Scientifically Sound Guidelines for THC in Food and Feed

nova-Institute March 2015 Authors Michael Carus (nova Institut), Dr. med. Franjo Grotenhermen (nova Institut), Prof. Dr. Rudolf Brenneisen (Universität Bern), Luis Sarmento (nova Institut), Dr. Dr. Gerhard Nahler (Clinical Investiagtion Support Gmbh), Eberhard Pirich (Clinical Investiagtion Support Gmbh) and Daniel Kruse (Hempro Int. GmbH & Co. KG) Editors Luis Sarmento, Linda Engel (nova-Institut)

nova-Institut GmbH Chemiepark Knapsack Industriestraße 300, 50354 Hürth Internet: www.nova-Institut.eu E-Mail: [email protected]

The European Industrial Hemp Association would like to thank all donors for making this report possible:

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Hempro Int. GmbH & Co. KG

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Propaganda Production

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Hemp Factory GmbH

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HempFlax

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Canah International

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UAB Agropro

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HANF FARM GmbH

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Nutiva

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Table of contents: 1

Introduction ................................................................................................................................ 4

2

Hemp food goods: small summary...................................................................................... 6 2.1 The value of hemp as food.................................................................................................................... 6 2.2 The hemp food market........................................................................................................................... 7 2.3 The presence of THC in hemp food goods ..................................................................................... 7

3

THC Guidance Values and Regulations around the World .......................................10 3.1 THC guide values and Regulations in Europe ........................................................................... 10 3.1.1 Switzerland............................................................................................................................. 11 3.1.2 German THC guidelines ..................................................................................................... 12 3.1.3 United Kingdom.................................................................................................................... 18 3.1.4 The Netherlands ................................................................................................................... 18 3.1.5 Italy ............................................................................................................................................ 18 3.1.6 Austria ...................................................................................................................................... 19 3.1.7 Belgium .................................................................................................................................... 19 3.2 THC guidance values and regulations in non-European countries ................................ 21 3.2.1 Canada ...................................................................................................................................... 21 3.2.2 USA ............................................................................................................................................. 22 3.2.3 Australia and New Zealand .............................................................................................. 24 3.3 Conclusion ................................................................................................................................................. 27

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EFSA feeding issue ..................................................................................................................29 4.1 Background .............................................................................................................................................. 29 4.2 EFSA 2011 report ................................................................................................................................... 30 4.3 Latest activity .......................................................................................................................................... 32 4.4 Conclusion ................................................................................................................................................. 32

5

Literature Review on No Observed Effect Level and Acceptable Daily Intake ..33 5.1 Pharmacological basis for a Lowest Observed Effect Level and No Observed Adverse Effect Level .......................................................................................................................................... 34 5.2 Conclusion ................................................................................................................................................. 38

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THC effects on human biological variations ..................................................................40 6.1 Increased sensitivity of children, neonates and foetuses ..................................................... 40 6.2 Genetic variation in the genes encoding CB receptors and metabolizing enzymes 43 6.3 Pharmacological basis for deriving an Acceptable Daily Intake ..................................... 43 6.4 Conclusion ................................................................................................................................................. 47

7

EIHA proposal on THC guidelines for different hemp food products ..................49

8 Delta 9-THC and delta 9-THC acid content in food raw materials, consumer goods derived from the hemp plant and feed raw materials. ........................................56 9

Impacts on the hemp market, remarks and final conclusions................................58 References: ............................................................................................................................................................ 60

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1

Introduction

Commented [MC1]: Draft

Although it was thought that Cannabinoids, one of the main components of the cannabis plant were unique to the plant (NCSM 2014), it has been found that some other plants contain cannabinoids or cannabinoid-like molecules; namely flax may contain cannabidiol (CBD) or a CBD–like molecule (Styrczewska et al. 2012); THClike molecules were found in the New Zealand liverwort Radula marginata (Toyota et al. 2002). Two cannabinoids (cannabigerol (CBG) and its corresponding acid) have been obtained from a South African Helichrysum (H. umbraculigerum) (Bohlmann & Hoffmann 1979). Nonetheless, cannabis remains an extremely important supper food due to its balanced ratio of omega fats and essential amino acids, relevant to human well being (Manku 1990; Science Daily 2014; Parker et al. 2003; Erasmus 1999; Simopoulos 2002; Ross et al. 2000; Lachenmeier and Walch 2005; Karimi and Hayyatghaibi 2006; Gibb et al. 2005; Leizer et al. 2000; Ross 1996). Delta-9-tetrahydrocannabinol (THC) is the most researched hemp constituent, as it is the main psychoactive ingredient of the plant. THC is a pharmacologically highly active substance that shows, as a function of dose, effects on a multitude of organ systems and body functions. The physical toxicity is low. Tests to establish a lethal THC dose for monkeys have been unsuccessful to date. The maximum administered dose of 9,000 mg/kg body weight did not result in the death of the monkeys. This corresponds to a dose of 15 kilograms of cannabis for a person weighing 70 kg, with an equivalent weight extrapolation (Thompson et al. 1973). Aside from health-impairing effects from high doses, such as loss of cognitive ability or drowsiness, beneficial effects at low doses were observed as well, e.g. immune-stimulating and neuroprotective effects. Nonetheless, THC at high concentrations can cause toxicity. Since different parts of the hemp crop contain THC in different concentrations, products, and in particular food goods, made from hemp contain varying levels of THC. Processing methods may also influence THC occurrence in finished goods. Therefore, production and commercialization of hemp food products must be regulated as to protect the consumer from potential adverse effects. However, to date, there are still no THC guidance values for food at the European level. Derived from this lack of Europe-wide control, some member states have left to themselves to draw guidelines on food products containing THC. One of these cases is Germany. Although several member states also use the German non-binding guide values, the lack of legal strength of these guidelines leaves traders and consumers alike, vulnerable. The European Industrial Hemp Association (EIHA) represents the hemp food producers in the EU and, with the public’s health in mind, would like to recommend a scientifically based regulation to give the industry and consumers alike a safe framework. In order to familiarize the reader with the current THC regulations around the world, this report will start by giving background information on the regulations in Germany and some other European countries, along with North America, Australia and New Zealand. It will also present the recent activities by the 4

European Food Safety Authority (EFSA), working for the EU Commission on THC limits for animal feed for meat and milk production. Subsequently, this report will put forward a comprehensive review of scientific literature on the topic of THC intoxication, in order to derive a No Observed Effect Level (NOEL) and an Acceptable Daily Intake (ADI) of THC. The term ADI is related to substances that are deliberately added to food or unavoidable residues. It is derived from NOELs by applying an uncertainty factor. Finally, European-wide THC guide values for different hemp food goods such as hemp seed, hemp oil, pasta, bread, snacks, and hemp-based beverages will be recommended. With this paper, EIHA aims at providing a scientific base for legislation to be drafted on the regulation of THC in food goods at the national and European levels. EIHA would like to contribute to the open discussion of THC in food with the aim of aiding the Commission in establishing fair and scientifically based THC guidance values in food and feed goods across Europe, protecting both consumers and producers, alike.

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2

Hemp food goods: small summary

Hemp (Cannabis Sativa L.) is a strain of the cannabis plant used for industrial purposes around the world. It yields natural fibres, seeds and shivs. Out of its main produces, seeds are commonly used in the food industry. It is not uncommon for hemp seed plantations to also be grown for other purposes. There are huge health benefits associated with the consumption of seeds and its derivatives (i.e. hemp seed oil or seed meal cake). The current market value of the hemp crop in Europe is steadily growing, following a worldwide trend. Due to the fact that hemp seeds contain trace amounts of delta 9tetrahydrocannabinol (THC), the psychoactive ingredient that makes the cannabis plant sought after by recreational users, guidelines on THC values ought to be introduced. Scientifically sound guidance values would give room for an industry to flourish while protecting the consumer. However, apart from THC, the plant contains several other substances (cannabinoids) that are rare in the plant kingdom, occurring almost exclusively in hemp. Some, such as cannabidiol (CBD), can have exciting beneficial effects to the consumer. Others, such as delta9-tetrahydrocannabinol carboxylic acid (THCA), have no effect on the human body in their purest form but may be ‘activated’ (decarboxylated) under certain circumstances. This chapter will introduce the reader to the hemp plant, exposing its nutritional and market values, to then cover in more detail the issue of THC content in food goods.

2.1

The value of hemp as food

Hemp Seeds can be used whole, hulled or for hemp oil. The pressing of hemp seed for oil generates, as a by-product, hemp seed cake, rich in protein and fibre. Hemp seed oil can be used for food, feed or cosmetics (particularly skin applications) (Hempro International, personal communication 2014). Hemp seeds and its derivatives are considered of particular important nutritional value due to their “almost perfect” balance of the omega-3 and omega-6 essential fatty acids plus the presence stearidonic acid (SDA) and gamma linoleic acid (GLA) (Manku 1990; Ross 1996; Science Daily 2014; Parker et al. 2003; Erasmus 1999; Simopoulos 2002; Ross et al. 2000; Lachenmeier and Walch 2005; Karimi and Hayyatghaibi 2006; Gibb et al. 2005; Leizer et al. 2000). A gross imbalance in the omega-3/6 ratio in the Western diet is now considered an important contributor to the high occurrence of inflammatory, cardiovascular, skin and even mental disorders. As a balanced source of these fatty acids, Hemp oil and seeds can help reduce their occurrence, in good taste. The healthy ratio of omega-6 and omega-3 fatty acids, and the relatively high phytosterol content of hemp foods, makes them beneficial to cardiovascular health as well as helping in the reduction of cholesterol by an average of 10% (Deferne and Pate 1996; Fenstrom 1999, Malini and Vanithakumari 1990). A diet with a proper balance of omega-6 and omega-3 fatty acids may also help delay or reduce the neurologic effects of Alzheimer’s and Parkinson’s diseases as well as increase immunity (Darshan and Rudolph 2000; Leson 1999). The ratio of these substances found in

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hempseeds has been shown to improve the quality of life of Alzheimer’s disease patients (Yehuda et al. 1996; Youdim et al. 2000). Hemp Protein – high quality Hemp seeds and its seed cake flour contain a high quality protein. It is easily digestible, and contains all essential amino acids in a balanced ratio that satisfies the protein needs of adults (Erickson 2007; Amerio 1998; Gibb et al. 2005; Hessle, Erikson and Turner 2008). Commercially available protein flour and powders are high in protein and dietary fibre. They are used in shakes and smoothies, as well as for baking. 65% of the proteins in hemp foods are in the form of the globulin edestin. Edestin is considered by many to be the most easily digestible protein for mammals. The remaining 35% is albumin, yet another easily digestible protein. (HempOil Canada, 2014)

2.2

The hemp food market

In Europe, during the year 2014 (based on seeds from the 2013 harvest) whole hemp seeds and derived hemp food and feed products are estimated to have a total market size of €45 million a year. Of this, €15 million were generated from EU seeds and an additional €30 million were generated from imported seeds/oils (EIHA 2014). Due to its unique properties, particularly its environmental benefits and the high yield of natural technical fibres, hemp is a valuable crop for the bio-based economy. Today hemp is a niche crop, cultivated on over 18,000 ha in the European Union (EIHA 2014). Of these, over 10,000 hectares are located in France and 8,000 across 18 other countries within the European Union (EIHA 2014). Production is estimated to increase in Romania, Hungary, and the Baltic States. Currently, France, the Netherlands, Germany and Austria are big processors of hemp raw materials (EIHA 2014). In Europe the total demand for Hemp seed has been increasing over the years and is at about 18,000 metric tons in 2013. Estimates for 2014 see the market reach 20,500 metric tons (EIHA 2014). This is covered ca. 50% by domestic production and ca. 50% by imports from China. Only a small share is cultivated organically, mainly used in the bio-food market (EIHA 2013). This is an increase from 2008 values of 15,500 metric tons (Hempro 2014; FAOSTAT, 2013). It is estimated that the production of hemp seeds will rise with demand for human food doubling in the next 5 years, although animal feed will remain the main market share (Hempro 2014; EIHA 2014, nova-Institut 2014). This is due to the fact that some feedstock species need lipids with a high share of omega-3 and omega-6 fatty acids for optimum development.

