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Evolution and classification of Cannabis sativa (marijuana, hemp) in relation to human utilization.

Current Economic Value of Fiber Hemp

Based mostly on fiber products, hemp was once touted, rather unrealistically, as "the new billion dollar crop" (Popular Mechanics, 1938), with the claim that it "can be used to produce more than 25,000 products, ranging from dynamite to Cellophane." Hemp is a natural fiber, and to appreciate its current importance it is desirable to have some background into the nature of fiber and the world market for it. "Fiber" has several meanings, but for purposes of this review it refers to thread-like material, either obtained from natural sources or human-made, and used in various forms (especially woven into fabrics, matted as in paper, or glued together as in fiberboard). Wood fiber provides over three-quarters of all fiber produced, but except for the category manmade cellulosics, this is excluded from the following analysis. "Mineral fibers" (mostly made of glass, steel, asbestos, or carbon) are also excluded from this discussion. There are two basic classes of fiber: natural and synthetic. The world's natural fiber market includes fibers extracted directly from plant and animal species. Cotton and wool are the leading natural fibers. By contrast, synthetic fibers are prepared from fossil fuels. Examples include polyester, polypropylene and nylon. Man-made cellulosics is an intermediate category (sometimes included in synthetics, and sometimes termed "regenerated fibers"); high-cellulose material, primarily salvaged from timber processing and crop residues (especially cotton), are chemically processed and converted to produce manufactured fibers. Rayon and acetate are examples. The world's fiber market today is dominated by synthetic fibers, especially polyester, which is made mostly from ethylene derived from coal. Polyester constitutes three-quarters of all synthetic fibers. The world's textile market uses fiber for fabrics generally and clothing in particular. Cotton currently accounts for almost 40 % of the total textile fiber market (and 85 % of the natural fiber textile market), but polyester is more important, accounting for over 50 % of the total textile fiber market. For years, polyester has been gaining market share while cotton has been losing ground. Animal fibers such as wool and silk, which are protein-based, have also been losing popularity.

Today, hemp constitutes only about 0.3 % (on a tonnage basis) of the world's natural fiber production (excluding wood fiber). The economic trend for fiber hemp has been discouraging: global production fell from over 300,000 tonnes in the early 1960s to about 30,000 tonnes in the first decade of the twenty-first century. The total world value of hemp fiber is about 6 % that of flax (the most comparable stem fiber), and about 0.05 % that of cotton, the leading natural annual fiber crop. (Curiously, all three of these crops are also employed as oilseeds.)

At present, there are only small, niche markets for the production of hemp fiber for various purposes. Traditional usage of the fiber for clothing, cordage and paper continues, but these products are very expensive and appeal to a very small clientele. However, the hemp industry has been reinvigorated by new fiber-based products (see Roulac (1997), Bouloc (2006) and Small (2014b) for extensive analyses). Both the outer (bark, phloem) long fibers and the short internal (hurds, wood) fibers are now being employed in specialty pulp products and composites. These usages include fiberboard, insulation, pressed fiber products, masonry products (concrete, stucco, plaster, tiles), carpets, straw-bale construction materials, livestock bedding, and a very wide range of plastics. The automotive industry has particularly pioneered the development of pressed fiber and moulded plastic components. The considerable rot-resistance of the fiber is being exploited in geotextile products such as landscaping fabric. The usage of hemp for these new fiber applications has been primarily in Europe, and subsidization was important in establishing the new hemp-related industries.

Modern Fiber Hemp Technology

The traditional and still major first step in extracting the most desirable ("long") fibers found in the phloem-associated tissues is to ret ("rot") away the softer parts of the plant. Traditionally this is accomplished either by exposing the harvested stems to microbial decay in the field ("dew retting") or by submerging the stems in water ("water retting"), the latter practiced only in countries which tolerate the associated pollution. The result is to slough off the outermost tissues of the stem and to loosen the inner woody core (the "hurds") from the phloem fibers. Occasionally, hemp is "stand retted"--the standing crop is dehydrated by the application of a desiccant herbicide and retting occurs while the crop is erect (and dead). Rarely, hemp is frost retted--the stems allowed to ret overwinter. A variety of experimental retting techniques have also been attempted, such as retting in plastic bags (Li et al., 2009) and ensilage (Idler et al., 2011).

In traditional hemp processing the long fibers are fractionated from the internal woody hurds in two steps, breaking (stalks are crushed, in more recent times using rollers that break the woody core into short pieces) and scutching (the remaining hurds, short fibers ("tow") and long fibers ("line fiber," "long-line fiber") are separated). Today, a single, relatively expensive decorticator machine can do these two steps as one.

As with other bast fiber crops, hemp phloem fibers are arranged in bundles parallel to the stem axis, and are embedded in a pectic polysaccharide network. The pectin network cementing the fibers together is the major obstacle to obtaining high-quality fiber. A commonly used technique to improve fiber separation is chemical processing with sodium hydroxide or diluted sulphuric acid. Steam explosion is a potential technology that has been experimentally applied to hemp (Garcia-Jaldon et al., 1998). Decorticated material (i.e., separated at least into crude fiber) is the raw material, and this is subjected to steam under pressure and increased temperature which "explodes" (separates) the fibers so that one has a more refined (thinner) hemp fiber that currently is only available from water retting. Other methods that have been considered to augment or replace traditional retting include ultrasonic techniques, enzymatic retting, and the use of improved decay microorganisms. (Traditional water retting is effective because bacteria that are present secrete pectinolytic enzymes; filamentous fungi producing pectinase are more important in dew retting.) Because ease of retting is important for fiber cultivars, there has been selection against the polysaccharide matrix cementing the fibers together.

Most hemp fiber used in textiles today is water retted in China (Zhang et al., 2008). Relatively crude alternatives may be employed to produce a less pure grade of fiber, mostly for non-textile applications. This involves production of "whole fibers" (i.e., harvesting an amalgamation of both the long fibers from the cortex and the shorter fibers from throughout the stem), and technologies that utilize shortened hemp fibers.

This approach is currently dominant in Western Europe and Canada, and commences with field dew retting (typically 2-3 weeks). A principal limitation is climate--the local environment should be suitably but not excessively moist at the close of the harvest season. Once stalks are retted, dried and baled, they are processed to extract the fiber. In general in the EU and Canada, fibers are not separated into tow and line fibers, but are left as "whole fiber."

How Selection has Modified Cannabis sativa for Fiber Production

The fiber from bast fiber crops comes particularly from the stem phloem tissues, constituting a ring of fibrous material just under the outer surface of the stem (Figs. 13 and 14). As in other stem fiber plants, hemp fiber serves to stiffen the stem, producing structural support, but at the same time providing flexibility so that the stem can bend but not break in response to wind and other environmental forces. The long axis of the fibers is parallel to the stem axis (an arrangement that naturally keeps the stem upright and resists stem bending). The fiber cells of hemp are alive initially, but die at maturity as their cells walls become blocked by deposit of lignin. The very valuable primary fibers are initiated in the apical meristem at the tip of the growing main stem, and subsequently elongate (much more so in the internodes than at the nodes). The primary fibers are slightly separated from the epidermis of the stem by several layers of cells (the cortex). Upon completion of internode elongation, a cambium (thin cylinder of meristematic tissue running the length of the stem), located internally to the primary fibers, produces (a) secondary bast fibers towards the outside of the stem (but inside the primary bast fibers) and (b) xylem (woody "hurds" tissue) towards the center of the stem. The term "bark" is often used to indicate all stem tissues external to the cambium, so that "bast fibers" is synonymous with "bark fibers" (de Meijer, 1994). A pith made up of undifferentiated cells initially occupies the center of the very young stems, but is more or less crushed by the developing hurd fibers, and the center of the pith tends to become hollow.

The mature hemp stem consists of several concentric cylinders of tissue (Fig. 14a). A multicellular cortex is found immediately internal to the unicellular epidermis; as with other stem fiber crops, removal of the cortex in "decortication" is a key initial step in fiber extraction (a partly decorticated hemp stem is shown in Fig. 13). Internal to the cortex is the primary phloem fiber tissue, in which the principal fiber of interest is found, and immediately internal to this is the secondary phloem fiber tissue, a less desirable fiber generated by the cambium, the next discernible layer proceeding toward the stem center. As noted above, the cambium produces the hurds towards the center, resulting in the degeneration of the pith that once occupied the center of the stem. Pith tissue is evident in young stems, but is mostly replaced in the growing stem by short-fiber--relatively soft, woody tissue which constitutes a secondary product of economic value. The center of the pith becomes hollow, but only to a limited extent at the nodes, and less so towards the base of the stalk. The woody tissue and the remnants of the pith constitute the "hurds." [The pith remnants constitute less than 1 % of the hurds, but some authors mistakenly refer to the entire hurds as pith; the phrase "woody core" is often applied to all tissues internal to the cambium, and the phrases "woody fibers" and "wood fibers" pertain to the hurd fibers. "Shives" rather than "hurds" is more often used for flax than for hemp, and "core" is more frequently applied to fiber cultivars of kenaf, Hibiscus cannabinus.] Like the trunk of most trees, the stalk becomes thicker (and woodier) towards the base, for support. This progressive thickness towards the base is due mostly to more hurd tissue being formed, but the primary fibers (the highest quality fibers) are progressively supplemented towards the base of the stalk by secondary fibers (of lower quality), and so the upper third of the stem produces higher quality fiber than the lower third. Traditionally, mechanical bending ("breaking") is applied to the decorticated stems to separate the phloem fiber from the hurds.

The primary bast fibers are the most valuable product of the stems, and are 3-55 pm long (van der Werf, 1994); they are amalgamated in fiber bundles which can be 1-5 m long (Fig. 14c). The fibers in the bundles are cemented together by a complex mixture of pectins, hemicelluloses and lignin. As the stem matures, the cambium produces additional (secondary) bast fibers, which are short (about 2 mm long) and more lignified. The woody core fibers of the hurds are even shorter, 0.5-0.6 mm long, and like hardwood fibers are cemented together with considerable lignin. Male plants, although less productive, produce a higher quality of fiber, in part because of their lower lignin content (van der Werf, 1994).

Fiber hemp plants, by contrast with Cannabis plants grown for marijuana or oilseed, and also in contrast with wild plants, have been selected for features maximising fiber production. Selection for fiber has resulted in strains that have much more primary phloem fiber and much less woody core than encountered in narcotic strains, oilseed strains and wild plants. Fiber varieties may have less than half of the stem made up of woody core, while in non-fiber strains of Cannabis, more than three quarters of the stem can be woody core. Moreover, in fiber strains more than half of the stem exclusive of the woody core can be fiber, while non-fiber strains rarely have as much as 15 % fiber in the corresponding tissues. Also important is the fact that in fiber strains, most of the fiber can be the particularly desirable long primary fibers (de Meijer, 1994).

