Source:Committee on the Health Effects of Marijuana – The Health Effects of Cannabis & Cannabinoids-National Academies Press (2017)
In the United States, cannabis-derived products are consumed for both medical and recreational purposes in a variety of ways. These include smoking or inhaling from cigarettes (joints), pipes (bowls), water pipes (bongs, hookahs), and blunts (cigars filled with cannabis); eating or drinking food products and beverages; or vaporizing the product. These different modes are used to consume different cannabis products, including cannabis “buds” (dried cannabis flowers); cannabis resin (hashish, bubble hash); and cannabis oil (butane honey oil, shatter, wax, crumble). The oil, which may contain up to 75 percent D9-THC—versus 5 to 20 percent in the herb or resin (Raber et al., 2015)—is extracted from plant material using organic solvents, such as ethanol, hexane, butane, or supercritical (or subcritical) CO2, and can be either smoked or vaporized by pressing the extracted oil against the heated surface of an oil rig pipe (dabbing). Cannabinoids can also be absorbed through the skin and mucosal tissues, so topical creams, patches, vaginal sprays, and rectal suppositories are sometimes employed and used as a form of administering D9-THC (Brenneisen et al., 1996). A broad selection of cannabis-derived products are also available in the form of food and snack items, beverages, clothing, and health and beauty aid products.
Potency of Cannabis
In the 1990s and early 2000s, the bulk of cannabis consumed in the United States was grown abroad and illicitly imported. The past decade has seen an influx of high-potency cannabis produced within the United States—for example, “sinsemilla”—which is grown from clones rather than from seeds. Data from the U.S. Drug Enforcement Administration (DEA) seizures record a substantial increase in average potency, from 4 percent in 1995 to roughly 12 percent in 2014, both because high-quality U.S.-grown cannabis has taken market share from Mexican imports and because cannabis from both sources has grown in potency (ElSohly et al., 2016; Kilmer, 2014).
Route of Administration
The route of administration of cannabis can affect the onset, intensity, and duration of the psychotropic effects, the effects on organ systems, and the addictive potential and negative consequences associated with its use (Ehrler et al., 2015). The consumption of cannabis causes a particular combination of relaxation and euphoria, commonly referred to as a “high.” When cannabis is smoked, D9-THC quickly diffuses to the brain, eliciting a perceived high within seconds to minutes. Blood levels of D9-THC reach a maximum after about 30 minutes and then rapidly subside within 1 to 3.5 hours (Fabritius et al., 2013; Huestis et al., 1992). Vaping has an onset, peak, and duration that are similar to those of smoking and produces a similar high (Abrams et al., 2007). “Dabbing,” a term for flash-vaporizing butane hash oil-based concentrates, has been reported to offer a different and stronger intoxicating effect than smoking/vaping (Loflin and Earleywine, 2014). By contrast, eating does not produce effects for 30 minutes to 2 hours, and the perceived high is relatively prolonged, lasting 5 to 8 hours or even longer. The slow action of orally ingested cannabis is due to D9-THC being absorbed by the intestine and transported to the liver (hepatic first pass) where it is converted into 11-OH-THC, an equipotent and longer-lasting metabolite (Huestis et al., 1992). Edibles make it harder to titrate the intoxicating effects due to the delayed and variable onset. Consequently, edibles have been tied to the ingestion of excessive amounts of cannabis under the misperception that the initial dose had not produced the desired effect (Ghosh and Basu, 2015; MacCoun and Mello, 2015). The availability of edibles has also been associated with increased rates of accidental pediatric ingestion of cannabis (Wang et al., 2014).