2.3

The presence of THC in hemp food goods

Hemp plant’s parts used for food originate from strains/varieties allowed for industrial cultivation in Europe, which should not exceed 0.2% THC (in dry matter of the upper 1/3 of the crop) (EU Commission 2008; Lachenmeier and

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Walch 2005). The strains of hemp legally allowed by the European Union can be found on Annex II of COMMISSION REGULATION (EC) No 145/2008 of 19 February 2008. From an average of 2151 samples collected in Europe between 2006 and 2008, the average concentration of THC found was of 0.075% (EFSA Scientific Opinion 2011), although samples in the EU showed values ranging from 0.05% to 0.2% (El-Ghany 2002; Mechtler et al. 2004). The prescribed use of certificated hemp seed by the EU and the increase of controls on manufacturers have obviously led to a significant decline of THC concentrations in hemp food and feed products to levels much lower than those considered harmful to humans (Lachenmeier and Walch 2005). It is important to take into consideration that accumulation of cannabinoids is influenced by factors such as maturity of the plant organ, sex of the plant, location of the plant organ on the plant and sampling procedures (Hemphill, Turner and Mahlberg 1980). The intoxicating properties of Cannabis sativa L. (THC) reside in the sticky resin produced most abundantly in the flowering tops of the female plants before the seeds mature (Karimi and Hayyatghaibi 2006). Generally, all parts of the cannabis plant can contain cannabinoids (Lachenmeier and Walch 2005). However, Australia's National Cannabis Prevention and Information Centre (NCPIC) (2011) has stated that the stalks and seeds have "much lower THC levels" than the flower, with the UN confirming that leaves can contain ten times less THC concentrates than the buds, and the stalks one hundred times less (UN 2009). The hemp seed itself, which is used for both food and feed, is almost free of THC but unavoidable contamination happens by contact between the shell (testa) and the flower or leaves of the plant. Only less than 2 μg/g for drug-type seeds and less than 0.5 μg/g for hemp-type seeds of THC is found in the kernel itself (internal area) (Lachenmeier and Walch 2005; Ross et al. 2000). THC concentration in seeds is a function of the type of seed and the extent of contamination of the seeds with plant debris (Lachenmeier and Walch 2005). Hemp seeds are cleaned before using, resulting in no significant THC content being found (Karimi and Hayyatghaibi 2006; Hemphill, Turner and Mahlberg 1980; Ross et al. 2000). In both North America and Europe, since 1998, a significant decline in THC concentrations has been reported. This is due to the planting and importing of low THC strains and a more careful cleaning of the seed (Leson et al. 2001). In fresh unprocessed hemp plants, THC mostly occurs in the form of its inactive carboxylic acid, i.e. THC acid A (THCA-A). THCA-A is present at a rate of about 90% of the total THC, and is devoid of psychotropic effects (Dewey 1986). However, when decarboxylated, i.e. converted into its active form, THC becomes non-carboxylated and, thus, biologically active. Decarboxylation occurs primarily as a function of time, pressure and temperature, for instance in food processing or when combusted. Thus, largely unprocessed foods, such as cold-pressed oils, may often contain large fractions of the pharmacologically inactive THCA-A. THC can naturally accumulate even if THCA-containing material is not heated, with a half-life of 35 and 91 days, whereas THC degrades to CBN only at a half-life rate of 24 to 26 months (Trofin et al. 2012). In order to take the possibility of THCA converting into THC into account, guidance values tend to be set on total THC. The EU limits of 0.2% in the crop, for

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example, take both THC and THCA into account. The same applies for many food guidance values, including the widely used BgVV’s (German guidance values). The exception is Canada where only THC is measured. In order to calculate total THC, one adds the amount of THC found in a sample to a factor of THCA present by 315/357. In other words, as only part of THCA present in a sample (roughly 88%) will convert into THC, a ratio is applied to THCA. As an example: If delta 9-THC were to be 0,28 mg/kg; and THCA were 0,91 mg/kg, the TOTAL THC would not be 1,19 mg/kg (= 0,28 + 0,91), but rather 0,28 + 0,91*315/357 = 1,08 mg/kg. This paper will refer to total THC as THC unless otherwise mentioned. The following chapter will showcase the current THC guidance values around the European continent and the world, in order to contextualize the reader to the current existing guide values in the food market and where there is room for improvement.

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Commented [LS2]: Is this clear?

3

THC Guidance Values and Regulations around the World

In 2011 close to 90,000 metric tonnes of hemp seed were produced globally (Department of Agricultural Economics, University of Kentucky 2013). In Europe the total demand for hemp seed has been increasing over the years and was at about 18,000 metric tons in 2013. Estimates for 2014 see the market reaching 20,500 metric tons (EIHA 2014). It is estimated that the production of hemp seeds will rise, with demand for hemp food doubling (Hempro International 2014; EIHA 2014, nova-Institut 2014). Canada is a major producer of hemp seeds (18,000 metric tonnes in 2011), which represents a considerable increase since 2005 of 6,500 metric tons in total. Almost all of the hemp produced in Canada is for the supply of seeds. These tend to be used for human food, either as, hulled seeds, hemp oil, or protein powder (Hempro International 2014). With demand for hemp food goods estimated to grow fast in Europe and North America by the end of the decade (EIHA 2013), regulations become an ever more pressing necessity. The following chapter will address the currently existing THC guide values in selected European nations, North America and Australia, New Zealand. This will facilitate the understanding and comparison of THC regulatory systems worldwide.

3.1

THC guide values and Regulations in Europe

When hemp seeds were reintroduced for human consumption in the mid-1990s, it was not uncommon to find THC levels in hemp oil from Chinese or European seeds in excess of 100 ppm (i.e. > 100 mg THC/kg). It was not until the mandatory farming of low-THC varieties combined with the cleaning of the seeds, that THC levels in oil from European producers was effectively capped at 10 ppm. Currently European THC limits only exist for hemp cultivation. According to EU law, solely the cultivation of hemp containing less than 0.2% (or 2.000 ppm (mg/kg)) THC in the upper 1/3 of the mature crop is permitted (Council Regulation (EC) No 1420/98)1 EU Regulations on General Food Law, which covers food during manufacture, preparation or treatment, recognises “…any product being extracted from or made on the basis of hemp can be considered as narcotic drugs in the meaning of the United Nations Convention on Narcotic Drugs (1961) and the United nations Convention of psychotic substances (1971). According to Article 2(g) of Regulation (EC) No 178/2002 (General Food Law), narcotic or psychotropic substances 1

http://eur-lex.europa.eu/legalcontent/EN/TXT/?qid=1414150819939&uri=CELEX:31998R1420

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covered by the aforesaid conventions should not be considered as “food” and consequently, they should not be allowed to be incorporated into the food during manufacture, preparation or treatment.” This separates the narcotic cannabis plant from hemp, being one penalized and the other permitted under certain controls. Member States that do not have specific THC regulations fall under EU and international law. However, food law is enforced at the discretion of individual Member States. The following subchapter will review the current status of hemp in several European countries. Within the EU, foods containing hemp products are allowed in several countries including UK, Germany, Austria, Finland, but highly restricted in others e.g. Italy, This is despite Italy allowing industrial hemp production for other purposes (Food standards NZ 2012). This sub-chapter will start with the Swiss high limits on THC, to then focus on the German case in more detail, the latter being the generic model for THC regulation in Europe. Finally, the sub-chapter will showcase THC guide values imposed by other EU member states.

3.1.1

Switzerland

Switzerland is a special case when it comes to THC limits in food. Due to the fact that biologically relevant concentrations of THC were found in Swiss hemp foods in 1996, the Swiss government introduced legal limits for THC in oil and other foods made from hemp seeds. The high THC content found in oils or cow milk was the result of the improperly cleaned seeds of high-THC varieties being used (Lehmann et al. 1997). This pushed Switzerland to be the first country in the world to adopt THC limits in food (Grotenhermen et al. 1998, Hemp Food 2001). Based on the review of scientific studies, the Swiss government divided food goods on sub-sets, according to a daily average uptake and general THC prevalence (Table 1) (Russo 2013, EDI 2014). To maintain a certain flexibility for farmers to breed new strains the THC limit for crops was set at 1% THC (Bundesamt für Gesundheit, Switzerland). Table 1 THC limits for food goods in Switzerland. Source: Fremd- und Inhaltsstoffverordnung, FIV 2014

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With the highest values in the world, the Swiss limits solely aim at avoiding psychotropic effects resulting from the ingestion of hemp food goods. Yet, the values are important as they help establishing the upper threshold of governmentally set limits in THC-rich food goods.

3.1.2

German THC guidelines

The Federal Institute for Health Protection of Consumers and Veterinary Medicine (BgVV), which in 2003 came to include the Federal Institute for Risk Assessment (BFR)2, developed the German THC guidelines in the year 2000. BgVV’s goal was to create a guidance value of THC per food good categories, in order to allow hemp in the food market but prevent adverse effects from excess ingestion of these products. For this effect, national consumption data was used to better bound each THC containing food category and its consumer uptake. The first step taken by BgVV in the development of the guidelines was to establish an Acceptable Daily Intake (ADI) for THC. The ADI is the amount of a specific substance (for instance a food additive, or a residue of pesticide) in food or drinking water that can be ingested daily over a lifetime without a significant health risk. Daily limits are usually established for any food component or additive that is harmless in small doses, but can have negative effects in larger amounts. It aimed at capping daily consumption of THC in order to avoid undesired secondary effects. ADI is calculated through the establishment of a Lowest Observed Effect Level (LOEL) that is then divided by a safety factor. Scientific literature tends to agree that a single dose of 2.5 mg of THC per person (70 kg body weight) per day can be regarded as a placebo, albeit this dose rarely may cause mild psychotropic or psychomotor effects in humans such as ‘light headedness’ (Please refer to section 4 in this paper). BgVV used this value as its LOEL per person. Once a LOEL was established, a safety factor was then applied. The factor is a way to protect several subpopulations that are more vulnerable to the particular substance. In the case of THC, this factor was determined to be 20. The division of the LOEL by the safety factor resulted in an ADI of THC of 0.125 mg per person per day. As an added safety round, this value was then rounded downwards to 0.120 mg per person per day. The following table (Table 2) summarizes this calculation: Table 2 BgVV/SKLM THC-guidance values for hemp-based foodstuffs BgVV/SKLM THC-guidance values for hemp-based foodstuffs Male weighing 70 kg, 25-50 years old Lowest Observed Effect Level (LOEL) per person

2,5

mg THC/day/person

divided by security factor of 20: Acceptable daily intake (ADI) of THC

0,125

mg THC/day * person

rounded to:

0,120

mg THC/day/person

(* 0.120 mg THC/d is equivalent to ~1.7 mcg THC/kg b.w./day for a 70kg subject)

2

Bundesinstitut für Risikobewertung, www.bfr.bund.de

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With an ADI of THC of 0.120 mg calculated, the next step was to derive guidance values to specific food groups. For this purpose, BgVV used consumption patterns relevant to foods that may be partially or fully made out of hemp goods. The following table (Table 3) shows the German average consumption patterns for selected goods that may contain hemp. Several food groups were gathered in three food categories, for latter simplification (column 1). The initial data was retrieved from an average annual consumption per capita of the German Federal government for the years 1994, 1995 and 1996 (column 4), and converted to daily uptake in column 5. An aggregated sum per category was calculated in column 6. Finally, these values were rounded upwards to create an extra layer of safety (column 7), in order to assure that any excessive consumption would not result in intoxication, due to the varying diets and quantities per serving. Table 3 Consumption data for years 1994, 1995 and 1996 for selected products. Source: BMELV 1997 General food groups Category

(German Federal Statistical Office)

Specific food goods

Annual Consumption (kg/year/capita)

Daily consumption (g/day/capita)

(l/year/capita)

(ml/day/capita)

 Including the quantities present in processed foods Oils

Edible oil

Finished products, pastries, and nonperishable foodstuffs

Sweets Finished food goods

Meats Pastas Dairy Products Breads, rolls and Nuts

Alcoholic drinks Beverages Tea Nonalcoholic drinks

12.1 (1996)

33

13,4 (1994)

37

7.3 (1996)

20

36.5 (1996)

100

Pasta

4.8 (1995 and 1996)

13



Yoghurt



Cheese

25.5 (1995 and 1996)

70



Breads and rolls



Nuts

84.9 (1996)

232



Beer



Wine



Sparkling Wine

169.6 (1996)

465



Spirits



Black

25.5 (1996)

70

225.5 (1996)

620



Olive oil



Other food oils



Waffles, biscuits



Chocolate, bars, nuts/seeds



Salty baked goods



Chocolate cream



Honey cake, gingerbread



Sweets and others



Sausage



Meat





Infusions



Refreshments



Fruit juices

Total daily consumption per category (g/day/capita) (ml/day/capita)

Total daily consumption per category rounded (kg/day/capita) (l/day/capita)

7*

0.007*

472

0.5

1155

1.2

* Value rounded due to culinary limitations of hemp oil

Finished food goods totaled 0.5 kg/day/person, while alcoholic and non-alcoholic beverages totaled 1.2 l/day/person. Even though the total daily consumption of oils reached 33g/day/person, hemp oil has the limitation that it cannot be heated for it will 13

lose quality properties. Therefore, a value of 7 gram/day/person was adopted within which it could be used to replace other oils without losing properties. With an Acceptable Daily Intake (ADI) of THC and a rounded daily consumption of certain grouped food goods, BgVV could now proceed with the calculation of the guidance values per category. Each category’s guidance value multiplied by the average daily consumption per person yields the daily THC uptake per person per category. The sum of all categories of daily THC uptakes per person ought not to exceed the ADI of THC of 0.120 mg per person per day. Taking hemp oil, a guidance value of 5 mg of THC per liter of product was established for pragmatic purposes. This is due to the fact that several samples tended to average this amount, with no registered intoxication cases. Furthermore, the fat soluble character of THC deemed it too difficult to reduce its presence beyond this level, even after precautionary measures, such as seed cleaning, had been applied. As previously mentioned, in order to calculate the daily THC uptake of hemp oil per person, one needs to multiply the daily THC guidance value of hemp oil per person by the average daily consumption of oil per person. In other words, the daily THC uptake of hemp oil, per person, is: 5 (the guidance value in mg/kg) multiplied by 0.007 kg (the average daily consumption), which equals 0.035 mg of daily-ingested THC per person. 0.035 mg is the total daily amount of THC one would ingest from oils if replacing 7 g of oil for hemp oil. Applying this reasoning to beverages, BgVV established a daily guidance value of 0.005 mg of THC per kg, resulting in a maximum of 0.006 mg of THC being ingested daily per person through drinks (0.006 = 0.005 x 1.2). In other words, once more, if one were to replace all its daily consumption of beverages by hemp-derived beverages, one would be ingesting a total of 0.006 mg of THC per day. In order to keep the ingestion of THC below the THC ADI, the sum of all categories of daily THC uptakes ought not exceed the limit of 0.120 mg per day per person. Consequently, BgVV divided the difference between the sum of the daily THC uptake per person of both hemp oil and hemp beverages (0.041 mg) by the average daily intake of remaining food goods (0.5 kg), to reach the guidance value for all other food goods of 0.158 mg per person per day. This value was rounded downwards, as a safety precaution to 0.15 mg/kg. The following table (Table 4) summarizes the previous calculations: Table 4 BgVV calculations for THC guidance values in foodstuffs

Guidance values in mg per kg by category

- Hemp oil (guidance value*consumption = uptake) - Hemp drinks (guidance value*consumption

BgVV THC guidance values (mg THC/kg) 5 0.005

Average daily intake (kg/day/ person) 0.007 1.2

Uptake in mg THC/day/person

0,035 0,006

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= uptake) Total

0.041

Remaining for (fixed) foodstuffs

0.158

0.5

0.079

Therefore, the following table was derived: Table 5 Current BgVV THC guidance values in food stuffs. Source: BgVV 2000