Since the stem nodes tend to disrupt the length of the fiber bundles, thereby limiting quality, tall, relatively unbranched plants with long internodes have been selected. Another strategy has been to select stems that are especially hollow at the internodes (Fig. 15, right hand side), with limited hurds, since this maximises production of long phloem fiber (although the decrease in woody tissues makes the stems less resistant to lodging by wind). Similarly, limited seed productivity concentrates the plant's energy into production of fiber, and fiber cultivars often have low genetic propensity for seed output. Selecting monoecious strains overcomes the problem of differential maturation times and quality of male and female plants. Except for being less robust and the troublesome characteristic of dying after anthesis, male traits are favored for fiber production. In former, labor-intensive times, the male plants were harvested earlier than the females, to produce the best fiber. Fiber strains have been selected to grow well at extremely high densities, which increase the length of the internodes (contributing to fiber length) and increase the length of the main stem while limiting branching (contributing to ease of harvesting). The high density of stems also contributes resistance to lodging, desirable because woody supporting hurd tissue has been decreased by selection. The limited branching of fiber cultivars is often compensated for by possession of large leaves with wide leaflets, which obviously increase the photosynthetic ability of the plants.

In summary, humans have modified Cannabis for fiber production. Fiber quantity and quality have been improved by selection for plants that are taller, have less vigorous branching, have slimmer, hollower, more easily rettable stems with more and longer primary phloem fiber, less secondary phloem fiber and less wood. Sexual reproduction has been limited so that the plants divert less of their energy into pollen and seed production. Selection was unconscious until recent times, when plant breeders realized that selecting for the traits listed above resulted in more and better harvest of primary fiber. Today, except in China which continues to grow hemp for fabric, fiber hemp is grown not just for primary fiber but also for the less valuable secondary phloem fiber and woody core, since there are many new applications for these. One may expect that future fiber cultivars will be selected that reflect these new uses.

In the Northern Hemisphere, most fiber strains (cultivars or land races) have been grown in relatively northern locations (mostly north of 35[degrees] north latitude), while most narcotic strains have been grown (outdoors) in more southern areas. Accordingly, most fiber strains are photoperiodically adapted to flower earlier than most narcotic strains. Since fiber plants have not been selected for narcotic purposes, the level of intoxicating constituents is usually limited.

Evolution of Essential Oil Production Under Domestication

The characteristic odor of Cannabis plants is due to its "essential oil" (volatile oil, ethereal oil), an indistinct chemical category of compounds responsible for scent. Commercial preparations of the essential oil, called "Cannabis flower essential oil" and "hemp essential oil," have been prepared from the female inflorescences and/or the younger foliage. Cannabis essential oil is a mixture of volatile compounds, including monoterpenes, sesquiterpenes and other terpenoid-like compounds that are manufactured in the same epidermal glands in which the cannabinoids of Cannabis (discussed in the "Evolution of Narcotic Drug Production Under Domestication" section) are produced (Malingre et al., 1975; Meier & Mediavilla, 1998). The cannabinoids are biosynthesized from some of the terpenoids, but are odorless (Clarke & Watson, 2002). The essential oil is quite different from fixed hempseed oil from the seeds, the topic of "Evolution of Seed Oil Production Under Domestication" section. Many of the terpenes (particularly limonene and alpha-pinene) volatilize readily and will only be available in fresh material, so the composition of extracted essential oil differs from the volatiles released around the fresh plant (Ross & ElSohly, 1996). Accordingly, a pleasant odor of the living plant is not necessarily indicative of a pleasant-smelling essential oil. Yields are very small--about 10 L/ha (Mediavilla & Steinemann, 1997), so essential oil of C. saliva is expensive, and today is simply a novelty. Essential oil of different strains varies considerably in odor, and this may have economic importance in imparting a scent to cosmetics, shampoos, soaps, creams, oils, perfumes and foodstuifs. Switzerland has been a center for the production of essential oil of C. sativa for the commercial market. Narcotic strains produce much higher numbers of flowers than fiber strains, the bracts associated with the female flowers providing most of the essential oil, so narcotic strains are naturally adapted to essential oil production. Switzerland has permitted strains with higher narcotic THC content to be grown than is allowed in other Western countries, giving it an advantage with respect to the essential oil market. Nevertheless, essential oil has often been produced from low-THC Cannabis. The THC content of essential oil obtained by steam distillation can be quite low, but produces a product satisfying the needs for very low THC levels in food and other commercial goods. The world market for hemp essential oil for simply flavoring products is very limited at present, and probably has weak growth potential. Aromatherapy--the therapeutic use of volatile oils--has become popular, and it is possible that Cannabis volatile oils could achieve considerable market penetration. There is no evidence at present that they are as effective as presently utilized aromatherapy oils. Nevertheless, there is a large market for Cannabis products of whatever nature merely because C. sativa is notorious, and it would not be surprising if its essential oils marketed for aromatherapy achieved market success.

What adaptive significance odor has for wild plants of C. sativa is unclear, although the terpenes present are repellent to some insects (Thomas et al., 2000) and are antimicrobial (Novak et al., 2001). Some wild populations produce quite nauseous smells, and the odor of some narcotic strains is also objectionable (note the popular strain Skunk). Perhaps facetiously, it may be pointed out that the odor of marijuana has affected human evolution, since the distinct smell has widely attracted law enforcement officers, resulting in the incarceration of millions, reducing their Darwinian fitness (potential for leaving progeny).

Narcotic strains tend to be more attractive in odor than fiber strains, and many of the marketed marijuana strains have attractive odors. Clarke and Merlin (2013) noted that "Pioneering marijuana breeders continued selecting primarily for strong potency (high [[DELTA].sup.9]-THC content), followed by more aesthetic considerations of flavor, aroma, and color. Modifying adjectives such as 'minty,' 'floral,' 'spicy,' 'fruity,' 'sweet,' 'purple,' 'golden,' or 'red' were often associated with selected varieties." Industries that offer products that are consumed by mouth, like marijuana, are very concerned about organoleptic preferences (taste, odor and texture) of their offerings since these are critical criteria by which consumers judge acceptability. Probably odor (which is interconnected with taste) is the only organoleptic factor of interest, although the abrasiveness of the foliage, caused by the presence of cystolith hairs (Fig. 16c), may also be significant since there has been some consumption by mouth. In southern Asia, "bhang" is a low-intoxicant preparation of Cannabis leaves, typically combined with milk products (THC is soluble in fat), and sometimes eaten by lower classes. In the illicit drag counterculture/underground trade, hundreds of strains of Cannabis sativa are offered, and as often reflected by their names (e.g., Lemon-lime Kush, California Orange Bud and Fruity Juice), some of these differ in olfactory and/or taste qualities, likely mostly because of different profiles of the terpenes that are present. Although the terpenes are volatile, some remain in the secretory glands unless they are crashed. The odor of fiber strains is quite divorced from the quality and quantity of fiber in the stem (the fiber has no particular smell), but the odor of marijuana harvested from narcotic strains is unavoidable, and so has been more susceptible to selection. It is plausible that in the past narcotic land races with pleasant odors were selected more often than was the case for fiber strains. However, it is also apparent that some strains with a foul smell are appreciated by many. Bouquet (1950) noted "Ganja [marijuana] has a pronounced fetid smell, much appreciated by addicts."

In the "Evolution of Narcotic Drug Production Under Domestication" section, the possibility that the terpenes of Cannabis modify its narcotic and medicinal effects is discussed. If so, it is possible that unconscious selection for terpene profile has been significant in the biochemical evolution of Cannabis narcotic strains.

Evolution of Seed Oil Production Under Domestication

As noted elsewhere in this review, the achenes of Cannabis are usually referred to as seeds. The true "seed" portion is enclosed within the fruit wall (pericarp), which (along with a relatively thin seed coat) forms the protective "hull." Most of the seed is made up of two oil-rich cotyledons, upon which the germinating seedling relies for nourishment. Edible oil is usually obtained by cold-pressing the seed.

A Brief History of Oilseed Production and Usage

Cannabis seeds have been employed for at least 3000 years as food for humans and livestock. Indeed, hempseed was one of the "five grains" of ancient China, along with foxtail millet, broomcorn millet, rice, and barley or wheat (Huang, 2000). In the past, hemp seed has generally been a food of the lower classes, or a famine food. Crushed peanut-butter type preparations have been produced from hemp seed in Europe for centuries, but were rather gritty since technology for removing the hulls was rudimentary. Until about 1800, hemp oil was one of the more popular lighting oils. The cultivation of hemp as an oilseed crop reached a zenith in 19th and early 20th century Russia, when, in addition to the edible uses, the seed oil was employed for making soap, paints and varnishes. However, for most of history the seeds were of very minor economic importance, and by the middle of the 20th century, commercial use was negligible, and selections suitable for dedicated oilseed production were unavailable. For most of the latter part of the last century the seeds were usually employed as wild bird and poultry feed, although occasionally also as human food. World hemp seed production (mostly in China) fell from about 70,000 tonnes in the early 1960s to about 34,000 tonnes at the beginning of the twenty-first century.

The Recent Development of Oilseed Products

At the close of the 20th century, reminiscent of how new hemp fiber applications resurrected the fiber crop mostly in Europe (as discussed in the "Evolution of Stem Fiber Production Under Domestication" section), a similar development of oilseed products, primarily in Canada, witnessed the founding of an expanding hempseed industry. Cannabis sativa is now being grown as a major new source of edible and industrial oilseed products. With the growing recognition of the health benefits of hempseed oil, discussed below, hemp seed production has been increasing. Indeed, the economic prospects for continued development as an oilseed crop are much better than for continued development as a fiber crop. Although China remains the major grower of hemp (both for fiber and oilseed), certified organic production of hemp seed for food purposes can often be done domestically, giving farmers in countries where cultivation is permitted an advantage. At present, oilseed hemp is not competitive with linseed for production of oil for manufacturing, or to sunflower and canola for edible vegetable oil. However, as mentioned in this section, there are remarkable dietary advantages to hempseed oil, which accordingly has good potential for penetrating the salad oil market, and for use in a very wide variety of food products. Additionally as noted later, there is also good potential for hemp oil in cosmetics and skin-care products.

For human consumption of the tasty embryo, the achene is hulled (= dehulled). Hulled hemp seed is a very recent phenomenon, first produced in quantity in Europe. Hemp seed is now often found canned or vacuum-packed. Modern seed hulling using mechanical separation produces a smooth, white, gritless hemp seed meal that needs no additional treatment before it is consumed. This seed meal should be distinguished from the protein-rich, oil-poor seed cake remaining after oil has been expressed, that is used for livestock feed. The seed cake is also referred to as "seed meal," and has proven to be excellent for animals (Mustafa et al., 1999).

Nutritional Aspects of Hempseed Oil

According to an ancient legend (Abel, 1980), Buddha, the founder of Buddhism, survived a 6-year interval of asceticism by eating nothing but one hemp seed daily. This apocryphal story holds a germ of truth--hemp seed is quite nutritional, primarily because of the very high content of unsaturated fatty acids (of the order of 75 %). Good general accounts of dietary aspects of hemp oil are Pate (1998b), Callaway (2002), Leson and Pless (2002) and Oomah et al. (2002).

