laboratory in vitro studies.  Jones et al (1994) showed that a compound extracted from the neem tree (azadirachtin), and some “semi-synthetic derivatives, block the development of the motile male malarial gamete in vitro“.  They saw this as raising, “the possibility of developing azadirachtin-based compounds as antimalarials with transmission-blocking potential.”

Benoit et al (1995) determined the 50% inhibitory concentrations (IC50) of a number of plant extracts and determined that, “C. tinctorum. IC50 values were […] about one-tenth of those reported for extracts of neem leaves (Azadirachta indica) and about half the values reported for Artemisia annua extracts.”  This indicates that extracts of other plants might be better than neem, or at least the particular abstract used in this work.

Dhar et al (1998) determined that, “Neem seed fractions are thus active not only against the parasite stages that cause the clinical infection but also against the stages responsible for continued malaria transmission”.

Udeinya et al (2006) tested the, “activities of two fractions (IRDN-A and IRDN-B) of an extract from the leaves of the neem tree”.  They were compared with chloroquine using, “in-vitro assays against Plasmodium falciparum“.  The two neem fractions out-performed chloroquine, leading the authors to conclude, “If they are found safe and effective in vivo, the neem-leaf fractions may form the basis of new antimalarial drugs that not only cure chloroquine-sensitive and chloroquine-resistant malaria but also markedly reduce transmission.”

Finally, Udeinya et al (2008) evaluated the activity of, “A crude acetone/water (50/50) extract of neem leaves (IRAB)” against both asexual**** and sexual… “forms of the malaria parasite Plasmodium falciparum, in vitro.”  It appeared to be effective and exhibit a dose-response relationship, with, “no parasites in the cultures containing 5.0 mg/µL” of this extract.  Again, the authors noted the potential of the extract, ” This extract, if found safe, may provide materials for development of new antimalarial drugs that may be useful both in treatment of malaria as well as the control of its transmission through gametocytes.”

On balance neem extracts seem to offer some promise as precursors for new anti-malarial drugs.  These in vitro studies do not, of course, justify claims of superiority over established anti-malarials or the use of neem extracts in treating malaria.  As we have seen from the limited evidence from animal (in vivo) models there is some way to go before neem can be said to have provided a safe and effective treatment.  It might even be that this early promise does not convert into real success, or that another plant might be better.

However, helping to reduce the threat of malaria is not just a matter of treating infected people.  Like other diseases carried by pests, reducing the number of pests (vector control) and avoiding being bitten are very important.  Most of the evidence that I have been able to find relate to these risk reduction activities.

Can neem kill mosquito larvae?

The use of neem as a potential lavicide seems to have attracted the most attention.  This makes sense; neem trees grow in areas where malaria is endemic.  If something that is widely available can be used to reduce the numbers of parasite-spreading mosquitoes, this has to be a good thing.

Nagpal, Srivastava and Sharma (1995) reported the use of wood shavings, made into a ball and soaked in neem oil diluted in acetone.  This was used to control Anopheles stephensi and Aedes aegypti breeding in overhead water storage tanks.  This appeared to be successful for 45 days, with, “Two balls soaked in 5% neem oil” giving the best results.  However, no controls appear to have been used (e.g. untreated water tank, balls soaked in the acetone solvent).

Again, in an experiment with no apparent controls Batra et al (1998) investigated the lavicidal effects of a neem oil-water emulsion in water tanks and desert coolers.  Using 5% neem oil in the emulsion “resulted in 100% reduction of III and IV instar larvae of An. stephensi after 24 h while, against Cx. quinquefasciatus it was 51.6 and 91.2% reduction in the larval density after Day 1 and 14 respectively. Similarly, application of 10% emulsion in desert coolers against Aedes aegypti @ 40 to 80 ml per cooler resulted in complete inhibition of pupal production.”

On a cautionary note, Awad and Shimaila (2003) found that, “The efficacy of crude neem oil appears to be below that of conventional larvicides” in a laboratory and field study.

