Azadirachtin, Hyperemesis and Herxing?

 

Image result for neemPeople have used Cannabis sativa L., (Cannabis) for thousands of years (2900 BCE in China) without a single sign of the purported ‘Cannabis Hyperemesis Syndrome’ (CHS) symptoms. Modern day organic insecticides have a lot to answer for, but nobody seems to be blaming them, when they should! At the beginning of the century, the evergreen Neem tree was highly esteemed by Indian migrants who took it to where they settled, introduced to Australia, Africa, south-east Asia and South America. Today, the Neem tree is well established in at least 30 countries across Asia, Africa, Central and South America with small scale plantations in Europe and the United States. 

Azadirachtin (C35H44O16) is the key insecticidal ingredient found in the Neem tree (Azadirachta indica), commonly called Indian (or Persian) Lilac or White Cedar. Neem trees were first introduced to Australia between 1940 and 1944 in the Northern Territory and Queensland. In the 1960’s, Neem trees were planted at Darwin Airport as part of a government–RAAF initiative. In Western Australia, governments promoted Neem as an amenity tree in the 1970’s (trees introduced into local landscapes with a deemed value to the community, i.e., for shade and mosquito deterrence) and in the late 1980’s, Comalco began trials of a new variety. The first Australian Neem workshop at the University of Queensland (1988) triggered a surge in interest. Landholders, scientists and companies started enthusiastically planting Neem trees and while heavily promoted, a viable industry did not develop and many plantations were abandoned. Neem has been sold as a nursery plant and at weekend markets for at least 20 years in Queensland.

Image result for neem oil on fruit and vegNeem has a range of uses but most interest lies in it’s pest control properties for which it is grown commercially. Azadirachtin is extracted from the seeds and leaves of the Neem tree and is promoted as an insecticide more ‘environmentally friendly’ than synthetics. However, in Australia in 1988, an economic assessment concluded, “Neem has little current demand with no local production and only small volumes of imports”. More than a decade later, in 2002, a report, ‘Pesticide use in Australia’, by the Australian Academy of Technological Sciences and Engineering, noted; The growth of the organic farming industry has created increasing interest in the possible use of naturally occurring products such as Neem … increasingly sought by growers for use in both agriculture and animal husbandry. Neem-based products are not currently registered as pesticides in the marketplace. Registration requires rigorous scientific assessment in terms of safety. Since such products are not currently registered, they cannot legally be used as pesticides”.

Image result for neem oil australiaIn May 2002, the Complementary Medicines Evaluation Committee (CMEC) noted an application to the National Drugs and Poisons Schedule Committee (NDPSC) had been made regarding Neem oil. The application had been evaluated by the Chemical Product Assessment Section (CPAS) of the TGA. The NDPSC discussed the toxicological profile of some types of Neem extracts which resulted in significant toxic effects in animals after oral administration, including testicular atrophy, impaired fertility and causing abortion (abortifacient) effects. There were case reports of lethal ingestion in children of doses as low as 5 ml and the NDPSC considered including Neem in Schedule 7 (Dangerous Poison) of the Standard for the Uniform Scheduling of Drugs and Poisons (SUSDP) with a Schedule 5 (Caution) entry for agricultural products. CMEC were advised the NDPSC foreshadowed inclusion in Appendix C of the SUSDP of Azadirachta indica (Neem) in preparations for human use. CMEC Members noted Appendix C lists substances, other than those included in Schedule 9, of such danger to health as to warrant prohibition of sale, supply and use. Members noted the foreshadowed action would directly affect the CMEC recommendation to permit listing of Neem seed oil and would prevent use of all Neem products in therapeutic goods, cosmetics or toiletries.

Image result for Complementary Medicines Evaluation Committee (CMEC)


Therapeutic Goods (Listing) Notice 2003 (No. 2)

Published in the Commonwealth of Australia Gazette No. GN 32, 13 August 2003
Therapeutic Goods Act 1989
I, TERRY SLATER, National Manager, Therapeutic Goods Administration, delegate of the Parliamentary Secretary to the Minister for Health and Ageing, under subsection 17 (5) of the Therapeutic Goods Act 1989, require the following therapeutic goods to be included in the part of the Australian Register of Therapeutic Goods for listed goods:

  1. preparations, referred to in item 3 of Schedule 4, Part 1 of the Therapeutic Goods Regulations (the Regulations) that contain, as an ingredient, cold-pressed Neem (Azadirachta indica) seed oil for topical application at concentrations up to 1%, and at concentrations greater than 1% when in a container fitted with a child resistant closure and labelled with the statements:
    • Not to be taken;
    • Keep out of reach of children; and
    • Do not use if pregnant or likely to become pregnant

Dated 4 August 2003. National Manager, Therapeutic Goods AdministrationDelegate of the Parliamentary Secretary


Image result for Commonwealth of Australia Gazette 2003


Australian Federal Poisons Standard (2017) entry for Neem, Schedule 5;

AZADIRACHTA INDICA EXTRACTS (Neem extracts), extracted from Neem seed kernels using water, methanol or ethanol, in preparations containing 5% or less of total limonoids, for agricultural use. 