The quality of an oil or fat is most importantly determined by its fatty acid composition. Hemp is of high nutritional quality because it contains high amounts of unsaturated fatty acids, mostly oleic acid (18:1; 10-16 % content in the achenes, depending on strain), linoleic acid (18:2; 50-60 %), alpha-linolenic acid (18:3; 2025 %), and gamma-linolenic acid or GLA (18:3; 1-6 %). [The notations C:D are the lipid numbers, with C specifying the number of carbon atoms and D the number of double bonds.] In contrast to shorter-chain and more saturated fatty acids, these essential fatty acids do not serve as energy sources, but as raw materials for cell structure and as precursors for biosynthesis for many of the body's regulatory biochemicals. The essential fatty acids are available in other oils, particularly fish and flaxseed, but these tend to have unpleasant flavors compared to the mellow, slightly nutty flavor of hempseed oil. GLA is a widely consumed supplement known to affect vital metabolic roles in humans, ranging from control of inflammation and vascular tone to initiation of contractions during childbirth. GLA has been found to alleviate psoriasis, atopic eczema and mastalgia, and may also benefit cardiovascular, psychiatric and immunological disorders. Ageing and pathology (diabetes, hypertension, etc.) may impair GLA metabolism, making supplementation desirable. As much as 15 % of the human population may benefit from addition of GLA to their diet. At present, GLA is available in health food shops and pharmacies primarily as soft gelatin capsules of borage (Borago officinalis) or evening primrose (Oenothera biennis) oil, but hemp is almost certainly a much more economic source. Although the content of GLA in the seeds is lower, hemp is far easier to cultivate and higher-yielding.

There are other fatty acids in small concentrations in hemp seed that have some dietary significance, including stearidonic acid (Callaway et al., 1996) and eicosenoic acid (Molleken & Theimer, 1997). Nutritional supplements featuring stearidonic acid are often made from black currant (Ribes species) seed, but some hemp cultivars are potential alternative sources. Stearidonic acid is apparently not an important human dietary supplement, but may be required for people with a deficiency of the enzyme delta-6-desaturase (Pate, 1998b). Eicosenoic acid is important in the production of cerebrosides, which are components of nerve membranes and the "white substance" of the brain. Because of the extremely desirable fatty acid constitution of hemp oil, it is now being marketed as a dietary supplement in capsule form.

Linoleic acid and alpha-linolenic acid are the only two fatty acids which must be ingested and are considered essential to human health (Callaway, 2004). While the value of unsaturated fats is generally appreciated, it is much less well known that many dieticians consider the Western diet to be seriously nutritionally unbalanced by an excess of linoleic (an omega-6 fatty acid) over alpha-linonenic acid (an omega-3 fatty acid). A century ago, the typical North American diet ratio of omega-6 to omega-3 fatty acids was about 1-3:1; today it is about 10-14:1. Inhempseed, linoleic and alpha-linolenic occur in a ratio of about 3:1, considered optimal in healthy human adipose tissue, and apparently unique among common plant oils (Deferne & Pate, 1996). Omega-3 fatty acids seem to reduce inflammation, prevent heart arrhythmias, dilate bloods vessels and counter clotting. By contrast, omega-6 fatty acids promote an inflammatory response and encourage clotting. When insufficient omega-3 is provided (relative to omega-6), there seems to be an increased incidence of common diseases, including heart disease, Crohn's disease, asthma, Alzheimer's and some kidney diseases.

Tocopherols are major antioxidants in human serum (Molleken et al., 2001). Alpha-, beta-, gamma- and delta- tocopherol represent the Vitamin E group. These fat-soluble vitamins are essential for human nutrition, especially the alpha-form, which is commonly called vitamin E. About 80 % of the tocopherols of hempseed oil is in the alpha form. The vitamin E content of hempseed is comparatively high. Natural antioxidants in hempseed oil, such as ct-tocopherol, are believed to stabilize the highly polyunsaturated oil, tending to keep it from going rancid, at least within the intact seed. Sterols in hemp seeds probably serve the same antioxidant function, and are also desirable from a human health viewpoint. Phytosterols are membrane constituents in all plants. Medically, they are known to reduce blood cholesterol and so are therapeutic for atherosclerosis (Molleken et al., 2001).

Hempseed protein has recently become very popular as a nutritional supplement, although evidence for its health value is relatively limited. Hemp seeds contain 25-30 % protein, with all eight amino acids essential in the human diet present, and a reasonably complete amino acid spectrum (although lysine is low, as in most vegetable protein). About two thirds of hempseed protein is of the edestin type, which is easily digestible. Although the protein content is smaller than that of soybean, it is much higher than in grains like wheat, rye, maize, oat and barley. The oilcake remaining after oil is expressed from the seeds is employed as a very nutritious feed supplement for livestock, but it also has potential for production of a high-protein flour. Proteins are potential allergens, but human allergies to hemp protein have rarely been reported (Nayak et al., 2013).

Environmental Control of the Development of Nutritional Components

In the "Evolution of Narcotic Drug Production Under Domestication" section, it is noted that the concentration of THC, the principal intoxicant chemical of C. sativa, depends to an extent on the environment in which the plant develops. Environment can also alter the fatty acid chemistry of Cannabis. This was demonstrated by Przybylski et al. (1997), who compared oilseed quality of hemp grown in Canada (under colder conditions) with the same varieties grown in Europe (under warmer conditions). The Canadian-grown seed oil was about 15 % higher in unsaturated fatty acids, with about 10 % more of alpha- and gamma-linolenic acids. It appears that in general a cooler climate is preferable for development of the unsaturated fatty acids, but if the growing season is too short, grain productivity is low and the fatty acid profile may be inferior.

Nutritional Cosmetics

Since the 1990s, hemp oil has become very significant as a "cosmeceutical" (cosmetic-nutraceutical), i.e., a body care product that promotes the health of skin and allied parts of the body because of the topical absorption of biochemicals. These products include bubble baths, creams, lip balms, lotions, moisturizers, perfumes, shampoos and soaps. Skin readily absorbs essential fatty acids, so that lotions rich in these substances can replenish cells damaged by sun and dry air (Wirtschafter, 1995). Linoleic acid, alpha linolenic acid and gamma linolenic acid specifically have several functions related to skin care: they influence cell membrane functions including fluidity, transport of electrolytes and activity of hormones, and they stimulate cell immunology; these fatty acids are considered to have potential for treating neurodermatosis and psoriasis (Vogl et al., 2004).

Industrial Fluids

The vegetable oils have been classified by "iodine value" as drying (120-200), semi-drying (100-120), and non-drying (80-100), determined by the degree of saturation of the fatty acids present (Raie et al., 1995). The suitability of coating materials prepared from vegetable oil depends on the nature and number of double bonds present in the fatty acids. Linseed oil, a very good drying oil, has a very high percentage of linolenic acid. Hempseed oil has been classified as a semi-drying oil, like soybean oil, and is therefore more suited to edible than industrial oil purposes. Nevertheless hemp oil has found applications in the past in paints, varnishes, sealants, lubricants for machinery, and printing inks, although petrochemical extracts have made these uses obsolete, and resurrection of such industrial end uses is unlikely because hempseed oil is expensive (de Guzman, 2001). However, larger production volumes and lower prices may be possible, in which case hemp oil may find industrial uses similar to those of linseed (flax), soybean, and sunflower oils, which are presently used in paints, inks, solvents, binders and polymer plastics. Hemp shows a remarkable range of variation in oil constituents, and selection for oilseed cultivars with high content of valued industrial constituents is in progress.

Hemp seed oil has been used experimentally as diesel fuel, but far cheaper vegetable oils are available.

The Narcotic Potential of the Oilseed

Hemp seeds contain virtually no THC, but if improperly processed, THC contamination can result from contact of the seeds with the resin secreted by the epidermal glands on the leaves and floral parts, and also by the failure to sift away all of the perigonal bracts (which have the highest concentration of THC of any parts of the plant) that cover the seeds (Ross et al., 2000). Seed oil prepared from seeds coated with resin may have small levels of THC, and the same is true for foods made with the seeds. It has been suggested that trace amounts of cannabinoids (and also terpenes) could have health benefits (Leizer et al., 2000) but, as noted next, the presence of cannabinoids is currently very disadvantageous from a regulatory point of view.

Although much of the Western hemp-growing world uses 0.3 % THC in the plant as a maximum concentration for authorized cultivation, regulations in various countries allow only a much lower level of THC in human food products manufactured from the seeds. Permitted levels in seeds in various countries range from 10 ppm down to 0.005 ppm. Limits have been set not just because of concerns about possible toxicity, but also because of potential interference with drug tests (Grotenhermen et al., 1998). Cannabinoids are very lipid soluble and accumulate in fatty tissue throughout the body. They are released very slowly and so can remain in the body for more than a month after consumption. The Drug Enforcement Agency and the Office of National Drug Control Policy of the U.S. raised concerns over tests conducted from 1995 to 1997 that showed that consumption of hempseed products available during that period led to interference with drug-testing programs for marijuana use. Federal U.S. programs utilize a THC metabolite level of 50 parts per billion in urine. Leson (2001) found that this level was not exceeded by consuming hemp products, provided that THC levels are maintained below 5 ppm in hemp oil, and below 2 ppm in hulled seeds.

How Selection has Modified Cannabis sativa for Oilseed Production

In the "Evolution of Propagules Under Domestication" section, it was noted that achenes in domesticated plants of C. sativa differ in several respects from those of wild plants. This information is not repeated here, but it should be noted that oilseed hemp seed shows all of the features characteristic of seeds of domesticated plants. "The Evolution of Shoot Architecture Under Domestication" section, which discusses the evolution of shoot architecture in the various groups of domesticated plants, supplements the information presented below on oilseed strains.

Today, there are very few cultivars bred specifically for oilseed production, and indeed most hemp seed in Europe is currently obtained from so-called "dual usage" plants (employed for harvest of both fiber and seeds), which are not capable of producing as much seed as oilseed strains. Growing hemp to the stage that mature seeds are present compromises the quality of the fiber, because of lignification in the stem. As well, the woody hurds that are useful as a secondary product become more difficult to separate. The lower quality fiber, however, is quite utilizable for pulp and non-woven usages. Of the European dual-usage cultivars, 'Uniko B' and 'Fasamo' are particularly suited to being grown as a source of oilseed.

