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Derivation of THC Limits for Food

Part I
1 Abstract
2 Approach
3 Basis for Determination of THC Limits
4 THC Limits for Food
5 Acknowledgments
6 Literature

1 Abstract

THC, pharmacologically the most relevant constituent of the hemp plant (Cannabis sativa L.) is a highly active substance which, as function of dosage, may exert a multitude of effects on various organs and functions of the human body. It is also responsible for the characteristic psychotropic effects of marijuana. During production, small quantities of THC may enter hemp-based foods. Amounts may vary with the planted variety, effectiveness of seed cleaning, and whether the seed hulls have been removed. For reasons of consumer protection, the determination of maximum permissible concentrations is indispensable.

The permissible concentration of THC in food depends on two factors: the quantity of THC that can be ingested safely with daily food, and the quantity of food that is consumed daily. Both factors were thoroughly evaluated by nova Institute in the establishment of THC limits.

Available scientific evidence suggests that a single dose of 5 mg THC and a daily dose of 10 mg THC do not cause acute perceptible effects or chronic detrimental effects on health. Using a safety factor of 10, this leads to a pharmacologically innocuous daily THC intake of 1 mg for a healthy adult, corresponding to 0.014 mg of THC per kilogram of body weight

Since consumption patterns vary for different categories of foods, foods which may contain hemp were grouped into four different categories, each with their respective THC limit. The procedure chosen is similar to the one used by Swiss authorities in setting their standards. The limits recommended by nova take into account these different consumption patterns while adding additional safety factors. Taking into account extreme consumption habits, the nova recommendations are more severe than the Swiss limiting values for the categories "hemp oil" and "finished products, breads and pastries, and pasta," while being less severe for beverages.

Based on our evaluation, nova Institute recommends the following limits for THC in hemp foods:

Hemp oil 20 mg THC/kg

Finished products, breads and pastries, pasta 1.5 mg THC/kg

Alcoholic drinks 0.7 mg THC/kg

Non-alcoholic drinks 0.3 mg THC/kg

These limits provide a sufficient margin of safety for the consumer and are achievable by industry if proper seed cleaning and production practices are used.

2 Approach

First, our derivation of THC limits for hemp food required the establishment of maximum single doses, as well as maximum daily doses of THC innocuous to health. A safety margin, commonly used in toxicology, was then applied in order to guarantee sufficient protection against undesired effects on sensitive people.

To this end, 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 (euphoria, fear) as well as on the cardiac circulation system (increase in cardiac frequency, changes in blood pressure).

Due to its long half life, THC may accumulate in the human body (see Chapters 2.3 and 3.5 in Part II). Thus, some researchers have expressed concern that chronic health effects may arise at THC concentrations in food below the limit for psychotropic effects. Above all, the effects on the hormonal system and fertility, on the immune system, as well as on pregnancy have been mentioned. For that reason, a detailed account of this query is provided (see also Chapter 5 in Part II).

Once the safely permissible THC doses by ingestion were determined, the corresponding maximum permissible THC concentrations in food had to be derived using consumption patterns for relevant hemp foods. While typical consumption habits served as a baseline, the consumption of quantities higher than average had to be considered as well. Since hemp-based foods may be consumed in widely varying quantities, several categories and their respective limits were established.

3 Basis for Determination of THC Limits

3.1 Methodology

Concepts such as the "lowest observed adverse effect level" (LOAEL) and the "no observed adverse effect level" (NOAEL) are commonly applied when developing standards intended to prevent negative health effects from chemicals which are known, or suspected, to cause such effects (for details, see Chapter 2.3, Part II). In order to provide a wide margin of protection, safety factors of about 10 are usually applied.

The majority of toxicological data for THC results from animal studies in which high doses were applied, as well as from cellular studies (see Table 1). For many of the potential health effects of THC, the NOAEL was found to vary at such high concentrations. Occurrence of other adverse effects at lower dose ranges is also discussed. They may be representative of the situation of a chronic Cannabis consumer (50 to 400 mg of THC per day). Even these doses exceed the threshold under question, i.e. that for psychotropic effects, by an order of magnitude. Thus, the available data provide a sound basis for the exclusion of most of these effects with a high margin of safety.