Foodstuff

German guide values (BgVV 2000)

Alcoholic beverages

0.005 mg/kg

Non-alcoholic beverages

0.005 mg/kg

Edible oils

5 mg/kg

Other foods

0.15 mg/kg

These values refer to the total THC-content, including delta-9tetrahydrocannabinol carboxylic acid (delta 9-THCA). According to a press release by the BgVV, these levels guarantee that “principles of precautionary consumer protection have been respected and no occurrence of harmful effects are to be expected according to the current level of scientific knowledge” (BgVV 2000, Text box 1). Compliance with these guide values currently constitutes the best possible protection against liability suits, but that does not mean it is equivalent to actual legal protection. The 2000 press release also stated that there was a need for further research, since not all health effects of THC were well understood: for example, there was a lack of detailed knowledge on the dose-effect relationship of the psychomotor and endocrine effects of THC when administered orally, nor was much known about interactions of other hemp ingredients and alcohol and/or medicines which affect the central nervous system. Recent research, however, has shone some light upon these issues (see Chapters 5 and 6). For hemp oil used in cosmetics, the BgVV also recommended that only oil that complies with the standards for edible oils should be used. Since most other EU countries have not developed their own THC guide values for hemp foods, the German standards are often used as a benchmark for the rest of the EU. Only a handful of countries, including Switzerland and Belgium, have their own comparable guide values. For edible oils, the values are four and two times higher than those in Germany, respectively (see 2.1.1 and 2.1.7). Although guide values must not be confused with mandatory limit values, those developed by the BgVV are widely accepted in practice and provide considerably reliable legal and planning conditions for producers. Most products are likely to comply with the guide values. Only products containing a high number of hemp seeds and hemp seeds themselves may, at

15

times, surpass the guidance values. This may also be the case in fat rich products, such as chocolates, since THC is fat-soluble. A factor that plays a role in keeping the THC content in these products low is the cleaning process of the hemp seeds. The seeds themselves contain only traces of THC at the surface and the THC content in the oil mainly originates stems from contaminations from other plant particles. However, seed cleaning is not sufficient to keep the THC content in certain products under current guidance values, apart from being deemed excessively cautious and strict.

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Text box 1: The original press release of the BgVV, 16.03.2000.

Available at http://www.bfr.bund.de/cd/1309 “BgVV recommends guidance values for THC (tetrahydrocannabinol) in hemp-containing foods Varieties of hemp which are low in narcotics can now be cultivated as useful industrial plants. Consequently, components of the hemp plant are increasingly being used to produce foods. The constantly growing range of products takes in for instance hempseed and hemp oil as well as cakes, pastries and pasta products, confectionary, sausage products, herbal teas, lemonades and beers produced using hemp. In the opinion of the Federal Institute for Health Protection of Consumers and Veterinary Medicine (BgVV) it is mainly the content of the diverse action, psychoactive delta-9tetrahydrocannabinol (THC) or its precursor delta-9-tetrahydrocannabinol carboxylic acid which is decisive for the health assessment of these products. Already in the past BgVV has recommended (Press Release 26/97) that the daily intake of THC in hemp-containing foods should not exceed 1-2 µg per kg body weight. Examination of these studies confirmed this assessment which means that it is now the basis for the proposals elaborated by BgVV for THC values in foods. Assuming that average amounts of various hemp-containing products are consumed every day, the following THC guidance values were derived for foods: 5 µg/kg for non-alcoholic and alcoholic beverages 5000 µg/kg for edible oils 150 µg/kg for all other foods The above values refer to ready-to-eat foods and apply to total THC including delta-9-tetrahydrocannabinol carboxylic acid. Compliance with this value means that the principles of precautionary consumer protection have been respected and no occurrence of harmful effects are to be expected according to the current level of scientific knowledge. Since the dose dependency of some effects of THC has not been clarified in a definitive manner, the proposed guidance values must be seen as temporary. They are meant as an orientation aid in food monitoring and for manufacturers. The guidance values suggested by BgVV were confirmed in consultations of the Senate Commission of the German Research Society for the Assessment of Health Safety of Foods (SKLM). In this context, a need for research was identified on all these issues. For instance, there is a lack of more exact knowledge about the dose-effect relationship of the psychomotor and endocrine effects of THC when administered orally to human beings. Studies on impairment of psychomotor abilities are especially important given the relevance of these effects for traffic safety and safety at the workplace. In this context, examinations must also be undertaken of possible interaction with other hemp ingredients and with alcohol and/or medicines which affect the central nervous system in man. A working group within BgVV is currently looking at the development of suitable standardised analytical methods for the determination of total THC in various foods. After consultation with its Cosmetics Committee, BgVV also recommends that only hemp oil which complies with the above guidance 17 value for edible oils should be used in cosmetics.”

3.1.3

United Kingdom

In the UK, the use of hemp in food is not regulated, at the moment, and it tends to be considered on a case-by-case basis. Factors considered include the amount of hemp present in the final product, the extent of use and anticipated intake. Cannabis is still considered a controlled drug and so the Home Office makes sure every product is subjected to review in order to clear its potential growth or commercialization as a narcotic. Several types of products can be found on the market, including seeds and protein powders. (Henry Braham 2015)

3.1.4

The Netherlands

Food containing hemp is sold and consumed in The Netherlands. The Dutch authorities do not have any specific laws governing hemp in food, therefore, EU laws and regulations are followed. There are no maximum levels for THC in food for the Netherlands, no licensing requirements, no import restrictions and no THC-based controls on the seed. This lack of regulation leaves several Dutch traders unsure about how to place their products in the market legally. The grey area also leaves suppliers vulnerable to prosecution, as they can be held solely responsible for the health effects of their food. Generally, Dutch companies use the German guidelines as a reference although clients can be more flexible in some products, such as oils, than others, such as protein powder. The German guidelines do not protect traders from legal action. The seeds from cannabis plants are exempt from the Dutch Opium Act (European Monitoring Center for Drugs and Drug Addiction 2014).

3.1.5

Italy

Italy allows hemp-based foods. The THC level is currently expected to be zero but this may be revised in the future. The Italian Health and Internal Affairs Ministries have been working with experts in an attempt to change the current tolerance level. However, changes in governments resulting from elections tend to slow the process down and render it unproductive or, at times, regressive as new governments want to restart the process from scratch. Food goods derived from hemp seeds are allowed, however, these goods are expected to contain no THC. This is due to the fact that THC is scheduled in the list of forbidden substances. Regardless of the zero-THC cap, hemp food goods containing THC can still be found, namely hemp oil, as some products are more tolerated than others. Seed and oil are currently classified as supplements and used in the treatment of menstrual pains and skin care.

18

If a company were to start selling hemp food goods, it is legally allowed to do so, although it is possible that it will run some risks due to police controls regarding THC-containing products. This is more frequent on hemp beer than other products, due to the perceived dangers of getting vulnerable people (alcoholics) exposed to yet another substance. Local health authorities, fraud squad and import authorities have the responsibility of checking the THC level in food. At the border the checks are carried out on the documentation plus sampling and analysis may be performed. Plans for legislation include using the German guidelines, although governments seem reluctant to approve it, as it may generate a boom in hemp farming and production of derived products. Furthermore, there are no strong local farming associations that can lobby the government and effectively defend a more specific THC regulation. Currently, production in Italy of hemp food goods is low and irregular. (Grassi 2014)

3.1.6

Austria

Austria permits the sale and consumption of hemp containing foods. There are no Austrian specific legal requirements for hemp foods, therefore EU laws and regulations are followed. The institution responsible for THC regulation is the Austrian Authority for Food Controlling or AGES (Agentur für Ernährungssicherheit - Agency of Food Safety). Based on the European General Food Law Regulation (EC) 178/2002 requirement that food has to be safe, the Austrian expectation is that the THC content in foods must not exceed 1-2 ug/kg bw/day, or 0.1 ppm per person per day, assuming an adult weighing 70 kg. Austria has no direct experience with drug testing results but refers to a German study (Rosenstock, Greifswald 2004) where students were fed hemp chocolate, granola bars etc which had quantifiable amounts of THC. Although large amounts were consumed and blood and urine samples were taken on an hourly basis no positive blood or urine results were obtained. Experiments involving considerable amounts of hemp tea produced similar results. The overall conclusion was that hemp-containing foodstuffs that meet German guidance values and consumed in normal amounts do not lead to blood concentrations associated with effects or positive cannabis results in body fluids. The Austrian Food Inspection Authorities are responsible for THC compliance in food. Hemp foods such as seeds, oil, butter, beer and chocolates are tested on a case by case-by-basis for THC content. Hemp tea is tested on a routine basis. 3.1.7

Belgium

Belgium permits the sale and consumption of hemp foods. Prior to the food being available for sale, it must be granted an exemption from the Belgian food

19

regulations. Exemptions are granted on a case-by-case basis. To date these include: tea-based beverages, alcoholic beverages, oil, seeds, and flour. For those foods where exemptions are granted the level of THC needs to be provided on a batch basis and maximum levels must not exceed these values. These provisions also apply to imported foods containing THC. The values were established on a pragmatic basis and under a decent risk evaluation.

Oil of seed: 10 mg/kg Seed and flour of seed: 5 mg/kg Other foods and drinks: 0.2 mg/kg

(A380 FSANZ 2012)

Belgian authorities use the batch testing for THC content to counteract the possibility of high-THC products getting into the food chain. In addition, any hemp production needs to comply with EU regulations and laws on type of seed used. Analysis reports must include batch number, the method of analysis and detection limit. (Joris Geelen 2015) The purchase of low-THC certified seeds or oil that is later used to make other products does not require a subsequent THC testing. In other words, the THCanalysis that comes with the prime material can be used for the end product. (Patrick De Ceuster 2014)

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3.2

THC guidance values and regulations in non-European countries

The US and Canada both established hemp and cannabis legislation early on. In 1938, mainly due to US lead anti-cannabis legislation, the cultivation of both drug cannabis and industrial hemp were banned in Canada and the United States. ince 1994, a small number of Canadian companies, as well as Canadian universities and provincial governments started researching industrial hemp production and processing. Due largely to their initiative, in 1998 the 60-year ban was lifted in Canada and the commercial cultivation of hemp was authorized. Today, hemp is enjoying a renaissance, with the global hemp market becoming a thriving, commercial success. In particular, a recent boom of the cannabis industry in North America has seen increasing demand for hemp goods. In the United States alone, estimated retail sales for hemp food and body care products exceeded $25 million in 2000, up from less than $1 million in the early 1990's. (TestPledge 2014) Until recently, hemp foods were not permitted for human consumption in Australia and New Zealand. Exceptions to certain cannabis seeds and products have recently been granted and hemp foodstuffs are now commercially available.

3.2.1

Canada

Canada was the second country to pass THC limits, after Switzerland, in 1998. However, the limit does not refer directly to food, but to hempen raw and semifinished products, such as hemp seed oil or flour. This allows other food goods containing hemp semi-finished products to be produced without the need for THC testing. Products containing hemp are exempt from further regulation if they contain hemp semi-finished or derivative goods which tested to contain 10 g or less THC per g (or 10 ppm). This regulation represents a de-facto limit for the handling of hemp. Unlike other countries, the limit applies to THC in its active form and not to total THC. Producers and traders alike believe that this method is more efficient at capping THC limits without interfering in the market. Guidelines, such as the German, are deemed too intrusive, costly and inefficient. There have been no cases of failures in work place drug tests derived from this method. (Hermann 2015) After it has been proven that the seeds are non-viable, the whole seeds are exempt from the regulations and unrestricted sale and provision is permitted. Although non-viable hemp seeds are exempt, derived products of non-viable seeds are not. The latter fall under the 10 ppm limit. It is deemed non-viable grain all intact viable grain which has been rendered non-viable using methods set-out in the Industrial Hemp Technical Manual and have been shown to be incapable of germination. These methods include: Steam heat, infra-red cooking processing, toasting. It is the responsibility of the processor, not the supplier of 21

the grain or the recipient of the oil or meal to assure that testing is done after processing. Accredited laboratories must also have authorization to possess industrial hemp grain or seed. (Food standards Australia and New Zealand 2012)

The THC limit for industrial hemp plant is 0.3% (3.000 ppm) of the dry weight of leaves and flowering parts. The THC levels in crops are usually regulated via an approved seed list. Licensed individuals must have their crops tested to verify they are complying with the law. On the origin of the 0.3% THC level, Dr. Ernest Small, Principal Research Scientist at the Eastern Cereal and Oilseed Research Centre, in Ottawa, a section of Agriculture & Agri-Food Canada (AAFC), the Canadian federal government ministry of agriculture, commented that: “this was simply a figure derived for taxonomic classification purposes to address infraspecific variation by recognizing just two groups – one obviously reflecting historical selection for “narcotic” kinds and the other historical selection for fibre kinds. However, while medical or risk considerations were not originally considered in deriving the 0.3% level, it can be assumed that legislators and regulators adopting this criterion were more or less aware that a figure of 0.3% THC in the upper third of female plants was related to the practical level of 0.9% THC often considered minimal in marijuana to produce marketable marijuana (obviously a much higher level is required today), and that for practical purposes the figure of 0.3% was reasonable for allowing the industrial hemp industry to develop while controlling the narcotic industry.” (Ernest Small, Private communication 2014) Dr. Small also pointed out that “the THC level in plants should not be a critical consideration when the level in seed oil and seed oil products is in fact the critical issue for regulatory concern.” (Ernest Small, Private communication 2014) Canada emerges as a growing influence on the global hemp production and trade, with an estimated plantation area of 43,911.52 ha in 2014 (Hermann 2015). This is an increase of 40% in surface area since 2013. Canada is estimated to surpass 50,000ha of hemp-planted land by 2015 (Hempro International 2014). 3.2.2

USA

The United States has no regulations on THC in hemp foods. Technically, a “zerotolerance” (0% THC) is expected on imported hemp goods. However, products with proper HS codes are allowed to be imported, including those under the Canadian 10ppm legislation.

