Background
Representative biosynthetic pathways in cannabis to produce THCA and CBDA followed by conversion to THC and CBD by storage and heat. The THC and CBD are each metabolized in vivo to many different cannabinoids
Although this chapter is not intended to fully present the synthesis and degradation of THC and CBD, the chemistry of the plant and the cannabinoids is summarized to assist in the understanding of the methods of preparation and use of Cannabis and the extracted substances. Marijuana and cannabis are used interchangeably in this chapter. In contrast to claims of many advocates of legalization that research on marijuana has been greatly restricted, the volume and breadth of scientific literature are so vast that attempts to summarize must only target limited and specific topics. As a result, this writing is to inform the reader as to the reasons for the methods of preparation and the manner of use of both THC and CBD by examining the characteristics of the plant and the chemical behavior of the two phytocannabinoids of primary interest. Cannabis product chemotypes are described (e.g., THC-dominant, CBD-dominant, balanced, or “hybrid” with relatively equal concentrations of THC and CBD), along with product formulations (e.g., edibles, concentrates) and methods of administration (e.g., smoked, vaporized, ingested orally).
The U.S. Drug Enforcement Administration (DEA) includes marijuana and THC in Schedule I of the Controlled Substances Act (CSA) and denied a petition to consider rescheduling marijuana in 2016 [4]. The decision was based on a five-element test of current criteria to establish medical use of a substance and found that marijuana did not meet the elements needed. The Ninth Circuit Court has upheld the action taken by the DEA [5]. Effective January 13, 2017, the DEA created a new CSA code number (7350) for marijuana extracts [6]. The Agricultural Improvement Act of 2018 (Farm Bill) removed hemp from the controlled substances and removed “…tetrahydrocannabinols in hemp (as defined under section 297A of the Agricultural Marketing Act of 1946)” from Schedule I of the CSA. Hemp is defined as cannabis containing less than 0.3% THC by dry weight measured following decarboxylation of the THCA [7].
Past year use of marijuana among people aged 12 or older, by age group: Percentages 2002–2018. In 2018, 12.5% (3.1 million) of adolescents aged 12–17, 1 in 3 young adults aged 18–25 (34.8%), and 13.3% of adults aged 26 or older were current users of marijuana. (Ref: Figure 12. Available from: https://www.samhsa.gov/data/report/2018-nsduh-annual-national-report.) + mark shows difference between this estimate and the 2018 estimate is statistically significant at the 0.05 level
Use of marijuana in the last 30 days among individuals 12 years and older in the 10 states with the highest and 10 states with the lowest prevalence of use in 2016–17
Top 10 | % | Low 10 | % |
|---|---|---|---|
Oregon Vermont Wash. DC Colorado Alaska Maine Rhode Island Washington Massachusetts Montana | 19.93 18.64 17.17 16.43 15.81 15.81 15.75 15.30 13.38 13.01 | Virginia Oklahoma Georgia South Carolina Iowa Kansas North Dakota Alabama Utah Texas | 6.96 6.90 6.74 6.66 6.65 6.62 6.44 6.37 6.25 5.98 |
CBD was first obtained in a pure form in 1940 [10]. THC was subsequently identified by Merchoulam in 1964 and has been investigated thoroughly over many years [11]. Marijuana and industrial hemp are different varieties of the same plant species C. sativa. Marijuana typically contains greater than 3% THC on a dry-weight basis, while industrial hemp is being defined as cannabis having a THC concentration less than 0.3% THC [12]; however, the two varieties are indistinguishable by appearance. The industrial hemp variety results from the absence or limited activity of THCA-synthase, the enzyme in the plant responsible for production of THCA [13]. DeMeijer et al. [14], in a study of 97 cannabis strains, concluded there was no way to distinguish between marijuana and hemp varieties without chemical analysis [15]. More recently, the varieties of cannabis may be differentiated by gene analysis of THCA-synthase [16].
The growing plant releases a volatile substance with a skunk-like odor that may emanate for hundreds of yards from large commercial grow areas. This odor is in contrast to the more pleasing aroma of the plant in flowering stage. Many growers now spray odor masking agents into the air as the air is exhausted from the grow house. The end result is that anyone breathing the exhausted air is inhaling the volatiles produced by the plant as well as the masking agent; the impact of chronic exposure to the exhausted air on persons with respiratory illness is not known and seems to not be a concern to policy makers. Cannabis contains many cannabinoids and terpenes such as limonene, myrcene, α-pinene, linalool, and β-caryophyllene. Of the many volatiles identified, myrcene appears to predominate [17]. The volatile oils released by fresh and air-dried buds have been evaluated as a means to identify the source of confiscated marijuana, however with limited success. Neither the precursors nor THC and CBD are volatile and so are not released to the atmosphere during the growing phase or in the aroma of the flowering stage.