Table 1: Ranges of THC doses and resulting concentrations in blood plasma (for references refer to table 7 in Part II)

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. Only at high concentrations, which are not encountered in the case of hemp food, are non-specific effects, such as direct effects on the cell membrane, also observed. THC's mode of action provides an additional margin of safety for two reasons (see also Chapter 2.3 in Part II):

1. As a rule, for most harmful chemicals, the toxicity increases and 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, the opposite applies, since the effect decreases with increasing exposure. This is due to the development of tolerance to THC by the receptors.

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.

3.2 Biological Basis

THC is a pharmacologically highly active substance which shows, as a function of dose, effects on a multitude of organic systems and bodily functions (see also Chapter 3.6 in Part II). The physical toxicity is low. Aside from health-impairing effects from high doses, beneficial effects at low doses were observed as well, e.g. immune-stimulating and neuroprotective effects. Tests to establish a lethal THC dose for monkeys have been unsuccessful to date. The maximum administered dose of 9000 mg/kg body weight did not result in the death of the monkeys. This corresponds to a dose of 15 kilograms of marijuana for a person weighing 70 kg, with an equivalent weight extrapolation.

3.2.1 Acute perceptible and psychotropic effects

Acute psychotropic effects from the consumption of products from hemp of the drug type, such as marijuana and hashish, are changes in mood ("high") typical for marijuana, and changes in the sensory perception, the feeling for time, etc. Acute physical effects are, for example, acceleration of heartbeat and dry mouth.

The limit for psychotropic effects is about 0.2 to 0.3 mg THC-single dose per kilogram of body weight when administered orally in a lipophilic (oily) base. Depending on body weight, this corresponds to a dose of 10 to 20 mg of THC for an adult person.

A single oral dose of 5 mg THC in a lipophilic base is rated as placebo dose with respect to acute perceptible psychotropic and physical effects: i.e. it cannot be distinguished from a placebo. Since THC is effective in therapeutic doses for 4 to 12 hours, 5 mg may be taken twice a day resulting in a NOAEL for acute perceptible effects of 10 mg THC per day (see also Chapter 4 in Part II).

3.2.2 Non-perceptible and chronic physical effects

In connection with a chronic consumption of Cannabis for intoxication purposes, the perils of a possible impairment of the lungs caused by inhalation of marijuana or hashish smoke, and the possible chronic effects on the psyche have been studied. These effects are of no importance when THC is taken orally in sub-psychotropic doses, such as with food. Therefore, the toxicological statement of the problem in this study differs in its focus from existing studies of Cannabis consumption for intoxication purposes.

While the maximum daily quantity of THC ingested in food must safely be below the psychotropic threshold, the question of whether non-perceptible and chronic physical health impairment may occur below the psychotropic threshold must also be addressed.

By virtue of the effects observed in studies relating to animal tests, four areas are of potential interest. They include effects on the genetic material, on pregnancy, on the hormonal system and fertility, as well as on the immune system. The available literature suggests the following evidence with respect to these effects.

Genetic material: If taken in doses typical for consumers of marijuana, THC is not mutagenic, not carcinogenic, and has no effect on cell metabolism. The NOAEL is above the concentrations relevant to the human consumption (see also Chapter 5.1 in Part II).

Pregnancy: There are only weak references to an influence on pregnancy caused by the consumption of marijuana. Animal studies show only inconsistent effects, even after the administration of doses of 10-20 mg THC per kilogram of body weight and more, i.e. 100 times higher than those causing psychotropic effects. There are indications of a slight impairment of the cerebral development of children of chronic Cannabis consumers, though this could not be confirmed by other authors. The NOAEL for various parameters related to pregnancy, e.g. parturition, duration of pregnancy, infantile abnormalities, weight at birth, and cerebral development, is in most cases above-and only for some parameters possibly within-the range of consumption of chronic marijuana consumers. It is above the psychotropic threshold (see also Chapter 5.2 in Part II).