The Poisons Standard June 2017 consists of the Standard for the Uniform Scheduling of Medicines and Poisons No. 17 (the SUSMP 17). Schedule 10 (Appendix C) lists AZADIRACHTA INDICA (Neem) including its extracts and derivatives, in preparations for human internal use except ‘debitterised Neem seed oil’.


Image result for neem anthelminticNeem seeds comprise 40% oil. Azadirachtin, the major active ingredient’s content in the oil varies depending on extraction technology and quality of the crushed seeds. Neem seed oil as a traditional medical remedyin widespread use across the Indian subcontinent, Malaysia, Sri Lanka and Singapore, is anti-bacterial, anti-fungal, insect repellent, treats skin diseases and acts as an anti-fertility agent. The bark, leaves and purified biochemicals are anti-cancer and anti-microbial and Neem leaf extract possesses anti-inflammatory properties. Neem seed oil comprises many triterpenoids, of which Azadirachtin is the most well-known, however, there is no antidote available for Neem seed oil poisoning. Azadirachtin is implicated in causing Neem seed oil poisoning, causing diarrhoea, nausea and general discomfort when the oil is given orally as an anti-helmintic (kills worm-like parasites – flukes, roundworms and tapeworms). 

Image result for no specific antidote available for Neem seed oil poisoning.In adults, it presents as vomiting, seizures, metabolic acidosis (excessively acid body fluids or tissues) and toxic encephalopathy (malfunction of the brain), sometimes accompanied by anoxia (deficiency of oxygen reaching tissues). Recovery is complete with symptomatic treatment (therapy that affects symptoms, not cause). Fatal poisoning cases due to Neem seed oil in India and Malaysia have been reported. Five to ten millilitres of oil given orally to children against minor ailments caused vomiting, drowsiness, tachypnea (abnormally rapid breathing) with acidotic respiration (lungs can’t remove enough carbon dioxide [CO2]), polymorphonuclear leukocytosis (increased white blood cells) and encephalopathy developed within hours of ingestion followed by seizures, associated with coma (in some cases). Autopsy demonstrated pronounced fatty acid infiltration of the liver and kidneys, with mitochondrial damage and cerebral oedema, changes consistent with Reye syndrome (a rarely diagnosed disorder).

https://i2.wp.com/www.abc.net.au/science/news/img/health/marijuana131004A.jpg

The original purported CHS was a serious misdiagnosis by two South Australian General Practitioners, initially featured by the Australian Broadcasting Commission (ABC) as, Pot heads can’t stop puking, in October 2004. The article quoted a study that stated chronic Cannabis use could lead to regular bouts of non-stop vomiting and an obsession with hot showers. Dr James Hugh Allen, then a GP in Mt Barker, South Australia, needed a study to complete his specialty (anaesthesiology) so he reported this ‘rare, new syndrome’ in the November 2004 issue of the journal, Gut. Allen said the first case presented in the late 1990’s. The patient had a severe bout of vomiting. “He would vomit continuously for two or three days. It was so bad he had to go to hospital and be put on a drip”. The patient was a heavy Cannabis user who started smoking at age 19, with the vomiting starting three years later. Whilst in hospital the patient would sit in a hot shower, which he said relieved his nausea and vomiting. “It became an obsession. He would have 10 to 15 showers a day”.