It appears that in the past when seeds were harvested from cultivated C. sativa, they came from plants that were grown additionally for other purposes, either for fiber or narcotics. Dewey (1914) noted that a Turkish type of land race called Smyrna, that he thought was a narcotic strain, was commonly used in the early 20th century in the U.S. to produce birdseed, because (like most narcotic types of Cannabis and unlike fiber types) it is quite branched, producing many flowers, hence seeds. Until Canada replaced China in 1998 as a source of imported seeds for the U.S., most seeds used for various purposes in the U.S. were imported from China. Small and Marcus (2000) examined the growth of some Chinese hemp land races, which were quite branched, and altogether rather reminiscent of Dewey's description of Smyrna. Although similar in appearance to narcotic strains of C. sativa, the Chinese land races examined were low in intoxicating constituents, and it is probable that what Dewey thought was a narcotic strain was not.

"The Evolution of Photoperiodism Under Domestication" section, pointed out that plants of C. sativa are locally adapted to increasingly shorter seasons of northern latitudes by becoming smaller, and this pattern would apply to plants grow for oilseed, as well as those cultivated for fiber and narcotics. The "Evolution of Shoot Architecture Under Domestication" section, dealing with shoot architecture, pointed out that plants grown for narcotics are spaced sufficiently apart to provide for branches (hence flowers and THC content) to develop well, and likely at whatever latitude C. sativa was grown, farmers learned the appropriate density required to maximize seed production. However, as pointed out in the next paragraph, large, branched plants do not appear to represent the best way to maximize oilseed yield.

Until very recent times, the widespread cultivation of hemp primarily as an oilseed was largely unknown, except in Russia. It is difficult to reconstruct the type of plant that was grown there as an oilseed, because (1) such cultivation has essentially been abandoned; (2) land race germplasm in the Vavilov Research Institute (St. Petersburg) seed bank, the world's largest collection, has been extensively hybridized (Small & Marcus, 2003; Hillig, 2004b) due to inadequate maintenance. A land race certainly was grown in Russia specifically for seeds, and Dewey (1914) gave the following information about it: "The short oil-seed hemp with slender stems, about 30 in. high, bearing compact clusters of seeds and maturing in 60 to 90 days, is of little value for fiber production, but the experimental plants, grown from seed imported from Russia, indicate that it may be valuable as an oil-seed crop to be harvested and threshed in the same manner as oil-seed flax." Some very recently bred oilseed cultivars are indeed short, compact, and ideal for high-density planting. These include 'FINOLA' and 'Anka', which are relatively short, little-branched, mature early in north-temperate regions, and are ideal for high-density planting and harvest with conventional equipment. It appears that modern hempseed breeders have intuitively reconstructed the kind of plant that used to be grown in Russia for oilseed. Low stature is desirable in fiber selections to avoid channelling the plants' energy into stem tissue, in contrast to fiber cultivars for which a very tall main stalk is desired. Compact clustering of seeds also decreases stem tissue, promotes retention of seeds, and facilitates collection.

Although some forms of C. saliva have quite large seeds, until recently oilseed forms appear to have been selected mainly for a heavy yield of seeds. In Europe, most cultivars have been selected for fiber yield, and these do not differ much in oilseed potential (Molleken & Theimer, 1997). By contrast, some drug strains (which have been selected for prodigious production of flowers), when left to go to seed can yield a kilogram of seeds on a single plant (Clarke & Merlin, 2013). Percentage or quality of oil in the seeds does not appear to have been important in the past (techniques for analysing the nutritional chemicals were simply not available until fairly recently), although selection for these traits is now being conducted. As noted in the "Evolution of Propagules Under Domestication" section, domesticated achenes are thinner-walled than wild achenes, and thinness of pericarp is an important criterion for modern hemp oil seed breeders since the pericarp is a waste product. Most significantly, modern selection is occurring with regard to mechanized harvesting, particularly the ability to grow in high density as single-headed stalks with very short branches bearing considerable seed.

Evolution of Narcotic Drug Production Under Domestication

Pharmacological Terminology for Marijuana

The word "narcotic," consistently used in this review to describe the psychological effects associated with marijuana, has been extensively and ambiguously employed in lay, legal and scientific circles. The term is most widely used as an arbitrary juridical category--a narcotic is simply a substance or preparation that is associated with severe penalties because of real or alleged dangerous, addictive properties. "Legally, cannabis has traditionally been classified with the opiate narcotics, and while they may share some euphorogenic and analgesic properties, they are otherwise quite distinct pharmacologically" (Le Dain, 1972). Etymologically, based on "narcosis," a narcotic would be expected to be a substance promoting sleep, and indeed some use the term to characterize any drug which produces stupor or insensibility. As will be seen, at least one compound in Cannabis has important sedative properties. The pharmacological classification of cannabis is controversial. It has been characterized as a sedative-hypnotic-general-anesthetic like alcohol and nitrous oxide; a mixed stimulant-depressant; a mild hallucinogen, especially at higher doses; a "psychedelic," like LSD at very high doses; and as a separate category of psychic experience (Le Dain, 1972). The following terms have been used to describe cannabis: psychedelic (mind-manifesting or consciousness-expanding), hallucinogenic (hallucination-producing), psychotomimetic (psychosis-imitating), illusinogenic (illusion-producing), and psychodysleptic (mind-disrupting); as noted in Le Dain (1972, p. 396), these terms are problematical. There is little dispute that cannabis is a "psychotropic" or "psychoactive" drug (one altering sensation, mood, consciousness or other psychological or behavioral functions). Clearly, it is popular (albeit largely illegal), employed primarily as a social inebriant and euphoriant. In this review the terms "narcotic" and "intoxicant" are used to refer to forms of C. sativa that are high in THC, and the term "non-narcotic" refers to forms low in THC. Although "narcotic" is often used pejoratively, the intent here is simply to indicate that there are associated drug-induced, intoxicating mental effects.

A Brief History of Narcotic Cannabis Drug Production and Usage

Russo et al. (2008) provide documented evidence for the earliest use of C. sativa as a pharmacologically active agent, in a 2700-year-old grave in China. However, over the last millennium cannabis consumption became more firmly entrenched in southern Asia from Afghanistan to India, than anywhere else in the world. Not surprisingly, the most highly domesticated drug strains were selected there. While Cannabis has been extensively used as a narcotic for thousands of years in the region and subsequently in the Near East, parts of Africa, and other Old World areas, widespread narcotic use simply did not develop in temperate region countries, where by contrast fiber hemp was raised. The use of Cannabis as a recreational inebriant in sophisticated, largely urban settings began substantially in the latter half of the 20th century. Up until then, drug preparations of Cannabis were used predominantly as a recreational intoxicant in poor countries and the lower socio-economic classes of developed nations. After World War II, marijuana became associated with the rise of a hedonistic, psychedelic ethos, first in the United States and eventually over much of the world, with the consequent development of a huge international illicit market. Cultivation, commerce, and consumption of chug preparations of Cannabis were proscribed in most countries during the 20th century, but narcotic cannabis contributes substantially to the current illicit drug problem of the world. According to the United Nations Office on Drugs and Crime (2014), cannabis is the most widely used illicit substance in the world, consumed by up to 227 million, constituting 4.9 % of those between the ages of 15 and 64. The highest prevalence occurs in Western countries and several nations in Africa. Estimates for the U.S., the leader in usage, range up to 25 %. Marijuana has been claimed to be at least the fourth most valuable crop in America, outranked only by com, soybeans and hay (Small & Marcus, 2002). Indicative of how widespread is the use of cannabis in the U.S., about 10 % of paper currency has been found to be contaminated with cannabinoid residues (Lavins et al., 2004).

Currently, there is an explosion of interest in narcotic forms of cannabis, in part because of possible medical applications, but also because of increasing tolerance of illegal recreational usage. Nevertheless, governments have long maintained a costly war against the consumption of cannabis. Although narcotics are widely viewed as intrinsically evil, the world's leading controlled narcotic crops have some legitimate, useful applications (Small, 2004; Small & Catling, 2009).

Cannabis drug preparations have been employed medicinally in folk medicine since antiquity in Asia, and were extensively used in Western medicine between the middle of the 19th century and World War II, particularly as a substitute for opiates (Mikuriya (1969); see Russo (2007) for an extensive review). Alcoholic tinctures were particularly popular. Medical use declined with the introduction of synthetic analgesics and sedatives, and until the end of the 20th century there was very limited authorized medical use. So-called "compassion clubs" in Western nations have dispensed marijuana to ill people, often illegally. Several European and Commonwealth countries and many states of the U.S. currently allow medical dispensation of marijuana, while Uruguay and several U.S. states permit the sale by licensed vendors of marijuana for recreational use. In the last several decades there has been a great upsurge of interest in using marijuana for treatment of various ailments, especially for alleviating nausea, vomiting and anorexia following radiation therapy and chemotherapy; as an appetite stimulant for AIDS patients; for relieving the tremors of multiple sclerosis and epilepsy; and as an analgesic for chronic neuropathic pain. Extracts have been used for specific purposes, notably THC for glaucoma, spasticity from spinal injury or multiple sclerosis, pain, inflammation, insomnia, asthma and other conditions; and CBD (described later) for moderating the effect of THC, and for some psychological problems. The medical efficacy of cannabis drugs has been examined in thousands of research papers and hundreds of reviews (e.g., Grotenhermen & Muller-Vahl, 2012), but is beyond the scope of this review (for an excellent source of information, see Pertwee (2014)). There is not yet a medical consensus that any particular cannabis-based treatment is preferable to other available therapies. Most Western countries are curiously ambivalent about the therapeutic status of cannabis, with limited prescriptions for marijuana, its constituents or chemical analogues, but nevertheless listing it as a Schedule 1 controlled substance, defined as having high potential for abuse and no currently accepted medical use.

Glandular Trichomes

The psychoactive chemicals of Cannabis (cannabinoids, notably THC, as presented in the following paragraphs) are produced in specialized tiny secretory epidermal glands. These are termed "trichomes" or "hairs" (the former term is often restricted to plants and the latter to animals). Different kinds of glandular epidermal trichomes occur (Fig. 16), often classified as long-stalked, short-stalked or sessile (essentially lacking a stalk, sessile glands hardly look like trichomes). Rather different glands are present on the anthers (Fig. 17), but since the female plants are the source of drugs, the discussion is confined to their glands. In the female's glandular trichomes, the essential part of the gland is a more or less hemispherical head, sometimes compared in size to the head of a pin. Inside the head at its base there are specialized secretory "disk cells," and above these there is a non-cellular cavity where secreted resin is accumulated, enlarging the covering sheath (a waxy cuticle) of the head into a spherical blister. This may eventually rupture, releasing resin onto the surface of the plant. Hot conditions seem to favor release of the resin, but apparently there has been selection for strains that retain resin within the gland heads so that when fabric sieves are used to prepare hashish (as described later), they will not become clogged with sticky resin. However, strains that produce extruded sticky resin have been favored when hands or leather are used to rub off the resin for hashish preparation (McPartland & Guy, 2004; Clarke, 1998). Clarke and Watson (2002) state that there is an "abscission layer" at the base of the head, although there seems no reason why dropping the heads is adaptive from the plant's perspective. However, it does seem that some strains have been selected for ease of harvesting the heads for making narcotic preparations. The resin is a sticky mixture of cannabinoids and a variety of terpenes. In marijuana varieties the resin is rich in THC, the chief intoxicant of Cannabis. The secretory glands differ notably in density on different organs of the plant (high concentrations occur on the lower surface of the young leaves, on young twigs, on the tepals, and especially on the perigonal bracts (Fig. 16), where they are very dense and productive). Given this distribution, the glands would seem to be protective of young and reproductive above-ground exposed tissues (the roots and achenes, which are not exposed, lack glands). Clarke (1998) observed that marijuana varieties differ widely in the size of glands. Selection of narcotic forms appears to have favored greater gland size, greater gland density, or both. Small and Naraine (2015) found that recently selected strains with very high levels of THC have very large gland heads. Mahlberg and Kim (2004) observed that the cannabinoid content of the long-stalked glands that they examined possessed about 20 times the cannabinoid content of sessile glands (which are usually much smaller than the former). The glands of Cannabis have been extensively examined by Mahlberg and associates (Hammond & Mahlberg, 1977, 1978; Kim & Mahlberg, 1995, 1997, 2003; Mahlberg & Kim, 1991, 1992, 2004; Mahlberg et al., 1984; Turner et al., 1980, 1981a, b). It has been established that cannabinoids are synthesized within the secretory glands, not elsewhere and transported to the glands (Sirikantaramas et al., 2005; Stout et al., 2012).