In an apparently uncontrolled laboratory and field experiment in Iran, Vatandoost and Vaziri (2004) tested what appears to be a commercial neem extract, Neemarin. It appeared to be more effective against Anopheles stephensi than Culex quinquefasciatus.  They claimed that, “The maximum time of efficacy was 7 days at the highest concentration (2 L/hectare).”

Using corn-oil as a control, Okumu, Knols and Fillinger (2007) found that, ” Neem oil has good larvicidal properties for An. gambiae s.s. and suppresses successful adult emergence at […] concentrations” in the 6 ppm to 11 ppm range.

Gianotti et al (2008) reported success with neem seed powder. Dua et al (2009) successfully trailed a neem oil lavicide “in different breeding sites under natural field conditions.”  Both of these teams saw potential sustainability and ecological benefits in their approaches.

NeemAzal was recently evaluated by Gunasekaran, Vijayakumar and Kalyanasundaram (2009) and claimed that, “because of its emergence inhibition activity [it] could be a promising candidate for the use in integrated vector management programme and replace chemical insecticides.”

It’s slightly unfortunate that a commercially prepared neem extract is contrasted with “chemical insecticides” when it is a synthetically extracted collection of potent chemicals.  This sort of wooly thinking can lead people to underestimate the potential harm of preparations derived from plants.  If they are biologically active against pests, there is a good case for carefully evaluating their effect on the ecosystem and human health.

Finally, Howard et al (2009) looked at the potential of, “neem wood and bark chippings in malaria vector control by evaluating their aqueous extracts as a larvicide and growth disruptor of Anopheles gambiae s.s. (Diptera: Culicidae) under laboratory conditions.”  The results were that, “Fifty percent inhibition of adult emergence (IE50) of all larval instars was obtained with <0.4 g of neem chippings in 1 liter of distilled water. For pupae, significant mortality occurred at 5 g/liter.”  They concluded that, ” Such larvicides can be particularly effective where larval habitats are relatively large and readily identifiable. Aqueous extracts of neem wood chippings can be produced locally and their use has the potential to be a low-tech component of integrated malaria vector control schemes in sub-Saharan Africa.”

On balance, it seems that appropriate neem extracts could be useful lavicides.  Whether they are more effective than the alternatives is unclear.  However, they have the potential to provide an economic vector control agent, though a number of these studies looked at very specific extracts; the production of these would incur significant cost.

Can neem disrupt mosquito activity?

Aside from killing larvae, mosquito activity can be disrupted in other ways. Nathan, Kalaivani and Murugan (2005) tested the effects of neem limonoids on Anopheles stephensi. They looked at a range of control mechanisms: larvicidal, pupicidal, adulticidal and antiovipositional activity.

These authors found that, “Azadirachtin, salannin and deacetylgedunin showed high bioactivity at all doses”. They found Azadirachtin to be the most effective, producing, “almost 100% larval mortality at 1 ppm concentration.”  Thus, they concluded that, “Neem products may have benefits in mosquito control programs.”  Interestingly, this study focused on pure neem limonoids – not just a simple extract of some part of the tree.

This is consistent with the earlier work of Dhar et al (1996), which found that volatile neem extracts suppressed oviposition in the Anopheles mosquito.

Lucantoni et al (2006) assessed the effect of Neem Azal on, “blood feeding, oviposition and oocyte ultrastructure” in Anopheles stephensi.  They found that, “Oral administration of Neem Azal to A. stephensi females through artificial blood meals did impair blood intake and oviposition in a concentration dependent manner. Similar results were obtained on females, which had consumed Neem Azal in sucrose solution before taking a blood meal of plain blood.”  They concluded, “this study indicates that Neem Azal) impairs hormone control of oogenesis and exerts a cytotoxic effect on both follicular cells and oocytes of the Asian malaria vector A. stephensi.”

Again, it looks like neem may be a useful vector control agent.

What about neem as a mosquito repellent?