Trends in Routes of Administration
There are no high-quality nationally representative data on the prevalence of the non-herbal forms of cannabis (e.g., edibles, oils, and other concentrates), but evidence suggests that they are more commonly used by medical cannabis patients in states with recreational or lenient medical cannabis policies (Daniulaityte et al., 2015; Pacula et al., 2016). Forty percent of 12th-grade past-year users reported using cannabis in edible form in medical cannabis states, versus 26 percent in states without medical cannabis laws (NIDA, 2014). In Washington State, an online survey from 2013 found that, among daily and near-daily cannabis users, 27.5 percent had used edibles, 22.8 percent had used hash resin, and 20.4 percent had “dabbed” in the past week (Kilmer et al., 2013). Data from recreational cannabis sales in Washington and Colorado provide a glimpse of trends that are specific to markets that have legalized cannabis. In Washington State, herbal cannabis remains dominant, having accounted for two-thirds of all sales revenues in June 2016, but it is losing market share as “cannabis extracts for inhalation” become more popular, at 21 percent in June 2016 as compared with 12 percent 1 year prior. The sales of liquid and solid edibles (9 percent) combined account for most of the remaining sales.4 Non-herbal varieties are even more popular on Colorado’s recreational market, where herbal cannabis accounts for a narrow majority (56 percent) and sales of solid concentrates (24 percent) and edibles (13 percent) are on the rise (Castle, 2016). Partly to provide a guide for the responsible use of non-herbal varieties of cannabis, states that have legalized the recreational cannabis have defined a standard “dose” of THC. Washington State and Colorado have set the standard “dose” of THC as 10 mg, while Oregon chose a lower limit of 5 mg. For perspective, the typical joint size in the United States is 0.66 g (Mariani et al., 2011) and the average potency is 8 percent THC (Fabritius et al., 2013), resulting in an average dose of 8.25 mg THC per joint; higher THC levels ranging from 15–20 percent or higher would yield a THC dose between 9.9–13.2 mg. Occasional users report feeling “high” after consuming only 2–3 mg of THC (Hall and Pacula, 2010); however, users who have developed tolerance to the effects of THC via frequent use may prefer much larger quantities.
CLINICAL FEATURES OF CANNABIS INTOXICATION
During acute cannabis intoxication, the user’s sociability and sensitivity to certain stimuli (e.g., colors, music) may be enhanced, the perception of time is altered, and the appetite for sweet and fatty foods is heightened. Some users report feeling relaxed or experiencing a pleasurable “rush” or “buzz” after smoking cannabis (Agrawal et al., 2014). These subjective effects are often associated with decreased short-term memory, dry mouth, and impaired perception and motor skills. When very high blood levels of D9-THC are attained, the person may experience panic attacks, paranoid thoughts, and hallucinations (Li et al., 2014). Furthermore, as legalized medical and recreational cannabis availability increase nationwide, the impairment of driving abilities during acute intoxication has become a public safety issue. In addition to D9-THC dosage, two main factors influence the intensity and duration of acute intoxication: individual differences in the rate of absorption and metabolism of D9-THC, and the loss of sensitivity to its pharmacological actions. Prolonged CB1 receptor occupation as a consequence of the sustained use of cannabis can trigger a process of desensitization, rendering subjects tolerant to the central and peripheral effects of D9-THC and other cannabinoid agonists (Gonzalez et al., 2005). Animals exposed repeatedly to D9-THC display decreased CB1 receptor levels as well as impaired coupling between CB1 and its transducing G-proteins (Gonzalez et al., 2005). Similarly, in humans, imaging studies have shown that chronic cannabis use leads to a down-regulation of CB1 receptors in the cortical regions of the brain and that this effect can be reversed by abstinence (Hirvonen et al., 2012).