There is some evidence for cannabinoid production outside of the epidermal glands, but only in trace amounts. Laticifers occur in the foliage and stems (Bouquet, 1950). These are of the unbranched, nonarticulated form, made up of an elongated secretory cell producing a kind of latex. Furr and Mahlerg (1981) detected cannabinoids in laticifers of C. sativa. Veliky and Genest (1972), Pacifico et al. (2008), and others found no production of TFIC in tissue cultures, suggesting that non-secretory cells do not produce cannabinoids. However, some experiments demonstrated production of cannabinoids in cell cultures of Cannabis, but in extremely limited amounts (Heitrich and Binder (1982); Hartsel et al. (1983); see review of Mandolino and Ranalli (1998)).

Cannabinoids

Cannabis contains a seemingly unique class of terpenophenolic secondary metabolites, the cannabinoids, of which more than 100 have been described (Grotenhermen & Russo, 2002; ElSohly & Slade, 2005; ElSohly, 2007; Radwan et al., 2009; de Meijer, 2014), but only a few are psychoactive (later, a broader conception of "cannabinoids" is presented). There are reports in the literature that cannabinoids occur in other plants (e.g., in the liverwort Radula variabilis (Toyota et al., 2002) and in the composite Helichrysum (Bohlmann & Hoffmann, 1979), but virtually all specialists on the cannabinoids are of the view that cannabinoids are more characteristic of Cannabis than any other plant. Additional chemical investigation is required to establish whether some of the cannabinoids that have been described occur as original metabolic products of the plant or are degenerative products or artifacts. The more important cannabinoids are shown in Fig. 18. These have a basic 21-carbon skeleton (22 in the carboxylated forms). In the living plant the cannabinoids exist predominantly in the form of carboxylic acids, which decarboxylate into their neutral counterparts (as shown in Fig. 18) with time or when heated, as provided when marijuana is smoked or cooked (e.g., in brownies). Delta-9-tetrahydrocannabinol ([[DELTA].sup.9]-THC, or simply THC) is the predominant psychoactive component (for other cannabinoid abbreviations, see the legend of Fig. 18). (The designation [[DELTA].sup.9]-THC employs formal chemical nomenclature for pyran-type compounds. In an alternative nomenclature system often employed in Europe, based on regarding the cannabinoids as substituted monoterpenoids, this is known as [[DELTA].sup.1]-THC.) THC is the world's most popular illicit chemical, and indeed the fourth most popular recreational chemical after caffeine, ethyl alcohol and nicotine, all of which are addictive. Other THC isomers also occur, particularly [[DELTA].sup.8]-THC, which is also psychoactive. [[DELTA].sup.8]-THC is much less abundant in C. sativa, occurring only in trace amounts if at all, and is somewhat less potent than [[DELTA].sup.9]-THC. CAN, the principal degeneration or transformation product produced when THC ages, has limited psychoactive potential (Russo, 2007), and the other molecules shown in Fig. 18 are not euphoriant, and if present almost always occur only in small concentrations. Oxygen, high temperatures, light, and high humidity gradually decrease the potency of cannabis drugs, but storage in a dark, cool place with exclusion of air minimizes loss of activity for up to several years.

THC is very potent in humans, causing a "high" at a dose of 10 pg/kg through smoking, 30-50 [micro]g/kg after i.v. injection and 120 pg/kg from ingestion. A THC concentration in marijuana of approximately 0.9 % has been suggested as a practical minimum level to achieve an intoxicant effect but, as discussed later, CBD (the predominant cannabinoid of fiber and oilseed varieties) antagonizes (i.e., reduces) and potentiates (modifies) the effects of THC. Concentrations of 0.3 to 0.9 % are considered to have "only a small drug potential" (Grotenhermen & Karus, 1998). The state of Colorado, which recently authorized the recreational use of marijuana, set a legal maximum limit for driving an automobile of 5 ng/mL THC of blood (many other states have zero tolerance). Grotenhermen et al. (2005) came to the following conclusions (cf. Armentano, 2013). After smoking "typical medium to strong doses" of 1520 mg THC, peak THC levels in blood occur 5-10 min after inhalation, and a waiting period of about 3 h after smoking seems sufficient to reduce THC level to below a THC blood level of 5 ng/mL. Typical oral doses in social settings are in the 10-20 mg range, the effects occurring later than do those of smoking, usually peaking 2-3 h after ingestion, and usually decreasing below the level of 5 ng/mL THC of blood in 4 h. Additional information contrasting smoked and eaten cannabis is provided later.

There is a general inverse relationship in the resin of Cannabis between the amount of THC present and the amount of CBD. Whereas most drug strains contain primarily THC and little or no CBD, fiber and oilseed strains primarily contain CBD and very little THC. CBD can be converted to THC by acid catalyzed cyclization, and so could serve as a starting material for manufacturing THC, but the illicit drug trade has access to easier methods of synthesizing THC or its analogues than by first extracting CBD from non-drug hemp strains.

There have been numerous studies of cannabinoid variation, mostly employing the predominance of either THC or CBD respectively as indicators of narcotic kinds and non-narcotic kinds (for examples, Fetterman et al., 1971; Small & Beckstead, 1973a, b; Small et al., 1975; Avico et al., 1985). In the "Classification and Nomenclatural Issues" section, two subspecies are recognized using THC content for separation. Cannabis sativa subsp. saliva has limited THC and C. sativa subsp. indica has appreciable THC. A dividing line of 0.3 % (dry weight content in the inflorescence or young infructescence) was established by Small et al. (1976) based on study of variation in several hundred populations, and subsequently was adopted in the European Community, Canada, parts of Australia, and the U.S.S.R. as a criterion between cultivars that can be legally cultivated under licence and forms that are considered to have too high a drug potential (in some countries the allowable level is currently different). For a brief period, the 0.3 % threshold was also accepted as maximum concentration for importing hemp into the U.S. As noted above, a level of about 1 % THC is considered the threshold for marijuana to have intoxicating potential, so the 0.3 % level is conservative, and some jurisdictions (e.g., Switzerland and parts of Australia) have permitted the cultivation of cultivars with higher levels. It is well known in the illicit trade how to screen off the more potent fractions of the plant in order to increase THC levels in resultant drug products. Nevertheless, a level of 0.3 % THC in the flowering parts of the plant is reflective of material that is too low in intoxicant potential to actually be used practically for illicit production of marijuana or other types of narcotic drugs.

CBC is a frequent minor constituent of highly-intoxicating strains of C. sativa, especially from Africa, and strains high in CBC have been selected for medicinal experimentation. De Meijer et al. (2009a) provide evidence that CBC is present in substantial amounts in juvenile plants and declines with maturation; these authors found variants in which CBC persisted into maturity, and noticed that this is associated with a reduced presence of perigonal bracts and secretory glands. CBG rarely dominates the resin of Cannabis (Fournier et al., 1987). Some geographical races with minor or trace amounts of cannabinoids have been described, notably for CBGM in some northeastern Asian populations, CBDV in some populations from central Asia, and THCV in some collections from Asia and Africa.

Adaptive Purpose of the Cannabinoids

The natural function of the abundant secretory glands, and of the large volume of resin they produce, has not been established. The glands are rich in terpenes, which are very common in higher plants, and are known to be protective against many harmful organisms, but why the plant elaborates some of these chemicals into cannabinoids is not clear. There is some evidence that drought, high light intensity, and high elevations (and therefore greater UV light) increase the release of exudate on the leaf surfaces, and this has led to the hypothesis that the resin is a protective sunscreen (Bouquet, 1950, stated that the resin is an "insulating protective varnish" against high temperature and moisture loss.) Pate (1983) hypothesized that THC is protective against ultraviolet-B radiation. However, Lydon et al. (1987) concluded that "the contribution of cannabinoids as selective UV-B filters in C. saliva is equivocal." The glands and consequently the resin that is secreted are concentrated on the abaxial ("lower") side of the leaves (the same is time for the perigonal bracts in the inflorescence); it hardly makes sense for a sunscreen to be present on the shaded lower side of the foliage rather than the exposed upper side, and employing a resinous sunscreen seems quite speculative in view of the fact that plants commonly use several other strategies for reducing the intensity of solar radiation (see, for example, Small, 2014a). The cannabinoids appear to provide some protection against bacteria and fungi (McPartland et al., 2000). Cannabis sativa has minor allelopathic properties (Inam et al., 1989; McPartland, 1997; McPartland et al., 2000), and chemicals leached into the soil may inhibit competing plants, as suggested by Haney and Bazzaz (1970). Insects are by far the principal herbivores of plants, which employ many chemical defences against them. Curiously, insects lack endocannabinoid receptors (discussed later in this section), and so are incapable of responding to the cannabinoids in the same way as most animal groups. Ledbetter and Krikorian (1975) suggested that exuded resin could be a mechanical defence, ensnaring small insects like flypaper. "Touch-sensitive glandular trichomes" rupture when touched by an arthropod, rapidly releasing a sticky exudate which can discourage, even kill herbivorous insects (Krings et al., 2002). In living (but not dried) cannabis glands, the resin head readily ruptures when touched, suggesting that the released resin is indeed anti-herbivorous. Why the cannabinoids have evolved remains open to speculation (indeed, why other species in the Cannabaceae have secretory epidermal cells is equally unclear). Most secondary compounds are likely a) metabolic waste products, b) generalized anti-biotics (against all harmful classes of organisms; see Pate (1994)), or c) evolutionary holdovers from ancestors in which the chemicals were adaptive. The cannabinoids probably fall within one or more of these categories.