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Furthermore, the industry has established its own standards that are voluntary but have been widely adopted. The goal was primarily to avoid any issues with drug testing and false positives for cannabis. For this effect, in the early years of the decade of 2000s, several North American companies got together to create ‘Test Pledge’, a voluntary regulatory agreement created by members of the industry. Pledge companies commit to implement quality control measures which limit the amount of trace residual THC in hemp nut and oil, thus eliminating the risk of a confirmed positive drug test. Producers and processors of hemp oil and hemp nut must commission THC tests on each and every lot of hemp nut and oil, performed by a properly accredited laboratory according to the official Health Canada protocol. All TestPledge distribution and/or manufacturing companies downstream must obtain and keep copies of THC tests on each and every lot of hemp nut and oil that is bought, used and/or sold. It covers only hemp nut and hemp oil, as these currently are in the hemp products most commonly consumed in the US market. The Drug Enforcement Agency (DEA) and Office of National Drug Control Policy (ONDCP) have attacked hemp food and cosmetics, mainly on the thin pretext that such products interfere with their campaign to eliminate the use of psychoactive cannabis. Until 1998, when thoroughly cleaned seeds from Canada and the European Union became widely available, hemp oil containing more than 50 ppm of THC was often found in the market. A study by a Canadian governmental research program (ARDI) and members of the hemp industry found that none of the 15 individuals who consumed up to 600 µg of THC per day were even close to producing a urine sample that was "confirmed positive". This and similar findings have not kept the federal government from using past drug-test interference problems as its pretext to harass the hemp industry, particularly as other food goods, such as poppy seeds, are not pressured despite the fact these may interfere with current narcotics drug-testing. Based on scientific research TestPledge requires that pledging companies achieve this goal by committing to the following THC guidance values: Hemp oil: 5.0 ppm Hemp nut: 1.5 ppm The more stringent THC limit in hemp nut compared to oil was set because hemp nut is more palatable and may be eaten in larger quantities. THC guidance values for TestPledge were set low enough to allow for the extensive daily consumption of both hemp oil and hemp nut without any problems. Production, transformation, and importing of hemp goods remain somewhat restricted in the United States, being the focus usually on non-viability of imported seeds. Although growing industrial hemp in the US is not strictly illegal, it requires a permit granted by the DEA, which tends to be difficult to obtain. New legislation has been put forward in order to solve this problem.

23

Any product containing any quantity of THC, unless exempted by the Drug Enforcement Agency (DEA), is considered a schedule 1 drug under the US Controlled Substances Act (CSA). Exceptions are also made for goods listed in another schedule based on FDA-approved medical use. DEA exempted products are all hemp items that do not result in THC entering the human body: paper, rope, clothing, animal feed mixtures, soaps and shampoos. (TestPledge 2014) 3.2.3

Australia and New Zealand

THC regulation in both Australia and New Zealand falls under the responsibility of Food Standards Australia New Zealand (FSANZ). Despite some state regulatory differences, Ministerial levels in both countries work very closely with regards to food standards. Hemp foods are not permitted for human consumption in Australia and New Zealand under laws regulated by FSANZ: Standard 1.4.4 – Prohibited and Restricted Plants and Fungi in the Australia New Zealand Food Standards Code. The Code prohibits all species of cannabis from being added to food or sold as food in Australia and New Zealand. Previous attempts to change the code to remove hemp had failed, including an application in 2002 cosponsored by the company Hemp Foods Australia. Hemp oil, exceptionally, has been permitted in NZ since 2002 under the New Zealand Food (Safety) Regulations. (http://www.foodstandards.gov.au/consumer/generalissues/hemp/Pages/defa ult.aspx) In 2012, FSANZ recommended that hemp be approved as a food source. The FSANZ report stated that: “It was satisfied that low THC Hemp foods are safe for consumption when they contain no more than specified maximum levels (MLs) of THC. Foods derived from Hemp seeds may provide a useful dietary source of many nutrients and polyunsaturated fatty acids, particularly omega-3 fatty acids. Hemp Foods have no psychoactive properties and therefore could not be detectable in drug tests. Hemp grows distinctively different to Marijuana and would easily be detectable by drug enforcement agencies.” Hemp Foods Australia 2014 Standard 1.4.4 has been varied to add an exception to certain cannabis sativa seeds and products. Although illegal, these may be purchased to add to food if containing 5 mg/kg of THC, ‘which is naturally present’, non-viable and hulled. Other products allowed in both countries and derived from hemp have different limits according to clause (2) of the document, and can be summarized as follows:

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Table 6 THC guidance values in foodstuffs in Australia New Zealand

Food product THC guidance value (mg THC/kg) Seeds 5 Oil 10 Beverages 0,2 Any other substance extracted or derived 5 from seeds To this, it is important to add that cannabis sativa is defined as containing no more than 0,5% THC in the leaves and flowering heads if the plants. The NZ Ministry of Health has no health concerns about hemp seeds in food as hemp seeds do not contain any THC and are not psychoactive. Ministry of Agriculture and Forestry (MAF) agrees that the generic nutritional composition of low THC cannabis sativa looks quite appealing as it has the potential to offer an alternative source of alpha-linolenic acid in the food supply. (MAF 2011 ‘THC hemp as food’) A proposal to change the current regulation is up for consideration at a meeting of the Forum in late January 2015.

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Table 7 THC guidance values and guide values in food goods in selected countries worldwide

Country Switzerland

Hemp Food allowed Yes

Germany UK Belgium Netherlands Italy Austria

Yes Yes Yes Yes Yes Yes

Canada

Yes

USA Australia

Yes No

New Zealand

No

Generic

Seed and Flour 10 mg/kg

Edible oil Non-alcoholic beverages 20 mg/kg 0.2 mg/kg

5 mg/kg On a case by case basis On a case by case basis No specific laws THC expected to be 0 THC expected to be such that exposure does not exceed 1-2 ug/kg bw/day (following European General Food Law Regulation (EC) 178/2002) No more than 10 ug/g on hemp semi-finished or derivative goods Pledge by the industry Not for human consumption Not for human consumption, however, Hemp Oil legally allowed as food

0.005 mg/kg

Alcoholic beverages Alcoholic drinks 0.2 mg/kg; Spirits 5 mg/kg 0.005 mg/kg

Other foods and drinks Breads and pastries 2 mg/kg; Vegetable food 1 mg/kg 0.15 mg/kg

5 mg/kg

10 mg/kg

0.2 mg/kg

1.5 mg/kg 5 mg/kg

5 mg/kg 10 mg/kg 0.2 mg/kg

0.2 mg/kg

5 mg/kg

5 mg/kg

10 mg/kg 0.2 mg/kg

0.2 mg/kg

5 mg/kg

3.3

Conclusion

Currently, only a hand full of countries in Europe has established limits or guide values for THC in food goods. Derived from the lack of Europe-wide control, some member states have taken up to themselves to draw guidelines for food products containing THC. The Swiss case, the highest limits recorded, is an example of the upper bounds currently practiced in Europe. This, of course, would go against EU regulations, in particular with regards to THC-rich hemp varieties grown. The Netherlands is another country that stands out for its lack of regulation. Its liberal approach to THC-containing products may be a consequence of its recreational use market, a factor that is unique to this country. On the other side of the spectrum are countries like Italy, in which a zero tolerance is expected. Both the UK and Belgium judge food goods containing THC on a case-by-case basis, with the latter ruling the judgment against rather high THC guidance values. The German threshold in food, commonly consulted as a non-biding reference, is the most widely used, regardless of its relatively conservative nature. The German Ministry of Health has demanded a "joint regulation for THC limits" at the EU level. Yet, at the intra-national level, progress has been slow (Hellweg 1998). Canada is unique in its THC limitations on hemp products due to the fact that they are applied across the spectrum of hempen raw and semi-finished products with a single value: 10 ppm. The Canadian THC limits have proven their value in practice. They apply solely to THC in its active form, and not to total THC. On the one hand, producers have been able to comply with them through proper manufacturing practices. On the other hand, no incidents of side effects due to the consumption of hemp based-food have become known following their adoption. This unique set of limits has stimulated a growing sector, revitalizing rural areas and expected to have grown at a rate of 25% in 2013 alone (Department of Agricultural Economics, University of Kentucky, 2013; Hempro International 2014). The United States, on the other hand, has no regulations on THC in hemp foods. Technically, 0% or no THC is expected for hemp goods. The industry, however, has established its own standards that are voluntary and have been widely adopted. The goal was primarily to avoid any issues with drug testing and false positives for marijuana. Finally, Australia and New Zealand have in place regulations that are a direct result of the drug policy in these countries. In an attempt to limit the usage of drugs, restrictions were applied to both narcotic and non-narcotic cannabis products. Although there has been a relaxing of certain limitations, hemp food goods remain a restrained market. Ministries and Food Standards alike seem willing to promote a change to the current restrictions. After analysing the different policies presented above, this paper will opt by using the German guidelines methodology, considered the most sound and

consistent on the subject matter by many European nations. It allows for a scientifically reasoned THC amount in food goods, maintaining the safeguard of the public in mind. By applying guidance values in THC containing hemp foods to an average per capita consumption of different food goods, the German guidelines bridge the industry’s and the consumer’s interests alike. This methodology will be structural to the European wide guidelines proposed by this paper. The report will continue by presenting the most recent call for THC legislation to be introduced, a case of THC-rich milk products that entered the European single market from Switzerland. As we have just seen, the Swiss THC limits are higher than that of the EU member states’. With a lack of appropriate restrictions, room remains for formal regulations to be introduced.

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4

EFSA feeding issue

4.1

Background

In the early 2000s, it came to the attention of the public that Swiss farmers had been feeding their cows flowers from high THC cannabis plants. The fibre hemp grown in Switzerland is subjected to high THC limits and hence a lot of the traditional cultivars and varieties contained considerable amounts of THC. In fact Switzerland had been the only European Country where the cultivation of highTHC hemp was allowed and not further regulated. On February 3rd 2004, a local newspaper “La Broye” published an advert depicting a boy holding a bottle of milk. The text said "since my dad feeds hemp to the cows, my milk tastes even better“ (NZZ 2005). The advert was ran by a company called SanaSativa, which was said to have around 60 Swiss farmers on its books (NZZ 2005). The Swiss authorities felt the need to check the claims and recognized that THC could go through into milk. The mandate to check THC levels in milk was given to Agroscope, the Swiss Federal Research Station for Animal Production and Dairy Products. A literature review found a Pakistani study that had detected traces of a metabolite of THC in milk from buffalos that were fed wild hemp. The non-hallucinogenic metabolite was found in 5 milk samples of the 10 animals tested. Adding to this, a separate test presented by Agroscope found traces of THC in milk in Swiss cows. The study dated back to 1998, in which pills with 625 mg pure THC were fed to cows, leading to milk with 0.03 mg THC per liter. Daniel Guidon, head of the department for security and quality, considered the findings enough to propose a ban of hemp as fodder to the Federal Assembly reasoning that not the amount of THC in milk but the perception of THC in society was crucial (NZZ 2005). Restrictions were introduced on cultivable varieties to 'Fédora 17'. To maintain a certain flexibility for farmers to breed new strains the limit was set at 1% THC. Barbara Früh, fodder expert for Bio Suisse, the Swiss umbrella group for organic organization, stated that the scientific foundations for banning hemp from fodder were rather "lean". The 15-year-old Pakistani test was done with cannabis that contained high THC values, not considered hemp under EU regulations. She added that a better solution would have been for both the Pakistani and Swiss case studies to undertake tests with hemp fodder containing a low amount of THC. (NZZ 2005) Additionally, farmers claimed that animals showed signs of better health and higher yield when fed cannabis plants, with most farmers also claiming it made the feeding process more affordable (NZZ 2005; BBC 2005). These claims were supported by SanaSativa adding that the ban was not sufficiently supported by scientific research and therefore illegal (SanSativa 2005). If confirmed, some of these claims could result in the drastic reduction of antibiotic intake by cattle, one of the main causes of the development of antibiotic-resistant bacteria. According to EU standards, all plants in question are not industrial hemp plants as their THC content exceeded the EU norm of 0.2%. Therefore, EIHA believes

29

the results from these feeding regimes should not be related to animal feed derived from industrial hemp in the European Union.

EFSA 2011 report

4.2

Nevertheless, a detailed risk assessment with regards to the risks for human health in relation to the presence of THC in milk and other food of animal origin was requested by the European Commission and was performed by EFSA’s Panel on Contaminants in the Food chain (CONTAM), in 2011. EFSA’s Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) adopted a scientific opinion on the safety of hemp (cannabis genus) for use in animal feed: – “EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP); Scientific Opinion on the safety of hemp (cannabis genus) for use as animal feed. EFSA Journal 2011;9(3):2011. [41 pp] doi: 10.2903/j.efsa.2011. 2011. Available online: www.efsa.europa.eu/efsajournal].“ In spite of several of the different human exposure scenarios considered showing estimated exposure higher than the established PMTDI (Provisional Maximum Tolerable Daily Intake) of 0.4 µg/kg bw, the scientific opinion concluded that, with regard to these previous findings, it is appropriate to consider the need to establish possible maximum levels for THC in milk and other food of animal origin in the frame of Council Regulation (EEC) No 315/93 of February 8th 1993 laying down Community procedures for contaminants in food. For that purpose a detailed risk assessment regarding the risks for human health in relation to the presence of THC in milk and other food of animal origin has been requested by the European Commission and will be performed by EFSA’s Panel on Contaminants in the Food chain (CONTAM). The Terms of Reference of the Commission request were as follows: In accordance with Article 29 (1) (a) of Regulation (EC) No 178/2002, the Commission asks EFSA for a scientific opinion on the risks for human health related to the presence of THC in milk and other food of animal origin. The scientific opinion should, inter alia, comprise the: 

Evaluation of the toxicity of THC for humans, considering all relevant adverse acute and chronic health effects.



Estimation of the dietary exposure (chronic and acute dietary exposure) of the EU population to THC from milk and other food of animal origin, including the consumption patterns of specific (vulnerable) groups of the population (i.e. high consumers, (young) children, pregnant women).