Image result for south australia cannabis lawsAllen set out to test the theory that chronic Cannabis use could be behind otherwise ‘unexplained’ cases of vomiting. He identified 19 chronic Cannabis users (South Australia had fairly liberal laws regarding possession of small quantities for personal use). Of the initial 19, nine cases, plus one from Sydney, demonstrated Allen’s purported link between chronic Cannabis use and vomiting. “They all had exactly the same ‘syndrome’Out of the 10 cases, seven abstained and all got better. Three took up smoking again and got sick again. Of these three, two gave up again and got better and one continued smoking and remained ill”. Allen said the illness was reasonably rare, affecting perhaps 1% of chronic users. “But some people are very sensitive to Cannabis”. He said further research was needed to test this. In January 2013, Dr Allen presented a Submission to the New South Wales’ Government ‘Inquiry Into Use of Cannabis for Medical Purposes’, on behalf of the Mt Barker South Surgery. Drs Allen and Heddle wrote to remind government of their purported syndrome (having presented no further research on the subject).

cropped-medical-weed.jpg


INQUIRY INTO USE OF CANNABIS FOR MEDICAL PURPOSES
Organisation: MT BARKER SOUTH SURGERY
Date received: 28/01/2013
We felt it was appropriate to inform the Committee about our original description of the entity of cannabinoid hyperemesis, which is a form of cyclical vomiting often needing hospitalisation that occurs in regular consumers of Cannabis, typically patients self-medicating with relatively high doses. If the medical use of Cannabis or synthetic cannabinoids is legalised, our fear is that use might increase the frequency of this syndrome, which is a distressing illness. This syndrome appears to be unique to Cannabis and our observations have over the last eight years been confirmed by reputable groups internationally … culminated in publication … of 98 cases from the Mayo Clinic … Dr Hugh Allen, MB,BCh, BAO, FRACGP, Dr Richard Heddle MB,BS, MD, FRACP


lapook-marijuana-1228en-transfer.jpg

Dr Kennon Heard, Colorado

Azadirachtin was first synthesised in the United States (US) over a decade ago (2007) and was given US Organic Materials Review Institute (OMRI) certification for sale. In 2000, use of Cannabis for medicinal purposes commenced in Colorado, US. The number of licensed patients initially grew at a modest rate, but in 2009, Colorado’s Board of Health abandoned the caregiver-to-patient ratio rule and the medical Cannabis industry took off. Increasing numbers of users started coming down with purported CHS. Coincidence? Not according to Dr Kennon Heard, Emergency Room physician at the University of Colorado Hospital in Aurora, Colorado. He published a study in 2015, ‘Cyclic Vomiting Presentations Following Marijuana Liberalization in Colorado’, and in 2016 told CBS News“They’ll often present to the emergency department three, four, five different times before we can sort this out”. The study shows since 2009, when medical Cannabis became more widely available, emergency room visit diagnoses for purported CHS in two Colorado hospitals nearly doubled. However, the study lacks scientific proof and according to experts, the symptoms are so rare it could simply be an allergy to certain terpenes, or an issue with unregulated flower. 

Image result for cannabis business allianceMark Malone, then Executive Director of the Cannabis Business Alliance, suggested the link between purported CHS symptoms and Cannabis use is far-reaching and unsupported. He called it an ‘alleged disease’ because real numbers are not presented and the study relies on information that patients “were more likely to endorse marijuana use” which proves nothing. While a few studies have generated interest in this topic, there have been no epidemiologic studies associating Cannabis use with the ‘alleged disease’. According to the same study, “this deficit is likely multifactorial due to the lack of formal diagnostic criteria for CHS, the relatively low prevalence of this syndrome and the social stigma regarding marijuana use that discourages self-reporting”. Malone is one of the many Cannabis experts who remain sceptical about the ‘alleged disease’. He said the study is unfounded and not well-researched.

Image result for cannabis industry coloradoThe study reveals no definitive link: “Patients presenting with cyclic vomiting after marijuana liberalization were more likely to have marijuana use documented in the ED record, although it is unclear whether this effect was secondary to increased use, more accurate self-reporting, or both”. Added Malone, “The industry in Colorado had not heard of this issue until this news story”. A third study from 2012 at the Mayo Clinic, used a relatively small sample of 98 patients, ten of which followed up with the researchers. Seven of the ten in the study stopped using Cannabis. Six of the seven went into remission. In the 2009 study the researchers note, “despite a high rate of marijuana use in our community, the absolute prevalence of cyclic vomiting remained low, underscoring that CHS is a relatively uncommon condition”