Factors Associated with Variation of THC

Cannabinoids levels in the plant generally increase from the seedling stage to the flowering period (Phillips et al., 1970; Latta & Eaton, 1975; Turner et al., 1975; Small, 1979b; Hemphill et al., 1980; Kushima et al., 1980). Seasonal fluctuations in relative proportion of THC and CBD have been observed (Phillips et al., 1970; Latta & Eaton, 1975; Pate, 1998a), with differences in staminate and pistillate plants (Turner et al., 1975). The plants of some populations of cultivars have proven to be rather uniform in THC content, whereas in others considerable variation among plants has been found (Mechtler et al., 2004).

Cannabinoid content differs in different parts of the plant, increasing in the following order: large stems, smaller stems, older and larger leaves, younger and smaller leaves, flowers, perigonal bracts covering the female flowers (and consequently covering the fruits). Epidermal secretory glands are present on all of the preceding structures, explaining the presence of cannabinoids. There are reports of cannabinoids in minute amounts in achenes (excluding bracts) and roots, but this could be due to contamination, as the resin of the plant is easily transferred. THC and other cannabinoids have been reported in the pollen (Paris et al., 1975; Ross et al, 2005), but it may be that this also is the result of contamination from the secretory glands of the anther (note Fig. 17).

Various environmental circumstances can modify, albeit relatively slightly, the cannabinoid content of Cannabis. Factors that have been examined include temperature (Bazzaz et al., 1975; Sikora et al., 2011), nutrient availability (Coffman & Gentner, 1975, 1977; Bocsa et al., 1997), light intensity (Potter & Duncombe, 2012), untraviolet light intensity (Lydon et al., 1987; Pate, 1994), light quality (Mahlberg & Hemphill, 1983), and photoperiod (Valle et al., 1978). Haney and Kutscheid (1973) demonstrated that wild hemp populations in Illinois were highest in cannabinoids when stressed, either by nutrient limitations or by drought, although shading did not have any measurable effect. However, stress tends to make the plants drop their lower leaves which are naturally low in THC, and so it is difficult to evaluate the effects of stress on a whole-plant basis. Stress also makes for smaller plants with less biomass, and hence a lower overall production of cannabinoids per unit area of land occupied. The range of THC concentrations developed by low-THC cultivars (those typically with no more than 0.3 % THC) under different circumstances on the whole is limited, for the most part generally not varying more than 0.2 percentage points when grown in a range of circumstances, and usually less.

Biosynthesis and Genetics of the Cannabinoids

The biosynthetic pathways of the major cannabinoids with pentyl side chains (CBC, CBC, CBG, and THC) were established in the 1990s. The first event in the pentyl cannabinoid biosynthesis is the production of cannabigerol (CBG), produced by condensation of a phenol-derived olivetolic acid and a terpene-based geranylpyrophosphate catalysed by the enzyme geranylpyrophosphate:olivetolate geranyltransferase (Fellermeier & Zenk, 1998). From CBG, [DELTA].sup.9]-THC, CBD, and CBC are synthesized, each by a specific synthase enzyme. The enzyme converting CBG to THC was clarified by Taura et al. (1995). The enzyme converting CBG to CBD was studied by Taura et al. (1996) and Taura et al. (1997). An outline of the biosynthesis of the two most important cannabinoids, THC and CBD, is shown in Fig. 19. For more complete analyses of cannabinoid biosynthesis, see Sirikantaramas et al. (2007), Flores-Sanchez and Verpoorte (2008), van Bakel et al. (2011) and Gagne et al. (2012).

As emphasized by Hillig (2002) and de Meijer et al. (2003), it is important to distinguish quantitative and qualitative aspects of cannabinoid inheritance. The absolute quantity of cannabinoids produced by an individual plant or by a population (on an average basis) depends on growth and development traits (such as size and proportion of tissues constituted by secretory glands), which are (a) probably determined polygenically, (b) are unrelated to cannabinoid biosynthetic pathways, and (c) are subject to strong environmental modification. Qualitative aspects, discussed in the next paragraph, relate to the genetic control of genes influencing the relative amounts of the cannabinoids.

[F.sub.1] hybrids between high-THC narcotic strains and high-CBD fiber cultivars are usually more or less intermediate between the parents. Small (1979b) found that numerous first generation hybrids were indeed more or less intermediate in THC proportion. Beutler and Der Marderosian (197S) crossed a ruderal low-THC form and a narcotic race with higher THC, and also found that the first generation hybrids were more or less intermediate, although many tended to have lower THC proportions. As expected for an outcrossing species, [F.sub.1] hybrids frequently show evidence of heterosis for various characteristics. Various authors have observed cannabinoid segregation ratios in [F.sub.2] generation hybrids (see literature citations in de Meijer et al., 2003), and as discussed in the next paragraph, this is due to allelic segregation.

Inheritance of the key cannabinoids THC and CBD has been shown to be determined by the allelic status at a single locus (referred to as B) (de Meijer et al., 2003; Mandolino et al., 2003; Pacifico et al., 2006). De Meijer et al. (2003; cf. Mandolino & Ranalli, 2002, Mandolino et al., 2003; Mandolino, 2004) found evidence that THC development in C. sativa is under the partial genetic control of codominant alleles. Allele [B.sub.D] is postulated to encode CBD synthase while allele [B.sub.T] encodes THC synthase. This model holds that plants in which CBD is predominant have a [B.sub.D]/[B.sub.D] genotype at the B locus, plants in which THC is predominant have a BT/BT genotype, and plants with substantial amounts of both THC and CBD are heterozygous ([B.sub.D]/[B.sub.T] genotype). De Meijer and Hammond (2005) found that plants accumulating CBG have a mutation of [B.sub.D] (which they term [B.sub.0]) in the homozygous state that encodes for a poorly functional CBD synthase; and de Meijer et al. (2009b) selected a variant of this that almost completely prevents the conversion of CBG into CBD.

Shoyama et al. (2001) transferred the THC-synthase gene from Cannabis to tobacco (Nicotiana tabacum), inducing it to convert CBG to THC. This raises the prospect that transgenic tobacco (or indeed any other plant) could be smoked as a marijuana substitute!

Breeding for High and Low Levels of Cannabinoids

Clandestine marijuana breeders, for several decades, have produced "improved" types of drug plants, and hundreds of selections have been named and offered in the illicit trade; Snoeijer (2002), Danko (2010), Rosenthal (2001, 2004, 2007, 2010), Grisswell and Young (2011), and Oner (2011a, b, 2012) list many named selections. Because of legal constraints, very few of these appear to possess protected status as accorded by national and international agreements governing registered cultivated varieties and intellectual property. In the Netherlands, some firms are (or were) authorized to distribute drug selections, and there have been some claims for property rights for these. In 1998, a pharmaceutical drug cultivar called 'Medisins' was registered in the Netherlands by HortaPharm, one of the earliest officially recognized drug cultivars, followed by 'Grace' registered by GW Pharmaeuticals in 2004, both awarded plant breeders rights (Clarke & Merlin, 2013). Pharmaceutical varieties developed in the Netherlands by HortaPharm BV were transferred to GW Pharmaceuticals, centered in the United Kingdom, which has plant breeder's rights to at least 30 to 40 selections (Anonymous, 2006). GW Pharmaceuticals, the world's leading pharmacological firm dedicated to cannabis-based drugs, is developing strains that predominantly produce one of the four major cannabinoid compounds (THC, CBD, CBC, CBG), as well as varieties with mixed cannabinoid or terpene profiles (Clarke & Merlin, 2013) Some of these selections produce single cannabinoids reportedly at high levels "over 10 %" without significant amounts of any other cannabinoids. Other private firms, especially in the Netherlands, have also selected "medicinal" lines with particular cannabinoid profiles as well as other attributes.

Breeding for low-THC cultivars in Europe has been reviewed by Bocsa (1998), Bocsa and Karus (1998) and Virovets (1996). Pacifico et al. (2006) were unable to detect cannabinoids in some plants of European fiber cultivars ('USO-31' and 'Santhica 23'). However, at present no commercial cultivar seems to be 100 % free of THC. THC content has proven to be more easily reduced in monoecious varieties, which are inbred, than in dioecious varieties, which are outbred.

A simple way of making plants THC-free is to eliminate the capacity to produce any kind of cannabinoid. De Meijer et al. (2009b) noted that there are two ways of accomplishing this: (1) disrupt the morphogenesis of the glandular trichomes, and (2) block one or more biochemical pathways crucial for the formulation of the cannabinoids. Gorshkova et al. (1988) reported on plants that lacked glandular trichomes and plants with odd glandular trichomes (with white heads), both types lacking cannabinoids, but a cultivar or selection in which all plants lack glandular trichomes has not been described. De Meijer et al. (2009b), based on selections from a fiber hemp cultivar ('USO-31'), discovered a genetic factor (termed a "knockout gene") that completely blocks cannabinoid biosynthesis in C. sativa, apparently functioning by preventing the conversion of the phenolic precursors of the cannabinoids into the cannabinoids.

Traditional hashish prepared in Asia is typically rich in both the intoxicant THC and the sedative CBD, and land races have been selected for making hashish. By contrast, most narcotic cultivars have been selected just for THC, and indeed most have limited or no CBD. An explanation for the presence of CBD in traditional hashish land races was offered by Clarke and Watson (2007): "Hashish cultivars are usually selected for resin quantity rather than potency, so the farmer chooses plants and saves seed by observing which one produces the most resin, unaware of whether it contains predominantly THC or CBD."

Endocannabinoids

The term "cannabinoids" has been expanded from its original meaning referring to a unique class of compounds synthesized by Cannabis. Some researchers also include in the term cannabinoids a) chemically synthesized analogues ("synthetic cannabimimetics" Ashton (2012)), and b) chemicals of quite different structure called "endocannabinoids" (endogenous cannabinoids), found in animals including humans, which trigger the cannabinoid receptors, particularly those that function in neurochemistry, as noted below.

In the early 1970s, opiate receptors were discovered in the brain that bind to morphine and other opiates (chemically, molecules that bind to cellular receptors are called ligands; pharmacologically, chemicals contacting and activating receptors are agonists, those that attach to a receptor but do not activate it or displace an agonist, preventing activation, are antagonists). Analogous to the discovery of opiate receptors, in the 1990s it was found that the brain and some other organs have specific G-protein coupled receptors that recognize THC and other cannabinoids, and trigger responses (Fig. 20). This discovery is key to understanding the molecular basis of cannabinoid pharmacological activity, and to exploring and developing cannabis-based therapies. While the receptors fortuitously respond to the cannabinoids from C. sativa, they appear to routinely function mainly in response to molecules produced by the body's metabolism (Grotenhermen, 2003, 2004a, b; Onaivi et al., 2005). These molecules, which, have a variety of metabolic functions, are called endocannabinoids, and are derivatives of fatty acids (they are thus quite distingushable chemically from the cannabinoids of C. sativa). Cannabinoid receptors have been located in nerve terminals in the central nervous system, as well as in peripheral tissues, including sympathetic ganglia, dorsal root ganglia, adrenal glands, heart, lung, urinary bladder, reproductive tissues, gastrointestinal tissues and immune cells. Cannabis drugs and extracts exert their biological functions through the receptors. Many of the potential therapeutic uses for cannabis drugs appear to be related to the ways the drugs act on the cannabinoid receptors and how this influences human physiology (Joy et al., 1999; Onaivi et al., 2005).