Assessment of the acute and chronic human health risks as the consequence of the presence of THC in milk and other food of animal origin, with particular attention to specific (vulnerable) groups of the population (i.e. high consumers, (young) children, pregnant women).

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EFSA’s Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) adopted a scientific opinion on the safety of hemp (cannabis genus) for use in animal feed. EFSA suggested to put whole hemp plant-derived feed materials on the list of materials whose placing on the market or use for animal nutritional purposes is restricted or prohibited and to introduce a maximum THC content of 10 mg/kg to hemp seed-derived feed materials. This suggestion was based on a LOEL (lowest observed effect level) of THC in humans of 0.04 mg THC/kg bw. By applying an uncertainty factor of 100, a PMTDI (provisional maximum tolerable daily intake) of 0.0004 mg/kg body weight (bw) was derived. Although the European Industrial Hemp Association (EIHA) welcomes the establishment of guidelines for THC concentrations in food and feed by the European Commission, EIHA has rebutted the values provided by EFSA in a statement released in May 2011. The publication refused EFSA’s arguments on a basis that they were derived solely from animal studies. “Toxicological data from animal studies can help to elucidate the toxicity of cannabinoids in humans. However, comparison of the data from studies on humans and animals reveals often considerable inconsistencies”. Therefore, it suggested that, “wherever possible, a quantitative risk assessment should be based on data from human studies” (EIHA statement 2011). EIHA disputed the notion that an uncertainty factor of 100 was indeed necessary. The value attempts to account for the differences between test animals and humans (factor of 10) and possible differences in sensitivity between humans (another factor of 10). However, EIHA believes that there are enough humanbased studies on the effects of THC for an interspecies factor not to be needed and that most of the references on differences in human sensitivity lacked updated scientific knowledge. Furthermore, EIHA did not see much scientific basis for a maximum tolerable daily intake to be provisional (PMTDI) since the toxicology of THC is very well investigated in humans, compared to other toxins. Usually, technical cleaning processes, commonly used processes for grain cleaning, directly lower the total THC on the outer seed shell. By comparison, the Swiss fed their cows “hemp pellets”, which had a total THC content of 1.7% (or 17.000 mg/kg). The drying process and pressure that was used to make these pellets certainly caused the transformation of THCA into THC. THC was, then, metabolized and detected in the cow milk (Callaway, 2014). This, however, would not have been the case if initial THC contents had been kept under EU regulations (0.2%) and the processing had been kept cold-pressed. In the fresh plant, about 90% of the total THC is actually THCA and the cannabinoid acids of THC (or THCA) are devoid of psychotropic effects (Dewey 1986). The typical ratio will range from 1:9 to 1:17 (Pitts 1992), with 1:>20 registered in some cases, like Switzerland (Brenneisen 1984). So, animals that are fed fresh hemp (stalks, leaves, flowering seed heads, etc.) will mostly receive THCA and very

31

little THC. This would mean very low (if any) amounts of THC in the animal and animal products. The production of THC from THCA is a function of time, temperature and pressure. Increasing any of these functions will also increase the production of THC from THCA. (Callaway 2014)

4.3

Latest activity

After the first statement by EFSA, in 2011 and above presented, the European Commission insisted on having a second more detailed and expanded statement, due in 2015. EFSA has contacted EIHA, in this regard, for information gathering on the topics of THC metabolic conversion in live stock animals and the market structure of hemp in Europe, in particular with regards to feeding and food. The information was provided on the 10th of October 2014. In November a document containing the lab results of 50 samples of hemp food goods analyzed for THC were provided to EFSA by EIHA. At the date of printing of this paper, no further communication had taken place between the agency and the association on this topic. With the last information gathered by EFSA in October/November 2014, the agency aims at publishing its next report in May 2015. After the release of the document, the Commission will hear stakeholders and other experts to discuss EFSA’s recommendations. EIHA would like to contribute to the discussion with this report with the aim of aiding the Commission in establishing fair and scientifically based THC guidance values in food and feed goods.

4.4

Conclusion

As stated above, the process of establishing European THC guidance values in food and feed has started in 2011, with the European Commission’s request. The action was a consequence of THC being detected in milk of Swiss origin. Although EIHA welcomes regulation on this issue, it reiterates that the Swiss samples should not be considered hemp due to their high THC content, exceeding EU’s norms. A new report will be published by EFSA in May 2015, after which a hearing will take place. This paper attempts to share some scientific information on the issue of THC in food and feed. The next chapter of this paper will present a quantitative risk assessment that is based on data from human studies. This will allow for a sound guidance value to be delineated.

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5

Literature Review on No Observed Effect Level and Acceptable Daily Intake

Concepts such as "No observed effect level" (LOEL) and “Acceptable Daily Intake” (ADI) are commonly applied when developing standards intended to prevent negative health effects from chemicals that are known, or suspected, to cause such effects. The term ADI is related to substances that are deliberately added to food or unavoidable residues. It is derived from NOELs by applying an uncertainty factor. This is in contrast with Tolerable Daily Intake (TDI), which is related to potentially harmful chemical contaminants and derived from adverse effects (LOAEL, NOAEL). This is an important distinction to make as EFSA stipulated its THC guidance values from NOEL, and yet suggests a “Provisional Maximum Tolerable Daily Intake” (PMTDI). This move labels THC’s intermediary and minor effects under the same toxicity level as long lasting detrimental effects of substances such as mercury, lead or bisphenol A. In contrast to many other substances, the recommended EFSA guidance value (PMTDI) for THC is not based on toxic effects (No Observed Adverse Effect Level, NOAEL) but on the lowest observed effect level (LOEL), which is a pharmacological effect. Such effects of THC are described in the literature as temporary, mild to moderate psychomotor- or cognitive effects. Effects, the biological half life, and the TDI arbitrarily set for THC contrast sharply with effects e.g., of methyl-mercury which is neurotoxic, has a half life 10-times that of THC, and for which the tolerable daily intake (TDI) is only slightly lower than that of THC. (Nahler 2015) THC differs from nonspecifically acting harmful chemicals in food in that it acts on compound-specific binding sites (cannabinoid receptors) on the surface of body cells. THC's mode of action provides an additional margin of safety for two reasons: 1. As a rule, for most harmful chemicals, when toxicity increases, the NOAEL correspondingly decreases with the duration of exposure. This fact must be taken into account when determining the safety factor. In the case of THC, however, the opposite applies. The effect of high THC doses decreases with increasing exposure due to the development of tolerance to THC by the receptors. Following the repeated ingestion of low THC doses no changes are expected on cannabinoid receptors, but also no increase of adverse effects. 2. Children are generally considered particularly sensitive to various harmful chemicals. Consequently, higher safety factors are chosen to provide sufficient protection. However, children have a significantly lower density of cannabinoid receptor sites. Thus, compared to adults, psychotropic effects occur only at higher THC doses. These assumptions have been confirmed in clinical studies with THC in children and following the treatment of children with cannabinoidbased medicines. Furthermore, it used to be the case that the majority of toxicological data for THC resulted from animal studies in which high doses were applied, as well as from cell studies (see Table 9, Chapter 6). For many of the potential health effects of THC, the NOEL had been found to vary. New data of THC effects on humans 33

provides a sound basis for the exclusion of uncertainty with a high margin of safety. The information above is important as it describes THC as a substance that requires a more detailed understanding of its influence in human subjects for consumption guidance values to be established. Cannabis is one of the most well studied plants on the planet. The following chapter will use scientific evidence from research papers in order to adequately extrapolate a Lowest Observed Effect Level and No Observed Adverse Effect Level. The evidence will be presented from a pharmacological point of view and will aid at understanding the vast and complex knowledge that science currently has on THC effects in humans.

5.1

Pharmacological basis for a Lowest Observed Effect Level and No Observed Adverse Effect Level

Several clinical studies, some of them large-scale, have been conducted in the past 10 years with oral THC or oral cannabis extracts with high concentrations of THC, casting new light on this research area (e.g. Wade et al. 2004, Strasser et al. 2006, Rog et al. 2005, Zajicek et al. 2003, 2005, Collin et al. 2007, Narang et al. 2008, Novotna et al. 2011). These studies add to the existing literature that aims at aiding the understanding of THC effects in the human body. Therefore, they ought to be used as the basis for the extrapolation of a Lowest Observed Effect Level (LOEL) and NOAEL for THC. Lucas & Laszlo (1980) found pronounced psychotropic reactions (anxiety, marked visual distortions) in patients undergoing cancer chemotherapy that had received oral doses of 15 mg THC/m2 of body surface corresponding to 25 mg THC for an average adult (body surface: 1.7 m2). A reduction to 5 mg THC/m2, about 8-10 mg THC, produced only mild reactions. In a study by Frytak et al. (1984), oral administration of 15 mg THC to 38 cancer patients caused psychotropic effects in 58% while 42% experienced no effects. Brenneisen et al. (1996) administered single oral doses of 10 or 15 mg THC to two patients. Physiologic parameters (heart rate) and psychological parameters (concentration, mood) were not modified by the administration. The authors suggest a threshold for psychotropic effects of 0.2-0.3 mg/kg bw. In a study with patients suffering from spasticity due to spinal cord injury by Hagenbach et al. (2007) patients tolerated daily doses of 15-60 mg oral THC. In some other cases, a single oral dose of 20 mg of THC caused symptoms as tachycardia, conjunctival irritations, “high feeling” or dysphoria within 1-4 hours in adults. (Lachenmeier and Walch 2005). The highest dose administered to a set of individuals was 210 mg/person/day, given over a period of 25 days. Not all subjects exposed had an Adverse Drug Reaction (ADR) to THC (Jones et al. 1976; Freinberg et al. 1975). THC has, therefore, an exceptionally large safety range. However, this was only the highest dose administered in experiments. The highest doses observed in clinical settings have been much higher, well above 1000 mg THC per day. For example in a study in Jamaica researchers investigated the effects of cannabis in people consuming 20-30g with a mean THC concentration of 4% (Bowman 1973). 34

In a study by Chesher et al. (1990) with healthy volunteers dosed orally with 5 mg of THC following a light breakfast, no difference in the subjective level of intoxication was found relative to placebo controls. Doses of 10 and 15 mg THC respectively caused slight differences relative to a placebo. An oral dose of 20 mg caused marked differences in subjective perception. In several clinical studies, psychotropic reactions were also observed following a single dose of 5 mg THC (Petro & Ellenberger 1981). However, these were generally indistinguishable from effects observed after the administration of placebos. At the lowest administered oral dose of 5 mg, Chesher et al. (1990) observed a decrease in several psychomotoric performance scores, primarily related to standing steadiness, reaction time, and arithmetic performance. It should be noted that the observed effects were small. Findings by other researchers suggest that even doses of 10 or 15 mg of orally administered THC generally result in minor psychomotoric effects (Brenneisen et al. 1996). With reference to the study by Chesher et al. (1990), authors concluded that an effect on skill performances can occur with a single oral dose of 5 mg THC/person. A review by Ramaekers et al. (2004) on isolated cognitive functions and psychomotoric skills related to driving performance indicates that "THC at doses between 0.04 and 0.30 mg/kg bw causes a dose-dependent reduction in performance," as observed in different tests. However, most of these effects have been investigated after inhalation of THC (cannabis). Ramaekers et al. (2004) stated that the "magnitude of the THC effects on performance furthermore varied with the application form, such as smoking or oral intake, and time post THC use." It is well-known that THC effects are considerably stronger after smoking (inhalation), and that the lowest effect doses have been observed after smoking (see Figure 1). Thus, the review by Ramaekers does not allow to derive a LOEL for THC in food. With regard to repeated exposure of THC two studies by Beal et al. (1995, 1997) have been referred, in which HIV patients received oral THC. The first study was a placebo controlled study with 139 patients, who received either THC (2 x 2.5 mg/person daily) or placebo for 42 days (Beal et al. 1995). The second study was an open long-term study, where patients received THC for 12 months (Beal et al. 1997). In the first study 25 of the 72 patients (about 35%) experienced psychotropic effects. In the long-term study similar effects were observed. However, an open clinical study is not very useful to assess psychotropic effects of THC since similar effects may be observed after placebo. For instance, Strasser et al. (2006) investigated the effects of THC (2.5 mg twice daily) in cancer patients in a placebo controlled three-arm study with THC, a cannabis extract and a placebo. 243 patients were randomly assigned and 164 completed the six-week trial. In contrast to the study by Beal et al. (1995) with HIV patients, who received the same dose for the same period of time, no differences where observed between THC and placebo for THC-related toxicity and other effects. Thus, a THC dose of 2.5 mg twice daily may be usually regarded as a placebo dose concerning THC effects. Later clinical studies abandoned the principle of administering fixed doses to patients in clinical studies, since only very few patients experience effects at a

35

dose of 2.5mg THC twice daily. Instead controlled clinical studies apply the principle of titrating the dose up to an individual effective dose. The largest clinical study ever conducted with THC was a 15-week three-arm study on THC, a cannabis extract and placebo in patients with multiple sclerosis (Zajicek et al. 2003). Patients were offered the possibility to continue into a 12month follow-up study, which was also a double-blind placebo-controlled study (Zajicek et al. 2005). In the short-term study 611 patients and in the long-term study 502 patients were evaluable. In the short-term study doses were slowly increased up to the occurrence of side effects or until the maximum dose (10-25 mg THC/day depending on body weight) was reached. The maximum dose was 10 mg for participants with a body weight below 50 kg and 25 mg for those with a body weight above 89 kg. Mean daily doses after the dose finding phase for participants with a body weight of 50-69 kg was 11.5 mg (or 0.17-0.23 mg/kg bw) and for participants with a body weight of 70-89 kg 15.8 mg (or 0.18-0.23 mg/kg bw). Thus, mean daily tolerable doses were about 0.2 mg THC/kg bw. Compared to the short-term study the long-term therapy with THC over a course of 12 months resulted in a dramatic reduction of adverse effects (Table 8). This may be due to the development of tolerance for some symptoms and the establishment of an individual tolerable dose for every patient. In the short-term study, doses were slowly increased until side effects appeared or the maximum daily dose was reached. Since several participants experienced side effects before reaching their maximum daily dose side effects were observed frequently. However, they were usually mild or moderate in intensity (Zajicek et al. 2003). In the long-term study by Zajicek et al. (2005) the incidence of side effects was no longer higher in the verum groups (THC and cannabis) compared to the placebo group except for the events "dizzy or light headedness" and "falls" (Table 8). In studies with THC taken by patients with HIV, similar observations of a reduction in frequency of side effects were made. While about 25% of patients reported a minor CNS-related adverse drug event during the first 2 weeks, only about 4% reported such an event during each of the following six weeks (Marinol prescribing information 2011).