Image result for Azadirachtin is used to controlAzadirachtin is used to control white flies, aphids, thrips, fungus gnats, caterpillars, beetles, mushroom flies, mealy bugs, leaf miners, gypsy moths and other ‘bugs’ on food, greenhouse crops, ornamentals and turf. The labelling for food (fruits and vegetables) says you can use it up to the day of harvest and Cannabis growers have been doing just that. There’s a long history of safe use of organic Neem and Azadirachtin products with fruits and vegetables (<30 ml, one fluid ounce, of Neem seed oil has 200-2,500 ppm of Azadirachtin). This history says root drenches do not work, because the plants do not uptake the compound through their roots. Well, Cannabis does, which means the studies of them being safe products are wrong, when it comes to Cannabis. Many producers of Azadirachtin contaminated Cannabis are otherwise exceptionally clean, ‘organic’ growers and the only thing missing is their education on Cannabis being hyper-accumulatory with phyto-remediation capabilities and not the same as a fruit nor vegetable (Cannabis is a herb). Cannabis sativa L., grown for food, housing, oil etc., is known as ‘Industrial Hemp’ because it has the capability of hyper-accumulation of industrial waste. 

hemp-farm-in-china-rolling-farmlands-in-background

Industrial Hemp (Cannabis sativa L.)


Hyper-accumulatory nature of Cannabis sativa L. is shown by accumulation of various metals (mg/kg) in industrial areas (Heavy metal contamination and accumulation in soil and wild plant species from industrial area of Islamabad, Pakistan’ 2010)

Concentration of metal (mg/kg) Root Shoot
Lead 29 mg/kg 30 mg/kg
Copper 29 mg/kg 18.2 mg/kg
Zinc 27 mg/kg 43.9 kg/kg
Nickel 13.6 kg/mg 11.3 mg/kg
Cobalt 24.7 mg/kg 14.8 mg/kg
Chromium 29.7 mg/kg 14.5 mg/kg

Azadirachtin is implicated in causing Neem seed oil poisoning and anecdotally, symptoms of Azadirachtin poisoning from contaminated Cannabis include:

  • Persistent early morning nausea
  • Inability to eat (not eating doesn’t help, however)
  • Recurrent episodes of severe nausea and intractable vomiting, hyperemesis (severe or prolonged vomiting)
  • Intense abdominal pain
  • Intense pain around the kidneys and lower back muscles along the spine
  • Severely increased muscle tension over entire body

Processed food only exacerbates the symptoms of nausea and pain. Temporary relief of symptoms including the back, gut and muscle tension pain can be had by taking a hot bath or shower and cessation of symptoms will follow when the Azadirachtin toxicity reduces and eventually ceases. ‘Clean’ Cannabis (without Azadirachtin) helps alleviate the symptoms. Benadryl (Diphenhydramine), an antihistamine mainly used to treat allergies can be used for nausea and provides some relief (anecdotally). Following the antihistamine with activated charcoal can help remove the Azadirachtin more swiftly. Further suggestions for remediation include anti-nausea medication (Maxalon used in hospitals) or ginger and cayenne pepper in food along with probiotics, yoghurt and even Kombucha.


The acute inhalation toxicity study in rats exposed to technical Azadirachtin showed the LD50 (Lethal Dose) is >2.41 mg/L per animal, the highest dose tested. Although this figure is below the 5.0 mg/L limit test dose for an acute inhalation study, the reported concentration was the maximum dose possible under test conditions. 

Image result for neem fruits vegetablesCurrent and historical misinformation across mainstream western medicine says the ‘alleged disease’ happens with mass use or ‘abuse’ of Cannabis. Reality shows this syndrome happens with even low use of heavily contaminated Cannabis. When plants are treated in vegetative or early flower stages, low concentration applications can produce lightly contaminated Cannabis. Anecdotally it takes a week or so of constant use for the Azadirachtin to build up to toxic levels. Gastroenterologist’s in the US were under the impression it took significant amounts of Cannabis use to cause the ‘alleged disease’ and were quite surprised to find it can be caused by even small amounts, heavily contaminated with Azadirachtin. They were even more surprised to find use of large amounts of Cannabis was not an issue, as long as the Cannabis was not treated with Azadirachtin.

An external file that holds a picture, illustration, etc.Object name is fnbeh-05-00060-g001.jpg

Timeline of synthetic cannabinoids and Spice products.

In October 2012 a case was presented at the American College of Gastroenterology, entitled ‘Spicing up the Differential for Cyclical Vomiting: A Case of Synthetic-cannabinoid Induced Hyperemesis Syndrome’. This described the severe illness of a 22 year old man with aggressive disease induced by JWH-018 and JWH-073 synthetic cannabinoidsThere is an escalating number of compounds with cannabinoid receptor activity being referred to as Spice or K2 (Cannabicyclohexanol), so-called synthetic ‘Cannabis’, of which almost nothing is known in terms of pharmacology, toxicology and safety and which were never meant to be combined, combusted and inhaled! Many ingredients are listed on Spice packets, with combinations greatly varying in number and concentration, often depending on country of distribution. A packet of Spice called ‘Banana Cream Nuke’ bought in the US had the following ingredients listed: alfalfa, blue violet, nettle leaf, comfrey leaf, Gymnema sylvestre, passion flower leaf, horehound and Neem leaf.