Some agents can be used to repel mosquitoes away from individual humans, rooms, or other places where they congregate.  My brief review located nine papers in this category.

Sharma, Ansari and Razdan (1993) trialled two percent neem oil mixed in coconut oil, applied to the exposed skin of human volunteers.  It doesn’t appear that any controls were used, but the authors claimed, “complete protection for 12 h from the bites of all anopheline species. Application of neem oil is safe and can be used for protection from malaria in endemic countries.”

Two of the same authors (Sharma and Ansari, 1994) assessed the repellent action of neem oil (seed extract) on mosquitoes at two villages near Delhi, India.  In this case Kerosene lamps were used to burn neem oil in the living rooms of the villages.  In this uncontrolled trial, they found that, “Neem oil (0.01-1%) mixed in kerosene reduced biting of human volunteers and catches of mosquitoes resting on walls in the rooms. Protection was more pronounced against Anopheles than against Culex. A 1% neem oil-kerosene mixture may provide economical personal protection from mosquito bites.”

Looking at the effect of neem as a repellent against different mosquito species Sharma, Dua and Sharma (1995) published an uncontrolled study and found that, “2% neem oil mixed in coconut oil provided 96-100% protection from anophelines, 85% from Aedes, 37.5% from Armigeres whereas it showed wide range of efficacy from 61-94% against Culex spp. Therefore, neem oil can be applied as a personal protection measure against mosquito bites.”  Although it doesn’t address how neem compares to other replants – or none – it does, again, highlight the basic plausibility of neem as a personal repellent.

Using an untreated group as a control, Dua, Nagpal and Sharma (1995) evaluated neem cream as a personal repellent, against, “Aedes albopictus, Ae. aegypti, Culex quinquefasciatus, Anopheles culicifacies and An. subpictus mosquitoes.”  The resulting levels of protection given by an application of 2.0 g/person were, “78 (range 65-95), 89 (range 66-100) and 94.4 (range 66-100) per cent protection against Aedes, Culex and Anopheles mosquitoes respectively.”  Tellingly, “Significant difference was observed between neem cream treated and untreated group of population for Aedes mosquitoes (p < 0.001).”  The authors concluded that neem cream was, “safe and suitable alternative to insecticide impregnated coils for personal protection against mosquitoes and one application was 68% effective for four hours.”

In an uncontrolled field evaluation, Mishra, Singh and Sharma (1995) used a range of concentrations of neem oil in coconut oil (1-4%), applied to the exposed skin of volunteers.  “Results revealed 81-91% protection during 12 h period of observation from the bites of anopheline mosquitoes. Neem oil is an indigenous product and a practical solution to curtail mosquito nuisance.”

Further work on the use of neem in Kerosene lamps (Ansari and Razdan, 1996) indicated that, “burning 1% neem oil in kerosene lamps resulted in the deviation of An. culicifacies from living rooms to cattlesheds […] This was also reflected when malaria incidence was compared in experimental and control villages. Cases/000 and Pf/000 were in experimental village as against 9.6 and 4.3 in control village. Discontinuation of burning 1% neem oil in kerosene lamp resulted in recurrence of An. culicifacies in living rooms and increase in malaria incidence in experimental village.”

Tawatsin, Thavara and Chompoosri (2002) reported a field evaluation of nine plants in mosquito coils for protection against night-biting mosquitoes.  With a blank coil used as a control, “mosquito coils provided protection against mosquitoes with a ranging from 50% to 71% reduction in biting activity while the blank coil consisting of inert materials only reduced mosquito attacks by about 43%.”  The leaves of citronella grass performed best (71%), whilst rhizomes of turmeric (50%) was the poorest performer.  Neem showed a repellency of 61.8%, ranking 5th.  For comparison, “commercial mosquito coils containing pyrethroids” showed repellencies of 84.5 to 86.5.  So, neem may be useful in this role, but other plant derivatives may be better.  Pyrethroids may be even better.