36

Table 8 Side effects in the studies by Zajicek et al. (2003, 2005). Mean daily doses: about 0.2 mg/kg bw (see text for detailed information). Daily doses were 10-15mg THC.

Adverse event

Short-term study (15 weeks)

Long-term study (52 weeks)

THC

Cannabis Placebo

THC

Cannabis Placebo

or 59%

50%

18%

8%

10%

2%

Sleep

35%

40%

33%

8%

8%

9%

Spasms or stiffness

34%

33%

33%

14%

15%

14%

Gastrointestinal tract

30%

37%

20%

9%

12%

7%

Miscellaneous

28%

30%

22%

7%

7%

7%

Pain

26%

24%

32%

10%

17%

10%

Dry mouth

26%

20%

7%

2%

1%

1%

Weakness or reduced 25% mobility

23%

20%

10%

12%

16%

Bladder

24%

26%

23%

10%

12%

15%

Infection

15%

16%

17%

9%

11%

11%

of 12%

10%

8%

5%

2%

2%

9%

8%

6%

6%

5%

or 9%

7%

7%

5%

4%

4%

6%

8%

2%

2%

2%

0%

or -

-

-

5%

6%

6%

-

-

-

4%

7%

3%

or -

-

-

2%

2%

1%

Other skin problems *) -

-

-

1%

5%

6%

Pressure sores *)

-

-

0%

1%

3%

Dizzy lightheadedness

Tremor or lack coordination

Depression or anxiety Numbness paraesthesia Vision MS-relapse exacerbation *) Falls *) Memory concentration *)

10%

-

*) Not measured in the short-term study Further clinical studies refer to the cannabis extract Sativex®. It has been approved as a medicinal drug in the UK, Spain, Germany, France, Canada, Denmark, Norway, Israel, Austria, Poland, Sweden, Italy, Finland, Switzerland and several other countries. CBD, another cannabinoid that is found in hemp, is known to reduce mainly psychological and psychomotor THC adverse effects.

37

This is the reason why Sativex® is a 1:1 ratio of THC and CBD. One spray of the cannabis spray Sativex® contains 2.7 mg THC and 2.5 mg CBD, since this dose is expected to cause some effects in only very few patients. No effects are expected below this dose and people usually experience some effects only after higher doses (several sprays of the extract). In clinical practice physicians usually start with 1x1, 2x1 (morning and evening) or 3x1 sprays (morning, lunch time, evening) corresponding to 2.7, 5.4 and 8.1 mg THC a day, respectively, which is increased thereafter up to the effective and tolerated dose (Koehler 2014). In a large study with advanced cancer patients researchers intended to evaluate the analgesic efficacy and safety of Sativex® (Portenoy et al. 2012). Patients received either 1-4 sprays, 6-10 sprays or 11-16 sprays of Sativex® per day. 263 patients completed the study. Adverse events were dose-related and only the high-dose group receiving 29.7-43.2 mg THC (11-16 sprays with 2.7 mg THC each) compared unfavorably with placebo. Medical use of THC is well-tolerated over months and years. For example, Rog et al. (2007) conducted an open-label extension study following a controlled study with Sativex® in patients suffering from neuropathic pain. The mean duration of open-label treatment was 463 days (median, 638 days; range, 3-917 days). In the 34 patients of this study reaching one year of treatment the mean number of sprays was 7.5 corresponding to 20.25 mg THC. Most patients experienced an adverse effect, which was usually mild even at higher doses, and overall the medication was well tolerated. In another long-term study with 161 patients mean treatment exposure was 334 days and patients administered on average 7.3 sprays per day (=19.71 mg THC) (Serpell et al. 2013). Authors noted that “no new safety concerns were identified with chronic Sativex® treatment, and serious AEs [adverse effects] were uncommon.” In another long-term study with Sativex® researchers concluded: “Even after more than 2 years of use, no new safety/tolerability signals have emerged with Sativex ®” (García-Merino et al. 2013). In a study investigating driving ability of multiple sclerosis patients, participants received a mean dose of 5.1 sprays per day corresponding to 13.77 mg THC (Freidel et al. 2014). Authors concluded from their research: “Treatment of MS patients with Sativex® does not negatively impact driving ability and may improve moderate to severe treatment-resistant MS spasticity.”

5.2

Conclusion

According to the analyzed literature, a high dosage could be considered upwards of 15 mg THC for an average adult, following the findings of Lucas & Laszlo (1980), i.e. pronounced psychotropic reactions in patients that had received the corresponding amount to 25 mg THC oral doses and Chesher et al. (1990), whose participants suffered from marked differences in subjective perception after an oral dose of 20 mg. Usually, single doses of 5-15 mg THC cause mild psychotropic effects (Lucas & Laszlo 1980; Brenneisen et al. 1996; Chesher et al. 1990; Brenneisen et al. 1996; Petro & Ellenberger 1981).

38

An acute dose of 2.5 mg THC (corresponding to 0.035 mg/kg bw assuming a body weight of 70 kg) may usually be regarded as a placebo dose, albeit this dose rarely may cause mild psychotropic or psychomotor effects in humans such as ‘light headedness’. These effects tend to be watered down with time, as the body builds up a tolerance to THC (Zajicek et al. 2003 and Zajicek et al. 2005). The method of administration causes direct variations in the intensity of the effects (Figure 1). The effects of a single dose of THC typically last anywhere between 4-6 hours, with some remaining up to 8 hours after consumption, in extreme cases (Lachenmeier and Walch 2005; Figure 1). Considering an average human being sleeps 8 hours a day, this results in 16 hours of waking state. Thus, the ingestion of an oral dose of 2.5 mg of THC twice per day, equivalent to 5 mg taken over the course of a 24-hour period (or 16 awaken hours), represents a safe LOEL for any reduction in human performance to be felt as a consequence of THC consumption. The following chapter will take into account human biological diversity with regards to THC reaction, in order to establish a safe uncertainty factor. Subjective high 10 9

intravenous (5 mg)

8

smoked (19 mg) oral (20 mg)

7 6 5 4 3 2 1 0 0

1

2

3

4

5

6

Time after administration (hours) Figure 1 Time course of subjective effects following three modes of administration. A rating of the degree of "high" was made by subjects on a 0 to 10 scale (estimated from figures of Hollister et al. (1981) and Ohlsson et al. (1980)). Taken from Grotenhermen (2003).

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6

THC effects on human biological variations

For several reasons, some humans may be more prone to suffer from adverse THC effects. Some subjects, such as children or pregnant women, are particularly vulnerable to general toxins in food. Others may be carriers of genetic variations that may be responsible for undesired THC intolerance. Therefore, an appropriate scientific understanding of the effects of THC in vulnerable humans is crucial in allowing to extrapolate a safe uncertainty value to apply on the recommended THC guidance values. The following chapter will address this problem with new data on children, neonates and foetuses, along with genetic variations within the human population that may be responsible for undesired THC effects. Finally, this chapter will present evidence why animal tests with THC are not a good source of scientific information for the determination of a scientifically sound uncertainty factor.

6.1

Increased sensitivity of children, neonates and foetuses

Children are considered particularly sensitive to many harmful chemicals. Consequently, higher safety factors are defined to provide adequate protection. However, clinical studies have indicated that children are less sensitive to the effects of THC (Abrahamov et al. 1995, Dalzell et al. 1986). Two long-term longitudinal studies on children, who have been exposed to THC in utero, have followed them into adolescence and beyond and examined effects of this exposure on cognitive and other performance (Goldschmidt et al. 2012, Porath et al. 2005). Both studies found subtle effects of cognitive performance, mainly on executive function, in later childhood and adolescence. One study on cannabinoid receptor (CB-R) density (Glass et al. 1997) found a similar receptor density in the human foetus and children compared to adults. However, other researchers have found that CB-R density increases fivefold from birth to adulthood in rats (Belue et al. 1995). In yet another study, low numbers of CB-R could be observed as early as the 14th week of gestation in humans (Biegon & Kerman 2001). Finally, CB-R density increased slowly but did not reach adult levels by the end of the 24th week. Glass et al. (1997) found that the fetal and neonatal human brains show patterns of CB-R distribution similar to those observed in the adult human brain. They found a similar density in several parts of the brain (neocortex, cerebellum) and a greater density in children in other parts (midbrain, basal ganglia). However, the authors admit some limitations of their study: “Due to the small numbers of cases available for the study, it is not possible to draw any definitive conclusions on the precise levels of CB-R binding within the developing brain. Also, since the fetal/neonatal and adult tissue was not processed together, considerable care must be taken in comparing the results of the fetal/neonatal studies with the results in the adult brains” (Glass et al. 1997). These observations contrast with the results of a study by Belue et al. (1995), who found that CB-R density in rats increases fivefold from birth to adulthood.

40

Rodriguez de Fonseca et al. (1993) also found an increase in CB-R binding in rats between birth and day 30, this time followed by a slight decrease until adulthood (day 60 and later). Another group (McLaughlin et al. 1994) found that CB-R mRNA (messenger ribonucleic acid) is present at adult levels as early as postnatal day 3, while CB binding increased almost 50% with increasing age. The last study may explain some of the contradictions between the different studies since CB-R density may be high in infants and children while CB-R activity may be low. With regards to studies on humans, Biegon & Kerman (2001) investigated the pre- and postnatal distribution of human brain CB-R type 1 using quantitative autoradiography with [(3)H]CP55,940 as a ligand. Normal fetal brains (N = 8, gestational age 14-24 weeks) were obtained from voluntary abortions and were compared with normal adult human brains (N = 16, age 18-78). In the fetal human brain, low densities of THC-displaceable, region-specific binding could be observed as early as 14 weeks gestation. Receptor density increased slowly with gestational age but did not reach adult levels by the end of the second trimester (24 weeks gestation). In addition, the distribution pattern in the fetal brains was markedly different from the adult pattern. The most striking difference was the very low density of binding in the fetal caudate and putamen. In contrast, the globus pallidus pars medialis has almost-adult levels of CB-R by 17-18 weeks gestation. The authors concluded, "The relatively low and regionally selective appearance of cannabinoid receptors in the fetal human brain may explain the relatively mild and selective nature of postnatal neurobehavioral deficits observed in infants exposed to cannabinoids in utero." Furthermore, other clinical studies have shown that children tolerate much higher doses of THC than adults before side effects become significant (Abrahamov et al. 1995, Dalzell et al. 1986). In one study, eight children, aged 3 to 10, who underwent chemotherapy, orally received 18 mg delta-8-THC per square meter of body surface, four times daily. Each child received an average of 60 doses, which caused only mild psychotropic side effects in two children and none in the other six. Thus, children with a body surface of 1.0 m 2 received 18 mg THC four times daily. Assuming a body surface of 1.8 m2 for an adult, this corresponds to single doses of 30 mg and a daily dose of about 120 mg THC. Delta-8-THC is assumed to be somewhat less psychotropic than delta-9-THC, with a relative potency of approximately 65% (Hollister & Gillespie 1973). Thus, a single 30 mg delta-8-THC dose corresponds to about 23 mg of delta-9-THC, a dose at which adults usually experience considerable psychotropic effects. Authors suggest that the lower CB-R type 1 density in children compared to adults may be responsible for the lower susceptibility of children to THC. According to case reports of the Centre for Palliative Medicine and Paediatric Pain Therapy of the University of the Saarland (Germany), THC is an effective and well-tolerated medication in the treatment of different severe illnesses in children (Gottschling 2011). All children received a slowly increased dose starting with 0.1 mg/kg bw, which efficiently avoided adverse effects. Mean THC dose was about 0.2 mg/kg bw in children suffering from spasticity and pain after finishing dose finding.

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As a rule, with regards to pregnancy, foetuses tend to be particularly susceptible to toxins. In both humans and animals, transfer of THC to the vascular system of the foetus occurs across the placenta. The time course of the THC-concentration in fetal blood is strongly correlated to that in maternal blood, though fetal plasma concentrations were found to be lower compared to the maternal level in rats (Hutchings et al. 1989), in sheep (Abrams et al. 1985–1986), in dogs (Martin et al. 1977), and in monkeys (Bailey et al. 1987). Following oral intake of THC by the mother, the ratio between fetal and maternal THC levels in plasma appear to be much lower—about one to ten—compared to intravenous and pulmonal THC administration, where fetal THC levels are about one third of the mother’s. This is likely due to the difference in metabolic pathways between oral, pulmonal (smoking), and intravenous administration. In a study on dogs, the brain of the fetus showed a THC concentration of one third of the mother’s concentration half an hour after intravenous administration (Martin et al. 1977). This relation was also maintained with multiple administrations, indicating that the maternal plasma THC and not the fetal tissue is the actual source for the fetal plasma THC. A study on THC transfer following oral administration that was carried out with rats (Hutchings et al. 1989), saw two multiple-dose groups were administered either 15 or 50 mg/kg THC once daily during the last two weeks of gestation. Although among the dams, plasma concentrations co-varied with dose, and multiple dosing produced higher concentrations than acute dosing, especially at the high dose, among the fetuses, both in the acute and the chronic dosing group, plasma concentrations were approximately 10% of those found in the dams. However, an important difference between intravenous, pulmonal and oral intake must be restated as much lower maximal peak concentrations of THC are found following the oral route (Figure 1). Inhalation of a single dose of 10–20 mg THC will result in THC peak plasma concentration in the order of about 50–100 ng/ml, whereas the same oral dose will result in a broader, less pronounced peak with maximum concentrations of typically 5 ng/ml (Grotenhermen 2003). This will also result in a lower broader THC peak in the fetal plasma. Since higher peak concentrations result in stronger effects for the same route of administration, it can be assumed that the fetus is less affected following oral ingestion, since oral and pulmonal routes of administration of the mother result in the same application route for the fetus, i.e. the blood vessels of the umbilical cord. This indicates that the absence of cognitive effects in the children of mothers who used oral cannabis in a Jamaican study (Dreher et al. 1994) may be due in part to the inefficient transfer, thus low fetal toxicity, of THC ingested by pregnant women. Pregnant women in Jamaica tend to use cannabis orally, while women in the USA and Canada, whose off-spring showed some cognitive impairment (see above) usually smoke the drug (Goldschmidt et al. 2012, Porath et al. 2005). Therefore, although it is known from clinical studies that children tolerate higher doses of THC with regard to body weight compared to adults, a possible higher susceptibility of foetuses and neonates allows to conclude that an uncertainty factor of 5 should offer a sufficient margin of safety.