There are at least two types of receptors, [CB.sub.1] receptors with an apparent neuromodulatory role, and [CB.sub.2] receptors which appear to be immunomodulatory. The two kinds have substantially different distributions, but collectively they are in virtually all organs and body tissues. Within the brain, the distribution of [CB.sub.1] receptors is consistent with the known effects of cannabinoids on cognition, memory and motor function. The distribution of [CB.sub.1] receptors on pain pathways in the brain, spinal cord, and on terminals of peripheral nervous system primary afferent neurons is also consistent with cannabinoid-induced analgesia. In the central nervous system, the [CB.sub.1] receptors are responsible for such effects of marijuana as catalespy, depression of motor activity, analgesia, and feelings of well-being. In peripheral neurons, activation of the [CB.sub.1] receptors suppresses neurotransmitter release to the heart, bladder, intestines and vas deferens. The distribution of [CB.sub.2] receptors primarily on peripheral and central immune cells has been hypothesized to modulate immune effects of THC, through release of cytokines.

Phytocannabinoids from Plants other than Cannabis

The endocannabinoid system described above (or variations of it) is extremely widespread in most groups of organisms, reflecting its importance to life. The molecules produced within a given species that regulate (activate or deactivate) its own endocannabinoid system are in many cases capable of influencing the endocannabinoid system of quite unrelated species. Higher plants do not have endocannabinoid systems. (Oddly, insects also lack functional endocannabinoid systems, as discussed by McPartland et al., 2001; facetiously, insects cannot get high from smoking marijuana). However, a considerable number of chemicals produced by higher plants has been discovered to influence the CB receptors of humans (Gertsch et al., 2010). The term "phytocannabinoids" was once restricted to the cannabinoids of Cannabis, but has been enlarged by Gertsch et al. (2010) as follows: "any plant-derived natural product capable of either directly interacting with cannabinoid receptors or sharing chemical similarity with cannabinoids or both." Very curiously, (3-caryophyllene, a major compound of the essential oil of C. sativa (and many other plants), directly activates the CB2 receptors, and thus C. sativa produces two quite distinctive classes of phytocannabinoids. Nalkyamide in echinacea (Echinacea species) has also been shown to directly stimulate the CB2 receptor system. Anandamide (N-arachidonoylethanolamine), the first-discovered endocannabinoid in humans (Devane et al., 1992), critically affects brain functioning, and THC exerts its effects by substituting for it (Fig. 20). Anandamide's tone (functionality) is affected by N-linoleoylethanolamide and N-oleoylethanolamide, which are found in a number of plants, most interestingly in cacao (Theobroma cacao L.) the source of chocolate, supporting the intuitive belief of many that the euphoric experiences from consuming chocolate and marijuana have some similarities (these chemicals do not directly affect the CB receptors, but exemplify indirect effects). Gertsch et al. (2010) provide other examples of plant constituents that directly or indirectly affect CB receptors. These authors point out that THC is the most potent phytocannabinoid activator of the [CB.sub.1] receptor yet discovered. They also note that dietary contact with phytocannabinoids during mammalian evolution may have played a beneficial role in adapting species for survival (McPartland and Guy (2004) extensively examine adaptive and co-evolutionary hypotheses between humans and plant constituents that affect the human endocannabinoid system.)

The Two Domesticated Kinds of Narcotic Plants Differing in Cannabinoid Balance

Two discemibly different groups of narcotic Cannabis were selected in Asia. The classification of these is explored in the "Classification and Nomenclatural Issues" section, where they are termed Group 3 ("sativa type") and Group 4 ("indica type") (the latter probably arose from the former). Here, some differences are examined. In Asia, strains of both kinds were often used to prepare hashish, but in most Western nations they are almost always employed to prepare marijuana. Table 1 summarizes differences that have been alleged to distinguish the two kinds (no adequate statistically based study of differences has been published).

Group 3 is referred to as the "sativa type" in the narcotics trade. Strains of this group tend to resemble European fiber cultivars, often being almost as tall although usually much more branched, and tending to have relatively narrow leaflets. These strains characteristically have very high THC level in the cannabinoids, and no or small amounts of CBD. As pointed out in the "Classification and Nomenclatural Issues" section, usage of the term sativa to indicate extremely intoxicating (high-THC) plants is quite inconsistent with the tradition of employing the epithet taxonomically for non-intoxicant plants. Group 3 is extremely widespread in the illicit trade of Western nations.

Group 4 is referred to as the "indica type" in the narcotics trade. (The terms indica and sativa are widely employed, in the senses explained in this and the previous paragraph, in innumerable books and websites providing instructions on how to (usually illegally) cultivate marijuana.) Indica strains tend to be short (about a meter in height) and compact under the conditions they are usually grown; they are often also highly branched, with large leaves and wide leaflets. The appearance is reminiscent of a short, conical Christmas tree. Strains of this group characteristically have moderate levels of both THC and CBD in the cannabinoid profile. Like the sativa type, the indica type has historically been employed to produce hashish in southern Asia, particularly in Afghanistan and neighboring countries. Hashish is prepared by pooling collections from many plants, so individual plants may vary in proportions of cannabinoids (i.e., not all plants necessarily have moderate levels of both THC and CBD). Clarke (1998) and McPartland and Guy (2004) interpreted Group 4 as having evolved in the cold, arid regions of Afghanistan and western Turkmenistan, and explained its short height as an adaptation to the relatively short growing season. The early-flowering nature of Goup 4 is also an adapation to a relatively short growing season.

Group 3 strains are very potent, hence more popular, although harder to grow indoors because of their tallness. Hybrids between the two groups have proven to be well adapted to indoor cultivation and are widely cultivated (Clarke & Watson, 2007). Increasingly, strains with alleged percentages of "sativa" and "indica" are being sold. There are varying descriptions in the literature about their contrasting psychological effects (see, for example, Hazekamp and Fischedick (2012) and Smith (2012); also see Table 1). These descriptions generally credit the high-THC sativa type with producing a more euphoric "high," and the lower-THC type with substantial CBD with producing a more attenuated experience, consistent with how CBD in marijuana substantially alters the effects of THC, as explained in the following subsection.

"The Evolution of Shoot Architecture under Domestication" section provided information on the evolution of stem architecture in the two groups of narcotic plants, and the "Evolution of Propagules under Domestication" section provided information on how the achenes of domesticated plants (including these narcotic groups) have been modified by comparison with wild plants. This information is not repeated here.

Medicinal Importance of Combining THC and CBD

Although widely said to be non-psychoactive, it has long been appreciated that CBD has sleep-inducing or sedative properties (Carlini & Cunha, 1981). It is apparent that CBD antagonizes (reduces) and interactively modifies (potentiates) the effects of THC. CBD ameliorates (in a therapeutic sense) the effects of THC, blocking anxiety provoked by THC, reducing psychotic experiences associated with high-THC marijuana, and attenuating memory-impairment effects of THC (Russo & Guy, 2006; Zuardi et al., 2006; Zuardi et al., 2012; Mechoulam, 2012). The combination of THC (a euphoric) and CBD (which reduces the high of THC but seems to prolong the duration) is now appreciated to have medicinal advantages. Reducing the intensity of the THC experience is considered especially beneficial for inexperienced users, who may be subject to panic and other disturbing symptoms on exposure to a high level of THC. Sativex[R] (Fig. 23a and b), a cannabinoid-based analgesic marketed by The United Kingdom firm GW Pharmaceuticals, exploits the advantages of combining equivalent amounts of THC and CBD. This buccal ("oromucosal") spray is applied under the tongue or inside the cheeks (never into the nose).

Herbal Mixtures vs. Pure Chemicals

In the prestigious report Marijuana and medicine: assessing the science base (Joy et al., 1999), the following statement is presented: "Defined substances, such as purified cannabinoid compounds, are preferable to plant products, which are of variable and uncertain composition. Use of defined cannabinoids permits a more precise evaluation of their effects, whether in combination or alone." Modern medicine has been said to prefer single-component "silver bullets" rather than multi-component "herbal shotguns" (Spelman, 2009). However, the issue is not as simple as it may appear.

Western-based medicine has become reliant on single-molecule pharmaceuticals, and indeed even with the resurgence of alternative (especially herbal-based) modalities, there is widespread disrespect (in the West) for traditional plant-based medicines because they are not precisely defined mixtures. However, the perspective that herbal (crude drug) preparations are inherently inferior is short-sighted. Many herbal products in Europe are standardized and have been clinically demonstrated to be efficacious in double-blind placebo-controlled trials.

Defenders of herbal medicine often point out that there may be synergistic (increasing potency or other desirable effects) or mitigative (decreasing toxicity), therapeutic interactions among the constituents of crude drags, and that over time humans have learned by trial and error the circumstances when these crude drags are efficacious (Lewis & Elvin-Lewis, 2003). Of course, research is required to examine the comparative merits of crude drags, extracts and synthetic analogues, and this is particularly true for C. sativa. Crude drags (marijuana, hashish) are currently the main options exercised for medical use of C. sativa, and indeed they are often chosen in preference to extracts and synthetic analogues by patients. It is very well known that extracted cannabinoids produce somewhat different effects from crude marijuana (Fairbaim & Pickens, 1981; Johnson et al., 1984; Pickens, 1981; Ryan et al., 2006; Segelman et al., 1974; Whalley et al., 2004; Wilkinson et al., 2003), and often do not satisfy patients as well as crude drags, and this suggests that interactions of natural constituents are very important therapeutically (McPartland 2001; McPartland & Russo, 2001; Russo & McPartland, 2003).

The non-cannabinoid components in marijuana may also contribute significantly to potential therapeutic effects, and so any consideration of medicinal marijuana and of THC delivery systems needs to take this into consideration. Potentiating interactions of the cannabinoids and various terpenes, as well as the 20 or so flavonoids that are present, have been hypothesized to modify synergistically the psychological and physiological effects of cannabis drags (Clarke, 1998; McPartland, 2001; McPartland & Mediavilla, 2002; Russo, 2011).

A number of psychoactive analogues of THC have been synthesized and tested experimentally (Russo 2003). The following two have been especially marketed commercially. Dronabinol is the synthetically manufactured (-)-trans-isomer of [[DELTA].sup.9]-THC. Marinol[R] is a dronabinol preparation, dissolved in sesame oil, provided as capsules. It is a registered trademark of Unimed Pharmaceuticals, Inc., and is available in North America and some European countries. Nabilone is a synthetic derivative of [[DELTA].sup.9]-THC with a slightly modified molecular structure. It is marketed under the name Cesamet[R], a registered trademark of ICN Canada Ltd., and is available in Canada, in the U.S. (through Valeant Pharmaceuticals International) and some European countries. These synthetic preparations of THC are expensive and are often considered to be less effective than simply smoking preparations of marijuana.