Hormonal system and fertility: There are no consistent findings on the influence on male and female sex hormones, or on fertility caused by the THC intake of regular consumers of Cannabis. The strongest indications of such effects relate to hormonal malfunctions during puberty and to a temporary influence on the concentration of prolactin and luteinizing hormone (LH) in women during a particular phase of the menstrual cycle. However, these were only isolated observations. The NOAEL for influences on sex hormones, other hormonal effects, or other effects relevant to reproduction are usually above, or for some effects within the range of consumption of marijuana consumers. Again, they are above the threshold for psychotropic effects (see also Chapter 5.3 in Part II).

Immune system: Animal and cellular studies indicate that THC produces suppressive effects on the cellular and humoral immunity. However, they can be attributed mainly to toxic non-specified effects and require extremely high doses. In fact, at low doses, various effects stimulating the immune system or no effects at all were found. The NOAEL for many relevant parameters relating to the immune system is clearly above the human consumption situation of Cannabis consumers. For some effects, conflicting observations could be made in the examination of humans and of cells of marijuana consumers. When such effects were described, they were, even in the case of heavy Cannabis consumption, very weak and with a doubtful relevance to health. The NOAEL is above the psychotropic threshold (see also Chapter 5.4 in Part II).

3.2.3 Factors reducing the biological efficacy of THC

Since they may strongly affect the biological efficacy of THC, two aspects have to be considered in connection with oral intake in food:

_ THC must be consumed in its phenolic form in order to be biologically efficacious. However, in unprocessed hemp plants, THC occurs in the form of the largely ineffective single-carbon acid (THC-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 non-efficacious THC-carbon acids (see also Chapter 3.3 in Part II).

_ 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, promote absorption. In Chapters 4.2.1 and 4.2.2 the most unfavorable case, i.e. full absorption of THC, was assumed for the determination of the maximum daily dose of 10 mg. This assumes that THC was taken in a lipophilic base, for example in oil. If present in less fatty matrices, such as breads, pastries or drinks (hydrophilic environments) the bioavailability of THC is typically reduced by 50% (see also Chapter 3.1 in Part II).

3.2.4 Summary and conclusion on biological effects

The experimental findings summarized above suggest a safe maximum THC single dose of 5 mg for a healthy person of 70 kg, corresponding to 70 micrograms per kilogram BW (body weight). The safe maximum THC daily dose is 10 mg, or 140 micrograms per kilogram BW. These doses do not result in any acute perceptible psychotropic or physical effects, nor in any chronic adverse effects. These doses are based on an assumption that THC is present in its active, phenolic form and is taken in a lipophilic base. If these conditions are not met, the tolerable dose is higher due to the lower absorption by the intestines.

The application of a safety factor of 10 results in a tolerable daily dose of 14 micrograms THC/kg body weight or 1 milligram THC for a person of 70 kg.

As already mentioned, the assumed safety factor of 10 represents a conservative choice for two reasons. First, since THC receptor sites may develop tolerance despite the accumulation of THC, a continuous supply of THC does not lead to an increase in possible health-impairing effects and to no decrease of the NOAEL common with other harmful chemicals. Secondly, children, generally ranked among the particularly sensible individuals, have a substantially lower density of cannabinoid receptors than adults, thus reducing the specific toxicity for psychic and physical effects conveyed by the receptors.

4 THC Limits for Food

The establishment of a concentration-based THC limit in food requires that two questions be answered:

_ How much THC can ingested safely with the diet? This question was dealt with in
Chapter 3.

_ At what rates may hemp-based foods be ingested? The issue of typical consumption rates for such foods will be discussed in Chapter 4.1

Based on the obtained answers, limits for different groups of food will be derived in Chapter 4.3. Prior to that, we will present the current status of the international discussion on THC limits in Chapter 4.2.

4.1 Consumption Habits

The following lists average consumption habits by Germans of commercial foods which may contain hemp products. The figures are taken from the database of the German Federal Statistical Office (Krueger 1998, Weber 1998).