42

6.2

Genetic variation in the genes encoding CB receptors and metabolizing enzymes

There is considerable inter-individual variation in the THC doses that result in pharmacological effects. This may be due to variations in polymorphisms of the specific genes (CNR1 and CNR2) that encode the most well-defined CB-R, i.e. CBR type 1 and 2, and polymorphisms in the enzymes that are mainly responsible for the metabolism of THC in the liver (mainly CYP2C9). Sachse-Seeboth et al. (2009) investigated the impact of the CYP2C9 polymorphism on the pharmacokinetics of orally administered THC in 43 healthy volunteers. THC pharmacokinetics did not differ by CYP2C9*2 allele status. However, the median area under the curve of THC was three-fold higher and that of the metabolite 11-nor-9-carboxy-THC was 70% lower in CYP2C9*3/*3 homozygotes than in CYP2C9*1/*1 homozygotes. CYP2C9*3 carriers also showed a trend toward increased sedation following administration of THC. They concluded that "the CYP2C9*3 variant may influence both the therapeutic and adverse effects of THC." Four of the 43 volunteers were carriers of the CYP2C9*3/*3 variant with a median maximum THC concentration in plasma of 6.3 ng/ml compared to a median of 2.7 ng/ml in carriers of CYP2C9*1/*1. It is reasonable to believe that several patients in the large clinical studies conducted with THC in recent years were carriers of the CYP2C9*3/*3 and this fact might have been the reason that in some studies even doses of 2.5-5 mg twice daily may have caused psychotropic effects since these carriers may have presented with comparably higher THC concentrations in blood at these low doses compared to other patients. Since an uncertainty of any origin is already largely taken into consideration by choosing a low LOEL, this paper suggests an uncertainty factor of 2 for the small part of the population (6-10%) that potentially suffer from this genetic polymorphism.

6.3

Pharmacological basis for deriving an Acceptable Daily Intake

A large number of studies have been conducted that address neuroendocine effects of THC. The following sub-chapter will prove human studies on the effects of THC in order for an Acceptable Daily Intake to be derived. This will prove that it is no longer necessary to mainly rely on studies with animals. For more than 20 years an epidemiological study is conducted at the University of Pittsburgh, USA, with more than 700 children of mothers who used cannabis and other drugs during pregnancy. These children are examined regularly since their birth and results have been published since then in more than 20 papers (e.g. Scher et al. 1988, Gray et al. 2005, Day et al. 2006, Willford et al. 2010, Day et al. 2011). For more than 30 years a somewhat smaller epidemiological study with about 300 children is conducted at Carleton University in Ottawa, Canada,

43

which resulted in an even larger literature on THC effects on foetuses in humans (e.g. Fried 1980, Fried 1995, Smith et al. 2004, Fried et al. 2005). Both longitudinal studies allow a good understanding of the consequences of THC exposure by the inhalation of cannabis to the foetus and the consequences to later life. It is no longer necessary to rely on studies with rats, like Wenger et al. 1988. In addition, the relevance of animal studies, which found increased risk of stillbirth and other adverse effects on the fetus following peritoneal injection of THC, to humans, is in principal highly questionable. No such effects have been found with humans after oral or pulmonal administration of much higher doses. The same applies to the reported impact of low THC doses on hormone levels in pregnant rats. There are several indications that the effects observed by Wenger and his colleagues should not be extrapolated to humans. E.g., in one of their studies (1989), i.p. injection of 0.001 mg/kg THC during the 3rd week of pregnancy in rats caused a significant prolongation of pregnancy and 42% of stillbirths. This contrasts strongly to studies in humans. There are many studies of pregnancy outcome in users of cannabis. None of them reported any increase of stillbirths relative to controls who did not consume cannabis or a prolongation of pregnancy. (see Table 9) Wenger and his colleagues also reported significant alterations following very low doses of i.p. administered THC, including a reduced Luteinizing Hormone (LH) concentration after i.p. injection of 0.001 mg/kg THC over the 1st, 2nd or 3rd week of pregnancy in rats (Wenger et al. 1988). In contrast, Tyrey (1980) administered i.v. THC in doses of 0.0312 to 0.5 mg/kg to female ovariectomized rats and found no effects on LH secretion at the lowest dose of 0.0312 mg/kg and significant effects at 0.0625 mg/kg and higher. It is unclear why an i.v. dose of 0.0312 mg/kg (corresponding to about 0.3 mg/kg oral THC with regard to bioavailabilty) should cause no effects while a 0.001 mg/kg THC dose should cause effects. Considering this contradiction in findings, EIHA suggests to challenge the findings by Wenger and his colleagues until confirmed independently. It should be noted that the studies by Wenger et al. have been conducted more than 20 years ago and no other research group reproduced their findings since then. Steger et al. (1990) found a significant decrease of LH and testosterone plasma levels following doses of 0.1, 1.0 and 10 mg/kg THC in male rats. There was no dose-response relationship; all doses were equally effective. However much higher THC doses than 0.1 mg/kg had no effect on testosterone levels in humans. E.g., Dax et al. (1989) investigated the effects on male chronic cannabis users by administering orally three times per day 10 mg of THC or inhaling three times per day 18 mg of THC for three days, following at least two weeks of abstinence. These conditions simulate routine cannabis drug use. The researchers did not find any alterations in the plasma testosterone concentration. Mendelson et al. (1978) could not detect any influence on the testosterone level in 27 cannabis users that had consumed a mean of 54 cannabis cigarettes or 120 cannabis cigarettes over a period of 21 days. In a National Institute on Drug Abuse (NIDA) Research Monograph, Mendelson et al. (1984) stated with regard to the effect of THC on female hormones:

44

“It is clear from the foregoing that THC consistently produces significant changes in pituitary gonadal hormones, which are essential for normal reproductive function in experimental animal models. The major unanswered question is: what is the relevance of these data for human females? There are often marked species differences even within animal models and the degree to which THC induced disruption of pituitary gonadal hormones in animals can be extrapolated to humans is an empirical question. Despite the predictive values (and relative economy) of studying drug effects in animals, the ultimate significance of these findings can only be determined in human studies” (page 105).

45

Table 9 Selected discrepancies between animal and human data on THC.

Target effect

Animal study

Human study

Male plasma– 0.1 mg/kg oral THC resulted in– 0.15 mg/kg oral THC three times daily testosterone decrease in male rats (Steger et did not cause an effect (Dax et al. 1989). hormone al. 1991). – 0.25 mg/kg inhaled THC three times concentration daily did not cause an effect (Dax et al. 1989). Male prolactin– Increase following 0.04 mg/kg– level in plasma THC intraperitoneally in rats (Daley et al. 1974). – – Decrease after 0.5 mg/kg oral THC in rats (Rodriguez De Fonseca et al. 1992).

No change following about 0.6 mg/kg inhaled THC (Cone et al. 1986).

Female – 0.0625 mg/kg intravenous THC– luteinizing caused a profound decrease in hormone (LH) rats (Tyrey 1980). concentration –

No change in LH level following about 0.3 mg/kg inhaled THC (Mendelson et al. 1985a).

Stillbirths

Duration pregnancy

Chronic cannabis users do not show any significant alteration in their prolactin levels (Vescovi et al. 1992, Cohen 1976).

However, a light significant decrement (p  0.02) was observed when the cannabis was consumed during the luteal phase. Chronic users present a normal LH-level (Block et al. 1991, Dornbush et al. 1978, Kolodny et al. 1979).

– 0.001 mg/kg intraperitoneally– No increased rate of stillbirths in any THC resulted in 42% stillbirths human study of female cannabis users. (Wenger et al. 1989). of– 0.001 mg/kg intraperitoneally– THC resulted in an increase of duration of pregnancy (Wenger et al. 1989).

Most human studies did not find any effect of cannabis use on duration of pregnancy (e.g., Shiono et al. 1995, Day et al. 1991, Zuckerman et al. 1989. Hatch and Bracken 1986).

– Some found a decreased length of gestation or a higher rate of premature births (Sherwood et al. 1999, Fried et al. 1984, Gibson et al. 1983). Birth weight

– 0.001 mg/kg intraperitoneally– Chronic cannabis use (about 0.1 to 2.0 THC reduced birth weight in rats mg/kg inhaled THC) did not cause (Wenger et al. 1991) reduced birth weight (Shiono et al. 1995, Dreher et al. 1994, several other studies).

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6.4

Conclusion

Biological differences among humans allow for a better understanding of the regulatory guidance values of THC. Although some studies have found that human foetuses and children have the same amount of CB-R than adults (Glass et al. 1997), the majority of the literature indicates that human foetuses and children have a smaller amount of CB-R in the brain, leading to a higher THC tolerance (Belue et al. 1995; Biegon & Kerman 2001; Abrahamov et al. 1995; Dalzell et al. 1986; Gottschling 2011). Foetuses experience significant exposure to THC following maternal cannabis ingestion. However, due to different pharmacokinetics of oral and pulmonal THC, fetal exposure after oral THC intake by the mother, e.g., with hemp foods, will be lower compared to inhalative THC intake by the mother, e.g., by smoking cannabis cigarettes. Assuming a systemic bioavailability of oral THC of about one third of that of inhaled THC (6-7% vs. 20%) and a fetus/mother plasma level ratio of 1:10, compared to 1:3 for inhaled THC, fetal exposure to THC ingested by the mother is about 11% of the exposure caused by the inhalation of the same dose (see Table 10). In addition, oral ingestion by the mother results in a much lower maximum peak concentration compared to inhalation of the same dose, further reducing possible impacts from THC. These differences in the transfer to the foetus between oral and inhalative uptake of THC thus provide an additional margin of safety from potential teratogenic effects.

Table 10 Comparison of dose-specific fetal toxicity caused by maternal ingestion vs. inhalation of THC.

Inhalation (smoking cannabis cigarette) Systemic bioavailability

20 %

a Oral intake (hemp) 6-7 %*)

Ratio of ingested THC to 1/5 THC systemically available

1/15

Ratio of THC 1/3 concentration in fetal and maternal plasma

1/10

Overall ratio

1/150

1/15

*) An extensive first pass liver metabolism reduces oral bioavailability of THC, i.e. much of the THC is initially metabolized in the liver before it reaches the sites of action. Ingestion of 20mg THC in a chocolate cookie (Ohlsson et al. 1980) and administration of 10mg dronabinol (synthetic THC) (Sporkert et al. 2001) resulted in a systemic bioavailability of 6  3% (range: 4-12%) or 7  3% (range: 2-14%) with a high interindividual variation.

Furthermore, it is reasonable to believe that several patients in the large clinical studies conducted with THC in recent years were carriers of the CYP2C9*3/*3

47

and this fact might have been the reason that in some studies even doses of 2.5-5 mg twice daily may have caused psychotropic effects since these carriers may have presented with comparably higher THC concentrations in blood at these low doses compared to other patients. Finally, toxicological data from animal studies can help to elucidate adverse effects of cannabinoids in humans. However, comparison of the data from studies on humans and animals has often revealed considerable inconsistencies. These may result from not only interspecies differences, but also different routes of administration. Particularly, the suitability of the intraperitoneal route for extrapolation to oral and inhalative exposure has previously been questioned (Abel 1985). The findings by Wenger and his colleagues, which contradict findings from human studies applying much higher doses and using the more representative oral or inhalative routes, are a case in point. Thus, wherever possible, a quantitative risk assessment should be based on data from human studies. EIHA suggests to neglect the results of Wenger and colleagues and to rely on the extensive and available human data for THC. Based on the previously stated scientific arguments, this paper suggests an uncertainty factor of 20 to be applied. This value was deduced from three different factors that may affect the way THC works in the human body. Firstly, large clinical studies have shown that there is considerable interindividual variation in susceptibility to THC and that some adults may experience slight psychotropic or psychomotor effects at twice a dose of 2.5 mg (or 0.07 mg/kg bw), while most individuals show only effects at considerably higher doses. This variation may be based on genetic polymorphisms of the genes encoding the cannabinoid receptors and the enzymes responsible for the metabolism of THC. We suggest an uncertainty factor of 2 since an uncertainty of any origin is already largely taken into consideration by choosing a low LOEL. Secondly, since THC may easily cross the placenta to the foetus and the foetus may be more susceptible than children and adults we suggest an uncertainty factor of 5 for a possible higher susceptibility of foetuses and neonates with still not fully developed drug metabolizing enzymes. It is known from clinical studies that children tolerate higher doses of THC with regard to body weight compared to adults. In addition, adverse effects from cannabis on the foetus, which have been observed in epidemiological studies are relatively low compared to other drugs. Therefore, an uncertainty factor of 5 should assure a sufficient margin of safety. And finally, although there is no hint for a measurable potentiation of THC effects

with an oral dose of 2.5 mg twice daily by alcohol or other drugs, an uncertainty factor of 2 should assure a sufficient margin of safety may this, in certain extreme cases, take place. Based on the above, an acceptable daily intake (ADI) for orally ingested THC of 0.0035 mg/kg bw was assumed to provide protection from both acute and chronic adverse effects in humans. Based on the literature reviewed and the concluded values, the next chapter will put forward guidelines for the THC concentration in food.