Moore, Lenglet and Hill (2002) tested the efficacy of three “natural” repellents (eucalyptus based, neem based, and a combination of several repellent essential oils) against Anopheles darlingi, and a control preparation of 15% DEET.  They reported, “The eucalyptus-based repellent containing 30% p-menthane-diol applied at a dose similar to those used in practice gave 96.89% protection for 4 h. Deet gave 84.81% protection. The other 2 products did not provide significant protection from mosquito bites.”

Ravindran, Eapen and Kar (2002) found that the application of 2% – 5% neem oil against Culex quinquefasciatus, ” gave 50 and 40.9 per cent protection in indoor collections and 17.4 and 5.6 per cent in outdoor collections as compared with that of untreated control respectively.”  However, “Autan, a synthetic mosquito repellent studied concurrently showed a relatively higher protection rate from the bites of Cx. quinquefasciatus.”

So, the evidence is somewhat mixed.  Neem may work as a repellent; though not all studies confirm this.  Neither is it clear that its better than other plant preparations.  The trails which contained a synthetic comparator, tended to show neem to be an inferior repellent.

Are neem-based interventions safe?

In one of the papers there appeared to be an assumption that a plant extract like neem is not “chemical” (Gunasekaran, Vijayakumar and Kalyanasundaram, 2009) and is by implication safer and more environmentally friendly than a synthetic compound.  Regrettably, Gupta (2004) builds on this theme:

“In this light, problems of pesticide safety, regulation of pesticide use, use of biotechnology, and biopesticides, and use of pesticides obtained from natural plant sources such as neem extracts are some of the future strategies for minimizing human exposure to pesticides.”

Karunamoorthi, Mulelam and Wassie (2009) similarly over-simplified the safety issue, “Indigenous traditional insect/mosquito repellent plants […] are not toxic like existing modern synthetic chemical repellents.”

It well be may be that neem extracts are less toxic than conventional pesticides, but that is not guaranteed by them being plant-derived.  This issue still requires careful evaluation.

One study (Awad, 2003) has investigated, “the preliminary environmental and mammalian toxicology of neem oil” along with, “temephos and chlorpyriphos-methyl/fenitrothion.”  Further, environmental impact was studied using Culex pipiens, Daphnia magna and Gambusia affinis.  The author reported, “A high level of toxicity was observed, with slight differences between organisms. The emulsifiers individually also displayed toxicity towards the tested organisms.”

In terms of mammalian toxicology, “Up to 90 days daily oral crude neem oil treatment (5 g/kg body weight) of laboratory mice did not cause any significant changes in weekly body weight gain, nor in serum liver damage indicators, direct bilirubin or total bilirubin. Blood parameters of treated mice up to 90 days were not statistically different from those of control mice.”

The author concluded that, “Neem oil could be used as an environmentally friendly alternative to the traditional chemical anopheline larvicides.”

One study also looked at the safety of neem-burning Kerosene lamps (Valecha et al, 1996).  The results were that, “Single application of neem oil (1%) did not produce skin irritation in rabbits and adverse effect on guinea pigs after exposure to aerosol. Clinical examination of 156 adults and 110 children did not reveal any major adverse effects after one year of exposure to 1% neem oil.”

The bottom line

Despite claims made by the Abha Light organisation: It is clear that there is no evidence that any neem extract works as an anti-malarial treatment in humans.  A single study using mice (Lucantoni et al, 2010) hints at promise, for a commercial preparation containing neem extract anyway.

Of the five in vitro studies identified, four (Jones et al, 1994, Dhar et al, 1998, Udeinya et al, 2006 and Udeinya et al, 2008) demonstrated anti-malarial properties of neem extracts.  The remaining in vitro study (Benoit et al 1995) hinted that other plant extracts might have more promise.

In terms of attempting to treat malaria with neem – there is clearly a very long way to go before it could be considered to be based on sound evidence.  As it stands, offering neem preparations as a treatment is unjustified.  Given that effective drugs are available, it is also deeply unethical and dangerous.