_ Edible oil (including the quantities present in processed foods): 12.1 kg/year and capita (1996), including olive oil at 218.6 g/year and capita (1996)

_ Nuts: 0.9 kg/year and capita (1994)

_ Finished products, breads and pastries, and non-perishable foodstuffs (selection):
Waffles, biscuits: 5.2 kg/year and capita (1994)
Chocolate, bars: 4.6 kg/year and capita (1994)
Salty baked goods: 1.3 kg/year and capita (1994)
Chocolate cream: 1.2 kg/year and capita (1994)
Honey cake, gingerbread: 1.1 kg/year and capita (1994)

_ Breads and rolls: 84 kg/year and capita (1996)

_ Pasta: 4.8 kg/year and capita (1995 and 1996)

_ Nonalcoholic drinks: 225.6 liters/year and capita (1996) including:
Refreshment drinks: 89.0 l/year and capita (1996)
Mineral water: 95.5 l/year and capita (1996)
Fruit juices: 41.1 l/year and capita (1996)

_ Tea: 25.5 l/year and capita (1996)

_ Alcoholic drinks: 169.6 l/year and capita (1996) including:
Beer: 131.7 l/year and capita (1996)
Wine: 18.0 l/year and capita (1996)
Sparkling wine: 4.6 l/year and capita (1996)
Spirits: 6.3 l/year and capita (1996)

For a further examination, the most relevant foods and their respective rounded annual and daily average consumption have been categorized as in Table 2.

Table 2: Foods and their respective rounded annual and daily average consumption

4.2 Existing THC Limits for Food

So far legal THC limits for food have only been adopted in Switzerland after THC-containing food resulted in side-effects for the consumers. They are shown in Table 3.

Table 3: THC limits in Switzerland

Source: Schweizer Bundesamt für Gesundheitswesen (Swiss Federal Office for Public Health) 1996 and 1998

The Swiss THC limits have proven their value in practice. 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.

In 1998, Canada was the second country to pass THC limits. However, the limit does not refer directly to food, but to hempen raw and semi-finished products, such as hemp fibers and seeds. Products containing hemp are exempt from further regulation if they contain less than 10 micrograms THC per gram (= 10 milligrams THC per kilogram). This regulation represents a de-facto limit for the handling of hemp food. Specific THC limits for hemp food are in preparation (source: www.hc-sc.gc.ca/hpb-dgps/therapeut).

In the European Union (EU), there will be no THC limit for food in the foreseeable future. The legal situation is determined by uncertainty and problems of legal authority - an unsatisfactory situation for the European food industry.

The German Ministry of Health, for instance, demands a "joint regulation for THC limits" at the EU level. On the national level, no progress may be expected (Hellweg 1998).

On the other hand, a representative of the permanent committee for food of the EU Commission does not see any relevant activities for an EU-wide regulation, and recommends to the member countries the implementation of national regulations by the respective food safety agencies (Klepsch 1998).

In the U.S., rumors concerning a proposed 0% THC limit continue to be spread. However, official statements do not exist.

4.3 Derivation of THC Limits

Chapters 3.2.4 and 4.1 supply the data basis for the derivation of THC limits for the above-listed food categories. According to Chapter 3.2.4, the maximum tolerable daily dose is 1 mg THC (for a person of 70 kg). This dose includes a safety factor of 10.

Chapter 4.1 furnishes the data for the average consumption of food containing hemp seed.

Limits for each food category can be derived from this data. They are presented in the fourth column of Table 4. In order to account for potentially higher consumption rates, the derived limit is multiplied by an additional safety factor which varies for the different groups of food (see column 3). This additional safety factor also takes into consideration the potential situation of a person ingesting hemp foods with the maximum permissible THC quantity in all listed food groups. In the case of extreme nutritional habits, the safety factor of 10 may be reduced to five. It can still be considered sufficient, due to the low toxicity of THC (see also Chapter 4.2.4). Furthermore, it is still higher than that for some other natural substances in food, as for example quinine, used as an additive in lemonade and in alcohol for the refinement of meat dishes.

The following example serves to illustrate the derivation of the limits recommended by nova. The average consumption of edible oil per day and capita (including the quantities employed by the food industry) is 33 g/day. An additional safety factor of 1.5 yields a maximum anticipated oil consumption of 50 g/day. In order to limit THC intake to 1 mg per day via hemp oil, it may only contain (1 mg THC/day) / (50 g/day) = 0.020 mg THC/g = 20 mg THC/kg.