Two other cases of the ‘alleged disease’ associated with ‘synthetic cannabinoids’ have been reported, both in 2013. Synthetic cannabinoids are created in a laboratory and despite purported similarities in action, differ enough from Cannabis metabolites that standard drug screens do not identify them as they are entirely unrelated to the actual plant. However, even reporting of the ‘alleged disease’ not being exclusive to propagated Cannabis, but occurring with ‘synthetic Cannabis’, does not add any weight to Dr Allen’s ‘alleged disease’, in fact, the opposite is true. The symptoms are those of Azadirachtin poisoning, which is what it is. In jurisdictions where Cannabis is legal, check the source and you’ll find an Azadirachtin product is being used. Nothing to do with the Cannabis, nor it’s use, as sporadic or even one-off use can replicate the symptoms. Cannabis is merely a carrier! It is everything to do with Neem, however.

Image result for cannabis plants azadirachtin

Cessation of Cannabis treated with Azadirachtin or increasing use of untreated Cannabis are both effective treatments for the toxic effects of the otherwise seemingly harmless Neem. Thus, the ‘alleged disease’, the purported Cannabis Hyperemesis Syndrome is a complete misdiagnosis and a total misnomer as it has nothing to do with Cannabis!


Dr Allen stated in his original study; “The triad of chronic Cannabis, cyclical vomiting and compulsive bathing is indicative of a new syndrome with Cannabis ‘toxicity’ as a cause”. Cannabis is entirely non-toxic. Hence, Cannabis ‘toxicity’, like the Unicorn, does not exist.


Finally, further to having nothing to do with Cannabis, the ‘alleged disease’ exhibits such similar symptoms to ‘herxing’, the nth degree of getting worse before you get better, it’s not funny nor is it a coincidence! You might never have heard the term ‘Jarisch-Herxheimer Effect’ but generally speaking, most people have experienced it. The term was coined from the names of two doctors, Adolf Jarisch (1860-1902) and Karl Herxheimer (1861-1942) both of whom noticed that in response to treatment, many patients developed not only fever, perspiration, night sweats, nausea and vomiting, but their ailments became worse before settling down and healing. The more commonly known Herxheimer Reaction is a short-term (from a few days to a few weeks) detoxification reaction in the body. As the body detoxifies, it is not uncommon to experience flu-like symptoms including headache, joint and muscle pain, body aches, sore throat, general malaise, sweating, chills, nausea and a variety of other symptoms. Herxing is an over-reaction of receptors which basically do not know how to assimilate the tsunami of toxins, and produces a toxic response.

Image result for ‘Jarisch-Herxheimer Effect’

 

Expanded from Cannabis Hyperemesis Syndrome (CHS) is Azadirachtin Poisoning, Marijuana Legalization in Colorado: Early FindingsTherapeutic Goods Listing Notice 2003 No. 2, Progress on Azadirachta indica based biopesticides in replacing synthetic toxic pesticidesPesticide Use In AustraliaComplementary Medicines Evaluation Committee – Minutes 34th Meeting 2002Azadirachtin, CHS (Cannabis Hyperemesis Syndrome) and BenadrylFinally, the Article on Cannabis Hyperemesis Syndrome that Readers DeserveComparative assessment for hyperaccumulatory and phytoremediation capability of three wild weedsRecognition and Management of Pesticide Poisonings, Neem oil poisoning: Case report of an adult with toxic encephalopathyAzadirachtinHandbook of Pesticide ToxicologyAzadirachtin, Cannabinoid Hyperemesis: A Case Series of 98 PatientsCannabinoid hyperemesis: cyclical hyperemesis in association with chronic cannabis abuseNeem Tree Risk AssessmentThe Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for ResearchBeyond THC: The New Generation of Cannabinoid Designer DrugsSynthetic Cannabinoid Leading to Cannabinoid Hyperemesis SyndromeCannabinoid Hyperemesis Syndrome: A clinical discussion and A Gut Gone to Pot: A Case of Cannabinoid Hyperemesis Syndrome due to K2, a Synthetic Cannabinoid

top

Advertisements

One thought on “Azadirachtin, Hyperemesis and Herxing?

  1. Pingback: Cannabis & the Emergency Room – At Cannabis Corner

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google photo

You are commenting using your Google account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s