Evolving Technologies for Preparing and Consuming Narcotic Cannabis

Marijuana (Fig. 21a), composed of inflorescences and the smallest leaves of intoxicant varieties, and prepared by forcing herbal material through a screen to break it up, has become the most widely used illegal drag in the world. Hashish (Fig. 21d and e) is a relatively pure preparation of the resinous secretions of intoxicant varieties of the plant. Marijuana is sometimes referred to as "herbal-type" cannabis, in contrast to hashish, a "resin-type" form of cannabis. Hashish oil ("hash oil") is a solvent extract (often of tar-like consistency). Up until the last 2 decades, in the Western world marijuana often included a substantial content of foliage. The bracts of the flowers are much richer in THC, and the market for marijuana has evolved towards the use of the inflorescences (so-called "bud," or much less frequently "cola," Fig. 21b). Indeed, races with female marijuana plants have been selected to produce flowering heads with abundant flowers in tight heads. Female plants are grown in the absence of male plants, so the females are protected against receiving pollen, and do not develop seeds (the expression "sinsemilla," based on Spanish for "without seeds," is used to characterize the product). Marijuana in current illicit markets typically has a THC content of 5 to 10 % (levels as high as 25 % have been reported), while medicinal marijuana currently marketed under license by authorized sources typically contains 10-20 % THC. Hashish in illicit markets typically has a THC content of 5 to 25 % (levels as high as 45 % have been reported), and hashish oil a content of 20-50 % (levels exceeding 60 % are occasionally reported).

"Hashish" as traditionally made in Asia is prepared by a variety of methods (see Clarke (1998) and Hamayun and Shinwari (2004)), but is always a mixture of resinous herbal material collected from the female inflorescences of C. sativa. It is predominantly prepared by filtering cannabis material through very fine fabric screens (such as silk) or sieves, and mechanically agitating the material to collect a resinous or powdery material with a higher concentration of the plant's secretory glands than in conventional marijuana. Additional treatments vary depending on region, but the result is normally a solidified, sticky mass of material, mostly pressed or rolled to form hardened resinous cakes. Hashish in the illicit trade may be prepared in part by the use of solvents, and may therefore contain toxic residues. Hashish oil is prepared by solvent extraction, and given the lack of quality oversight in illegal operations may be particularly dangerous.

An alternative method of preparing hashish in Asia (now largely abandoned because it is so labor-intensive) is to rub the female inflorescences by hand so that the sticky resin glands and secretions stick to the hands, and are scraped off. Similarly in the past, people dressed in leather brushed against the sticky inflorescences until resin accumulated on their garments, subsequently scraping off the resin (Bouquet, 1950). Stickiness of the secretory glands is due to terpene secretions over the outer surface of the glands. In very windy, dry or cold environments, secretions tend to volatilize more readily, decreasing stickiness; by contrast, in hot, still environments (whether outdoors or under intense grow-lights) secretions appear to accumulate more readily, and the gland surfaces can become very sticky. It is unclear whether narcotic land races were selected that were particularly suitable because they tended to secrete resin readily rather than retaining it within the gland heads, but this seems plausible.

New, Western-country technologies have been created to produce preparations rich in the THC-containing resin glands. The Asian tradition of using filters is employed, but the millipore screens now commonly used have much smaller openings (50150 microns in diameter), and the techniques utilized produce a material that is very much richer in presence of secretory glands, very much lower in presence of other herbal material, and is (usually) higher in THC, by comparison with conventional Asian hashish. Clarke (1998) refers to the preparations so produced as "high-tech hash." In the illicit drug trade, the usually powdery preparations first produced (very inappropriate called "pollen;" more aptly termed "resin powder") are often compressed so that they have a superficial similarity to conventional but much cruder Asian hashish. Some technologically sophisticated, commercially available devices for production of high-grade hashish are shown in Fig. 22. Preparations can be produced that consist mostly of resin glands and have over 30 % THC (even over 50 %). These advanced techniques are very wasteful of material (although the low-THC residue can be salvaged for other uses), and so high-tech hashish is sold at premium prices, and consumers employ efficient smoking or vaporization methods. "Dry" technique involves simply agitating material on a motorized flat screen or in a drum-like screen. An example of this kind of apparatus is shown in Fig. 22a. Sometimes the material is frozen just prior to sieving, as the stalked glands become much more easily detached. Ultrasonic vibrators have been employed as an alternative to the use of motor-driven shakers. "Wet technologies" exploit the fact that mature secretory glands are heavier than water (as well as the property of the resin of being basically insoluble in water), while most plant parts are lighter than water. When mixed with water, the glands can thus be substantially separated. Freezing can also be employed to make the secretory glands more separable. Examples of this class of apparatus are shown in Fig. 22b and c.

Safer Drug Delivery Systems

The extremely serious health hazards of smoking tobacco are well known: bronchitis, emphysema, lung cancer, heart disease and numerous other disorders. As a system for delivering the target chemical (nicotine in the case of tobacco), smoking of any herbal is likely to also deliver hundreds of toxins, and this unhealthy consequence is certain when marijuana is smoked. Many of the ingredients common to marijuana and tobacco smoke (including hydrocyanic acid, oxides of nitrogen, acrolein, reactive aldehydes and several known carcinogens) are known to be toxic to respiratory tissue. Accordingly, in the interests of harm reduction, it is preferable to utilize efficient systems that increase the proportion of cannabinoids taken up while decreasing exposure to numerous other volatilized substances. Smoking cannabis preparations with an increased proportion of TFIC is the most common way of achieving this. The widespread criticism that, because cannabis products in the illicit trade have increased in potency (THC content) during the past 20 years (Cascini et al., 2012), they are more dangerous, tends not to be taken seriously by informed pharmacologists. This is not only because higher potency material means less material needs to be smoked, but also because cannabis dosage is titrated by experienced users. Similarly when consuming alcoholic beverages, whether beer, wine, or liqueurs, experienced users tend to self-dose up to a particular level of intoxication, and the different concentrations of alcohol present is of relatively limited importance. (However, King et al. (2005) stated that "how far this parallel hold for cannabis is unknown.")

Regardless of smoking technique, because of incomplete decarboxylation of THCA, loss through exhalation, and destruction by pyrolysis, a maximum of about 30 % of the THC in cannabis preparations is absorbed (Russo, 2007).

Properly prepared hashish contains much higher levels of the cannabinoids than does marijuana (this is often not true in the illegal trade), and therefore a smaller quantity needs to be consumed in comparison to marijuana. Accordingly, less toxins are absorbed in smoking, and at least in this limited sense hashish is safer than marijuana.

Water pipes (devices to draw smoke through water; small contraptions are commonly called bongs, larger ones are hookahs) are widely employed to smoke cannabis in order to filter out toxins created by combustion and reduce pulmonary irritation. Water filters like these do remove gas-phase smoke toxins, such as ammonia, acetaldehyde, benzene, carbon monoxide, hydrogen cyanide, and nitrosamines, but are mostly ineffective against tars (polycyclic hydrocarbons).

A technique now extensively used in the consumption of cannabis drugs is vaporization, i.e., heating to produce steam or vapor without burning. Devices that heat marijuana to 180 to 190[degrees]C vaporize THC without burning plant materials, thus not producing "smoke." Inhaling the resulting steam is a way of reducing (but not eliminating all of) the toxic materials produced during burning. Modern vaporizers have become popular, but do not eliminate polyaromatic hydrocarbons (Russo, 2007)

Medicinal Marijuana Preparations

Medicinal marijuana is currently being dispensed in many jurisdictions. A variety of forms are available, as shown in Fig. 23, including edible preparations. Oral consumption in the form of foods or tinctures is a way of avoiding all lung problems, and during the 19th century oral use was common both for medical and recreational use. However, becoming "high" from oral consumption is notoriously slow and comparatively unreliable. Some degradation of THC by acids in the stomach and gut may occur. Because THC is lipophilic, orally consumed cannabis is absorbed better by the intestinal mucosa if some fat is ingested simultaneously (this is usually accomplished by adding a fatty liquid, such as cream to cannabis tea, or considerable butter when baked in brownies; animal lard and vegetable oils are also used). Smoking produces effects within seconds to minutes, with a maximum after about 30 min, and a duration of 2 or 3 h. The rapid action of smoking is due to THC being transported quickly to the brain. By contrast, eating does not produce effects for 30 min to 2 h, and the effects are relatively prolonged, lasting 5 to 8 h or even longer. (Eating raw cannabis material that has not been heated to decarboxylate the acidic form of THC will produce only a minimal effect.) The slow action of orally ingested THC is due to its being transported from the stomach to the liver where it is converted to 11-hydroxy-THC, a more potent and longer lasting cannabinoid than THC. Smoking and eating modes of metabolizing THC are contrasted in Fig. 24.

Cannabinoids can be absorbed through skin (hence concern has been expressed about the possible presence of THC in hemp oil used in cosmetics), and so patches are sometimes employed. Cannabinoids can also be readily absorbed through mucosal tissues, and vaginal sprays and rectal suppositories are occasionally used as a form of THC absorption. Rectal absorption is lower than oral absorption, but is more constant. Sativex (described above), taken by mouth, represents mucosal application.

Summary of Recent Evolutionary Changes in Narcotic Strains

As detailed above, narcotic forms of Cannabis were initially selected many centuries ago, and during these early times fairly primitive techniques were employed to make intoxicant preparations. Particularly in recent decades, a considerable understanding of the biochemistry and genetic control of cannabinoid metabolism has been achieved, and strains are now being generated rich in particular cannabinoids for potential medicinal applications. Sophisticated techniques for breeding strains have been developed, including the generation of all-female lines. Technologies have been created to collect and concentrate the THC-rich heads of the glandular trichomes, and this development seems to have resulted in the selection of strains in which the THC-rich heads abscise readily. Strains have been selected differing in architecture, cannabinoid profile (geographical biotypes have been found with one or more rare cannabinoids in unusually high presence), terpene profiles (a variety of different essential oil profiles seem to have been selected), concentration and distribution of the secretory glands (very large densities of the glands and larger glands are present on the floral bracts of some strains), and inflorescence color (white and purple are popular in recent times). In response to demand for very high levels of THC, there has been selection for congested female inflorescences (production of numerous, well-formed "buds" being a recent quality criterion). The two basic kinds of narcotic plants (Group 3, characterized by very high THC levels, and Group 4 characterized by moderate amounts of THC supplemented by sedative CBD) have become foundational breeding material for generating by hybridization a wide range of strains.
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Title Annotation:p. 222-259
Author:Small, Ernest
Publication:The Botanical Review
Article Type:Report
Date:Sep 1, 2015
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