Table 4: THC limits for food recommended by nova Institute

The comparison of the nova-recommended THC limits for food (column 4) to the Swiss limits suggests the following:

_ Edible oil: The nova-recommended limit of 20 mg THC/kg is below the Swiss value of 50 mg THC/day. The main reason is the difference in assumed daily consumption of oil(nova-study: 33 g/day, Switzerland: 10 g/day). It is due to the fact that the nova value includes edible oils employed by the food industry in processed foods. The additional safety factor of 1.5 for higher-than-normal consumption is lower than for other food categories. This reflects the fact that the food industry rarely employs oils for food processing that are high in polyunsaturated fatty acids, such as hemp oil. High-grade oils with intense taste, such as walnut, olive and hemp oil are mainly used openly, for example as salad oil.

_ Finished products, breads and pastries, non-perishable food, and pasta: The nova-recommended limit of 1.5 mg THC/kg is somewhat lower than the Swiss limits (2-5 mg THC/kg). Nova took into account more extreme consumption habits here as well.

_ Alcoholic drinks: The nova-recommended limit is 0.7 mg THC/l versus the Swiss limit of 0.2 mg THC/l. We consider the value of 0.7 mg THC/l sufficiently low, all the more since the effect of alcohol by far outweighs pharmacologically the effect of THC. In order to exceed the placebo limit for THC (5 mg), more than 7 liters of alcoholic drinks would have to be consumed.

_ Nonalcoholic drinks: The nova-recommended limit of 0.3 mg THC/liter is similar to the Swiss limit of 0.2 mg THC/l. The additional safety factor is higher because particularly large quantities of nonalcoholic drinks may be consumed without other pharmacological effects dominating as in the case of alcohol .

Considering the conservative nature of the assumptions underlying nova's recommended limits, the latter provide the consumer with a high degree of safety and protection from any acute perceptible psychotropic and physical effects, as well as adverse chronic health effects produced by THC. At the same time, experience made by the manufacturers of hemp foods in the last few years has shown that these limits can be achieved through good production practices without posing an undue burden.

5 Acknowledgments

This study was made possible by the kind support from the following individuals and entities. The authors would like to extend their sincerest thanks to them.

_ Australian Hemp Resource And Manufacture, Brisbane, Australia

_ Dave Pate, International Hemp Association, Amsterdam, The Netherlands

_ Davert-Mühle Rainer Welke GmbH, Senden, Germany

_ dupetit Natural Products, Richelbach, Germany

_ Euro-American Marketing & Promotion Service, Amsterdam, The Netherlands

_ Genossenschaft Gärtnerei Enetbrugg, Ossingen, Switzerland

_ HanfDampf Großhandel & Produktentwicklung, Hochdorf, Germany

_ Hempola, Mississauga, Ontario, Canada

_ Jace Callaway, University of Kuopio, Finnland

_ MBR Agrar Service Taunus-Westerwald GmbH, Montabaur, Germany

_ Mörk Naturprodukte, Nürtingen / Neckarshausen, Germany

_ North American Industrial Hemp Council, Madison, Wisconsin, USA

_ R&D Hemp, Toronto, Ontario, Canada

_ Richard Rose, The Hemp Corporation, Santa Rosa, California, USA

_ The Ohio Hempery Inc., Guysville, Ohio, USA

_ Treuhanf AG, Berlin, Germany

6 Literature

Schweizer Bundesamt für Gesundheit (Swiss Federal Health Administration) 1996 and 1998: Lebensmittel-Info, Verwendung von Hanf in Lebensmitteln und Gebrauchsgegenständen, Kreisschreiben Nr. 2 vom 13.3.1996. Fremd- und Inhaltsstoffverordnung, FIV (AS 1998): Liste der zugelassenen Höchstkonzentrationen (Toleranz- und Grenzwerte) für andere Fremdstoffe oder Inhaltsstoffe (Use of hemp in foods and utility items, list of acceptable maximum concentrations for ingredients).

Mr. Hellwig 1998: personal communication 03.07.1998 (Federal Health Ministry, Bonn, Germany).

Mr. Klepsch 1998: personal communication 03.07.1998 (Staff member of the permanent EU Commission on Foods, Brussels, Belgium).

Mr. Krüger 1998: personal communication 08. und 16.06.1998 (Federal Office for Statistics, Berlin, Germany).

Ms. Weber 1998: personal communication 08.06.1998 (Federal Ministry of Food, Bonn, Germany).

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