A single study in rabbits showing that water extracts of neem leaf can decrease blood levels of chloroquine (Nwafor et al, 2003) should give sensible people further pause for thought.

There seems to be reasonable justification for using neem as a vector control agent and (perhaps) a repellent.  However, it may not perform as well as conventional agents; though cost, environmental and accessibility factors could make it a viable choice.

One study (Awad, 2003) examined mammalian toxicity and environmental impact.  Whilst it reported favourably on neem, assuming that it is safe because it is a plant extract is unwarranted.

Related Post

Deluded and Dangerous. July 31, 2010.

Disclaimer

I try to make sure that what I write is both accurate and fair.  If you think that I have got anything wrong please let me know.  If you are right I will happily change what I have written.

This is not medical advice.  If you need that see a properly qualified and registered doctor.

Notes

*I found no information on the contents of Ekanem (1971), Sharma, Nagpal and Srivastava (1993), Udeinya (1993), Kant and Bhatt (1994), Singh, Mishra and  Saxena (1996), Singh and Singh (2000) and Anyaehie (2003)

**kills gametocytes

***kills schizonts

****trophozoites/schizonts

† …gametocytes

References

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Anyaehie, USB. Changes in some Physiological parameters of HIV/AIDS patients on Anti retroviral and neem (Azadirachta indica) extract in Enugu, Nigeria. 2003.  Ph.D. thesis, Abia State University, Uturu, Nigeria.

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4 Responses to “Keen on neem?”

  1. [...] This post was mentioned on Twitter by gimpy, badscienceblogs and Evidence Matters, Alan Henness. Alan Henness said: RT @gimpyblog: apgaylard: showing the rest of us how to critique homeopathy papers http://bit.ly/cTofwQ [...]

  2. dingo199 said

    I’m unsure as to what became of this Abha foundation neem malaria prophylaxis study (i don’t see it in any of your refs above):

    http://hpathy.com/homeopathy-scientific-research/the-effect-of-a-homeopathic-neem-preparation-for-the-prophylaxis-of-malaria-%E2%80%93-an-exploratory-trial-in-an-at-home-setting-in-tanzania/

    It was touted by Tredinnick in Parliament as cast iron proof of homeopathy’s efficacy in 2008.

    http://www.badscience.net/2008/02/magnificent-torrent-of-canards-in-parliament-from-david-tredinnick-mp/

    The study itself was supposedly ongoing and due to be formally published (aren’t they all?).
    It looked at the incidence of “malaria” in an area of Tanzania, and then again after people had taken Neem for 6 months.

    The trial was a methodological farce and probably unethical for at least 2 reasons.

    It was a small, open-labelled, uncontrolled, unblinded study entirely reliant on historical recollection of possible “malaria” (ie no-one bothered to even establish if anyone actually had malaria!) and was conducted among study participants who lived in an area where seasonal fluctuations in malaria incidence occur and where any fool could predict that malaria transmission might be reduced after the end of the rainy season (which is when they did their follow-up).

    It also consisted of an unethical and underhand attempt to see if neem had any sterilising birth control effect on the local women. I doubt that was mentioned in the consent forms for the trial (if they ever had any to start with).

    “The secondary objective for this trial was to research whether there was evidence of a birth control effect of neem when used in the homeopathic preparation.”

    • apgaylard said

      Thanks for the comment. I only searched pubmed, so I guess that this study hasn’t made it into any pubmed listed journal yet. Looking at it, I’d be shocked if it did. Terrible rot, as you say. Decent evidence doesn’t exist for treating malaria with neem – let alone when you factor in that Abha Light’s treatment is only 5 drops/day of 1% (their extract) of neem leaf.

  3. [...] Keen on neem? « A canna’ change the laws of physicsNeem [Azadirachta indica A. Juss] is a tree of the mahogany family.  Various claims have been made for its health-giving properties.  As the Abha Light organisation seems keen on neem as an anti-malarial, I decided to do a brief review of the literature.  What follows is a commentary based on searching PubMed… [...]

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