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7

EIHA proposal on THC guidelines for different hemp food products

“The THC level in plants should not be a critical consideration when the level in seed oil and seed oil products is in fact the critical issue for regulatory concern.” (Small 2014) Following the literature review of the previous chapters (5 and 6), two aspects have to be considered relating to oral intake in food: -THC must be consumed in its free, non-carboxylated form in order to be biologically active. However, in fresh unprocessed hemp plants, THC occurs in the form of its inactive carboxylic acid, i.e. THC acid A (THCA-A). It is decarboxylated, i.e. converted into its active form, primarily by heat during baking and other forms of food processing, and when smoked. Thus, largely unprocessed foods, such as cold-pressed oils, may often contain large fractions of pharmacologically inactive THCA-A. THCA does naturally decay to THC with a half-life of 35 and 91 days, whereas THC degrades to CBN only at a half-life rate of 24 to 26 months, effectively resulting in THC accumulating even if THCAcontaining material is not heated (Trofin et al. 2012). THC guidelines tend to account for this process by measuring the total THC in a product. -The degree of absorption of THC by the human intestines also depends on the physical and chemical properties of the carrier. Generally, lipophilic carriers, such as oil, increase absorption. If THC is present in less fatty matrices, such as breads, pastries or drinks (hydrophilic environments) the bioavailability of THC is typically reduced by 50%. (Grotenhermen 2014) As described in chapter 3, countries like Italy expect a zero tolerance of THC in food goods. The value has been established as a reference from the US drug policy and not from health research practices. Not even toxic food contaminants or pollutant (see Table 11), such as pesticides or heavy metals, are held to such limiting restrictions, and popular foods containing trace amounts of other natural drugs, such as morphine (in poppy seeds), are not a matter of official concern. This is deemed by many critics as prohibitive to the industry, as a whole, particularly with the growing scientific evidence of the low or absent pharmacological effects in humans of low doses of THC.

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Table 11 Maximum Tolerated Daily Intake of THC proposed by EFSA vs other substances. Source Nahler 2015

Therefore, there is demand for more scientifically accurate THC guidance values in food and beverages that can take into account both the consumer’s and the producer’s concerns, providing the former with more choices and the latter with room to develop the industry. This chapter will put forward new guidelines to food and beverages that contain THC. The methodology behind the German guidelines, already generally accepted and considered the most sound, complete and consistent in the subject matter, will be structural to the Europe-wide guidelines proposed by this paper (for the German guidance values, refer to section 2.1.2.). Applying the same methodology used by BgVV, the first step is to set a Lowest Observed Effect Level (LOEL) innocuous to health. A safety factor is then applied, yielding an Acceptable Daily Intake (ADI) of THC. The factor is a way to protect several subpopulations that are more vulnerable to the particular substance. Following the German annual average consumption patterns, a daily average per product category is reached. The selected food category data will correspond to 50

hemp products already existing on the market. THC guidance values are then put forward for each food category that, multiplied by the average daily intake, generate the uptake in mg of THC per person per day per category. Finally, the sum of all categories’ uptakes ought not surpass the initial ADI of THC.

Acceptable Daily Intake (ADI) of THC An ADI is will be the maximum allowed ingestion of THC by an individual in a day. This limit is usually expressed in mg of THC per kg of body weight. First the placebo limit for acute psychotropic and physical effects from THC ingestion had to be determined from the literature. In the case of THC, the most relevant effects are those on mood and cognition (euphoria, fear, reduced cognitive functions) as well as on the cardiac circulation system (increase in cardiac frequency, changes in blood pressure). Usually, single doses of 5-15 mg THC cause mild psychotropic effects (Lucas & Laszlo 1980; Brenneisen et al. 1996; Chesher et al. 1990; Brenneisen et al. 1996; Petro & Ellenberger 1981). As mentioned in Chapter 6, an acute dose of 2.5 mg THC (corresponding to 0.035 mg/kg bw assuming a body weight of 70 kg) may usually be regarded as a placebo dose, particularly as effects tend to be watered down with time, as the body builds up a tolerance to THC (Zajicek et al. 2003 and Zajicek et al. 2005). The effects of a single dose of THC typically last anywhere between 4-6 hours, with some remaining up to 8 hours after consumption, in extreme cases (Lachenmeier and Walch 2005; Figure 2). Since usually nobody ingests all its food at once, the uptake of an oral dose of 2.5 mg of THC twice per day, equivalent to 5 mg taken over the course of a 24-hour period (or 16 awaken hours), represents an appropriate and realistic minimum daily effect dose per person.

51

Subjective high 10 9

intravenous (5 mg)

8

smoked (19 mg) oral (20 mg)

7 6 5 4 3 2 1 0 0

1

2

3

4

5

6

Time after administration (hours) Figure 2 Time course of subjective effects following three modes of administration. A rating of the degree of "high" was made by subjects on a 0 to 10 scale (estimated from figures of Hollister et al. (1981) and Ohlsson et al. (1980)). Taken from Grotenhermen (2003).

This paper states that an uncertainty factor of 20 should be applied. This value was deduced from three different factors that may affect the way THC is metabolized in the human body. As stated in chapter 6, the value of 20 results from a combination of inter-individual variations (2), higher vulnerability of foetuses and neonates (5), and potential interference with other substances (2). Therefore, a dose of 2.5 mg per kg twice daily divided by the safety factor of 20, results in an ADI of 0.125 mg per kg, twice daily. In order to follow the same safety rounds as those applied by BgVV, the value of 0.125 mg per kg twice daily will be dropped to 0.120 mg per kg twice daily. The following table summarizes the previous calculations: Table 12 EIHA THC-guidance values for hemp-based foodstuffs EIHA THC-guidance values for hemp-based foodstuffs Male weighing 60 kg, 25-50 years old Lowest Observed Effect Level

2 x 2,5

mg THC/day/person

divided by security factor of 20: Acceptable Daily Intake of THC

2 x 0,125

mg THC/day * person

rounded to:

2 x 0,120

mg THC/day/person

52

Updated consumption patterns

The next step of the process is to calculate the guidance values for each individual food group. Using the annual consumption data for selected food goods for the years 2011 and 2012, an average daily consumption was calculated (columns 4 and 5, Table 13). The specific food goods selected were picked for their availability on the market. Only food goods that could partially or fully be made out of hemp were used for this calculation in an attempt to replace as many food goods as possible for hemp containing products (see column 3 on Table 13 for a detailed list of products). In this assumption, hemp products will directly replace the German average consumption, and its ingestion should pass the previously stated 0,120 mg of THC per person twice daily. All food goods were grouped in four major categories: Oils, High Volume foods, Low Volume foods, Beverages (Column 1, Table 13). As it was the case with the German calculations, hemp oil could not replace all oil consumption. Although hemp oil is rich in several essential proteins and amino acids, its consumption can only replace the use of raw fats (such as spreadable fats or oils for salad). This sees the general consumption of oil change from the German average of 30.4 g/person/day to 7. The difference includes, among others, cooking oils. The Second and third categories of food goods were created to distinguish the volume of food one tends to eat. Accordingly, ‘High volume’ goods is understood as all foodstuffs that comprise the major part of a dish or meal, such as cereal, bread, baked goods, pasta and pastries; ‘Low Volume’ goods are all other food goods that do not comprise the major part of a dish or meal, i.e. proteins (meats, sausages, etc) and food goods usually consumed in low amounts, such as chocolate bars or food supplements. While ‘High Volume’ foods yielded a total daily consumption in grams of 299, ‘Low Volume’ foods’ aggregate was of 286. The last category is Beverages. Once more, all drinks that could be made with hemp as an ingredient were chosen and their consumption included in the list. For more details please see Table 13 below. Beverages totaled 1232 ml of daily consumption.

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Table 13 Consumption data for the years 2011, 2012 for selected products. Source: BMELV 2012 General food groups Category

Oils

(German Federal Statistical Office) ·

Olive and salad oils

·

Oils and spreading fats

·

Other food oils

·

Flour

·

Bread

·

Breakfast Cereals

Pasta

·

Pasta

Nuts

·

Seeds and nuts

·

Sausage

·

Meat

·

Chocolate bars and Chocolates

·

Protein shakes

·

Waffles, biscuits

·

Salty baked goods

·

Chocolate cream

·

Honey cake, gingerbread

Edible oil

Cereal products High Volume Foods

Meats

Low Volume Foods

Sweets and Food Supplements

Baked Goods

Alcoholic

Beverages

Specific food goods

Non-Alcoholic, non-heated drinks Non-Alcoholic, heated drinks

·

Beer

·

Wine

·

Sparkling Wine

·

Spirits

·

Soft Drinks

·

Fruit Juices

·

Milk

·

Black tea

·

Infusions

Annual Consumption

Daily consumption

(kg/year/capita)

(g/day/capita)

(l/year/capita)

(ml/day/capita)

Total daily consumption per category (g) (ml)

11.1 (2012)

30.4

7*

96,5 (2012)

265

8 (2011)

22

4,38 (2012)

12

87 (2012)

238

9,8 (2011)

27

299

286 7.6 (2011)

21

135.5 (2012)

370

238 (2012)

652

77 (2012)

210

1232

* Value rounded due to culinary limitations of hemp oil

With an ADI and a rounded daily consumption of certain grouped food goods, we can now proceed with the calculation of the guidance values per category. Each category’s guidance value multiplied by the average daily consumption per person yields the daily THC uptake per person per category. Once more, the sum of all categories of daily THC uptakes per person ought not pass the maximum allowed THC uptake of 0.120 mg of per person twice daily.

New proposed guidance values The limit for each category is a function of the average consumption per category and the sum of all THC uptakes per category that ought not surpass ADI. Considering the twice-daily limit of 0.120 mg of THC per person, this paper created the following THC guidance values. The values were derived from the assumption that usually no one eats all his daily food all at once, allowing for a bigger margin of THC uptake without adverse effects. 54

Even if a hemp enthusiast were to eat all possible range of hemp products available on the market at the usual daily consumption rate, the guidance values prevent the individual from being intoxicated with THC, by a safe margin of 34.26 mg of THC per person per day (Table 14). Allowing both the industry and the consumer more product availability and margin of maneuver, the proposed guidance values are an efficient and safe manner of keeping the industry and the consumer satisfied, while preventing severe market distortions, industry vulnerability to lawsuits and, most importantly, consumer vulnerability to THC. Table 14 EIHA calculations for THC guidance values in foodstuffs

Consumption data:

Oils 'High Volume foods' 'Low Volume' foods

Original BgVV THC guidance values (mg/kg)

Proposed THC guidance values (mg/kg)

5 0,15 0,15

8 0,15 0,3

0,005 0,005 0,005

0,02 0,02 0,005

Average Consumption (g/day/person)

Uptake in mg THC/day/person (guidance value * consumption = uptake)

7 299 286

56,00 44,85 85,80

652 210 370

13,04 4,20 1,85

(ml/day/person) Non-heated Non-alcoholic beverages Heated Non-alcoholic beverages Alcoholic beverages

TOTAL

205,74

Twice daily minus total

34,26

The scientific findings shown above allow to conclude that a LOEL and an uncertainty factor of 20 should result in the establishment of guidelines for the THC concentration in food. The LOEL is based on two doses of 2.5 mg THC that is 5 mg per day (70kg body weight), resulting in an acceptable daily intake (ADI) of 0.0035 mg/kg bw for THC, or 0.240 mg assuming a person with 70 kg of body weight.

The next Chapter will see the analysis of some hemp food goods already in the market, for THC content.

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8

Delta 9-THC and delta 9-THC acid content in food raw materials, consumer goods derived from the hemp plant and feed raw materials.

The tables show the content of THC in hemp products available in Europe, divided into food raw materials, end consumer goods and feed raw materials. The values, expressed in mg/kg, show the levels of THC, THC acid and the total THC content (free THC + THC resulting from decarboxylation of THCA) of each product, along with the range of total THC. The data was calculated from lab tests that took place in October-November 2014, in Germany, on 62 samples provided by Hempro International GmbH & Co. KG. According to the values presented, hulled hemp seeds have a range value of < 0.1 mg/kg (biological) to 1.47 mg/kg (conventional) total THC, and contain the lowest THC values of all products. This is due to the fact that most THC in seeds comes from surface contamination (Lachenmeier and Walch 2005; Ross et al. 2000). Raw materials used for food have a total THC level range that goes from 0.1 mg/kg in biological hulled hemp seeds, to 5 mg/kg in refined and conventional hemp oils (Table 15Error! Reference source not found.). The higher value of total THC in some products is due to the fat-soluble nature of the substance. Thus, products like hemp oils present higher total THC values than other defatted products, such as hemp flour or hemp fibre.

Product Hemp seed Conv Hulled Hemp Seed, Conv Hemp oil Conv Hemp seeds bio Hulled Hemp Seed, Bio Hemp oil bio Hemp seed organic Hemp oil organic Refined Hemp Oil Hemp Fibre Hemp Flour Protein Powder 50%

THC average 1.10 0.21 3.43 1.02 < 0.1 1.56 1.00 0.93 5.26 0.28 0.50 0.66

THCA average 1.87 0.75 2.88 0.34 0.15 1.38 1.66 1.94 < 0.1 0.91 0.96 2.24

mg/kg Total THC average 2.71 0.85 5.12 0.72 0.13 3.02 2.48 2.64 5.26 1.08 1.35 2.64

Total THC range 2.17 – 3.25 0.25 – 1.47 4.10 – 6.14 0.58 – 0.86 < 0.1 – 0.16 2.42 – 3.62 1.98 – 2.98 2.11 – 3.17 4.21 – 6.31 0.86 – 1.30 1.08 – 1.62 2.11 – 3.17

Table 15 THC levels in food raw materials (in mg/kg), nova 2014 based on Hempro International 2014

The same analysis found that the total THC content to be expected in end consumer goods is much lower than in food raw materials, ranging from