The U.S. Food and Drug Administration (FDA) has licensed three drugs based on cannabinoids (see Table 2-2). Dronabinol, the generic name for synthetic D9-THC, is marketed under the trade name of Marinol® and is clinically indicated to counteract the nausea and vomiting associated with chemotherapy and to stimulate appetite in AIDS patients affected by wasting syndrome. A synthetic analog of D9-THC, nabilone (Cesamet®), is prescribed for similar indications. Both dronabinol and nabilone are given orally and have a slow onset of action. In July 2016 the FDA approved Syndros®, a liquid formulation of dronabinol, for the treatment of patients experiencing chemotherapy-induced nausea and vomiting who have not responded to conventional antiemetic therapies. The agent is also indicated for treating anorexia associated with weight loss in patients with AIDS. Two additional cannabinoid-based medications have been examined by the FDA. Nabiximols (Sativex®) is an ethanol cannabis extract composed of D9-THC and CBD in a one-to-one ratio. Nabiximols is administered as an oromucosal spray and is indicated in the symptomatic relief of multiple sclerosis and as an adjunctive analgesic treatment in cancer patients (Pertwee, 2012). As of September 2016, nabiximols has been launched in 15 countries, including Canada, Germany, Italy, Spain, the United Kingdom, and has been approved in a further 12, but not in the United States.5 In response to the urgent need expressed by parents of children with intractable epilepsy, in 2013 the FDA allowed investigational new drug studies of Epidiolex®, a concentrated CBD oil (>98 percent CBD), also developed by GW Pharmaceuticals, as an anti-seizure medication for Dravet and Lennox-Gastaut syndromes.
SYNTHETIC CANNABINOIDS AS RECREATIONAL DRUGS
In addition to nabilone, many other synthetic cannabinoids agonists have been described and widely tested on experimental animals to investigate the consequences of cannabinoid receptor activation6 (e.g., CP-55940, WIN-55212-2, JWH-018) (Iversen, 2000; Pertwee, 2012). The therapeutic application of these highly potent molecules is limited by their CB1-mediated psychotropic side effects, which presumably provide the rationale for the illicit use of some of them as an alternative to cannabis (Wells and Ott, 2011). Preclinical and clinical data in support of this claim remain very limited, however. Internet-marketed products such as Spice, K2, and Eclipse are a blend of various types of plant material (typically herbs and spices) that have been sprayed with one of these synthetic cannabinoids (as well as other non-cannabinoid psychoactive drugs). Since 2009 more than 140 different synthetic cannabinoids have been identified in herbal mixtures consumed as recreational drugs. The synthetic cannabinoids used in “herbal mixtures” are chemically heterogeneous, most of them being aminoalkylindole derivatives such as naphthoylindoles (e.g., JWH-018 and JWH-210), cyclopropylindoles (e.g., UR-144, XLR-11), or quinoline esters (e.g., PB-22). They seem to appeal especially to young cannabis and polydrug users because they are relatively inexpensive, easily available through the Internet, and difficult to identify with standard immunoassay drug screenings. In contrast to D9-THC, which is a partial agonist of the CB1 receptor, many of the synthetic cannabinoids bind to CB1 receptors with high affinity and efficacy, which may also be associated with higher potential of toxicity (Hermanns-Clausen et al., 2016). According to the National Institute on Drug Abuse (NIDA, 2012, p. 2), people using these various blends have been admitted to Poison Control Centers reporting “rapid heart rate, vomiting, agitation, confusion, and hallucinations.” Synthetic cannabinoids can also raise blood pressure and cause a reduced blood supply to the heart (myocardial ischemia), and in a few cases they have been associated with heart attacks. Regular users may experience withdrawal and symptoms of dependence (Tait et al., 2016).
CANNABIS CONTAMINANTS AND ADULTERANTS
The large economic potential and illicit aspect of cannabis has given rise to numerous potentially hazardous natural contaminants or artificial adulterants being reported in crude cannabis and cannabis preparations. Most frequent natural contaminants consist of degradation products, microbial contamination (e.g., fungi, bacteria), and heavy metals. These contaminants are usually introduced during cultivation and storage (McLaren et al., 2008). Growth enhancers and pest control chemicals are the most common risks to both the producer and the consumer. Cannabis can also be contaminated for marketing purposes. This usually entails adding substances (e.g., tiny glass beads, lead) to increase the weight of the cannabis product (Busse et al., 2008; Randerson, 2007) or adding psychotropic substances (e.g., tobacco, calamus) and cholinergic compounds to either enhance the efficacy of low-quality cannabis or to alleviate its side effects (McPartland et al., 2008). Additionally, some extraction and inhalation methods used for certain dosing formulations (tinctures, butane hash oil, “dabs”) can result in substantial pesticide and solvent contamination (Thomas and Pollard, 2016).