Trichomes are epidural appendages covering the leaves of cannabis. This photo shows two types of trichomes – hair like and glandular with a resin head. Secretory cells at the base of the resin head of the glandular trichomes secrete the phytocannabinoids. The resin head is attached to the leaf by a stalk. Cannabis can be identified by the types of trichomes present and the attachment to the plant [18]. (Photo used by extended license #143447216 from Adobe Stock)
THC
Initial changes to acceptance of marijuana included medicalization (marijuana recommended by a physician for a medical condition) followed by legalization (laws or policies which make the possession and use of marijuana legal under state law). In states with full legalization, the result has been full commercialization of all forms of marijuana with little control over the products or use of the THC. For example, the Colorado Code of Regulations (CCR) Medical Marijuana Rules, 1 CCR 212-1 establishes the regulatory framework for medical marijuana and states “Medical Marijuana-Infused Product” means a product infused with Medical Marijuana that is intended for use or consumption other than by smoking, including but not limited to edible products, ointments, and tinctures. Such products shall not be considered a food or drug for purposes of the “Colorado Food and Drug Act” [24]. Thus, a marijuana extract that is widely advertised and distributed as a “medicine” and is frequently included as an infusion in a food product is exempt from Colorado food and drug rules.
The high THC content achieved in the plant has resulted in an ease of preparation of extracts containing THC in highly concentrated forms. The THCA and CBDA are lipophilic, and extracts of plant material can be prepared using many lipophilic type solvents, e.g., critical point carbon dioxide, butane, or various alcohols. Butane was favored initially but has been widely replaced as extraction processes performed without appropriate knowledge, and equipment may produce an explosive air:solvent mixture as the butane flashes off the extracted phytocannabinoids. Many house fires and explosions resulted from the evaporating butane being ignited by an electrical spark. The extracted material when dry may appear like an amber glass and is called shatter. If water or other materials are included either intentionally or accidently, or if THCA precipitates, the material may be waxy or butter-like. The THC content is high in all preparations; however, the appearance of the various preparations is quite different. An extract prepared in hemp, coconut, or other oil may be called 710 (reversed OIL). The extractions are not specific to THC and CBD, and as a result the extracts may contain both THC and CBD and a variety of cannabinoids and other substances such as terpenes, heavy metals, pesticides, and plant oils. Contamination is a concern and includes fungi, molds, heavy metals, growth promoters, and substances added for marketing [25]. If leaf and bud material is allowed to dry, the resinous parts may detach and may be collected as a concentrated THC material, known as kief, to be added back to leaves for smoking or other uses. Hashish (Hash) is a cannabis product composed of compressed or partially purified preparations of resin. Sinsemilla is the flower from a female plant that has not been pollinated, and increases in THC concentration of the flower are responsible for much of the increase in THC potency measured in marijuana.
Methods of Use
Oral ingestion of raw plant material: Ingestion of unheated plant material produces little effect since very little active THC is available and the absorption of any available THC is subject to first-pass metabolism [26].
Smoking: Traditional use of marijuana plant is to smoke joints, blunts, spliffs, or pipes. The joints and blunts contain only marijuana and vary by the paper used and the rolling procedures. The spliffs are a mixture of marijuana and tobacco and blend the effects on the user of the two substances. Countries other than the U.S. may describe preparations in different terms. Various types of pipes are used where the marijuana is placed in the bowl and a flame applied followed by inhalation of combustion products. Smoking produces active drug that goes directly to the lungs and by-passes first-pass metabolism. The user inhales the many combustion products in addition to the THC. A significant percentage of the marijuana is lost by pyrolysis and by side stream smoke. A study of marijuana smoke testing cytotoxicity, mutagenicity, and ability to induce chromosomal damage found that marijuana smoke is more cytotoxic and mutagenic than the corresponding method of smoking tobacco [27]. California completed a comprehensive review in 2009 and concluded there is evidence for the carcinogenicity of marijuana smoke [28].
Vaping: Vaping is the process of converting a THC-containing material to vapor and activating the THC or CBD without the combustion process. Many procedures are used for vaping but most provide a temperature of 360–375°F. Vape pens are now available with adjustable temperatures so the same pen can be used for a variety of preparations of THC (wax, budder, oil) or other drugs. Without full combustion, the vape pens produce limited smoke or odor.
Dabbing: A small piece or portion of extracted THC material is a “dab.” Figure 1.5 shows a “rig” used for dabbing – a recent method of ingestion of highly concentrated THC [29]. The short cylindrical glass cup to the right is called the “nail.” The nail is heated with a torch for 30 seconds or so and the “dab” of THC (wax, shatter, budder, etc.) is added while the nail is hot. The small glass cap is then placed on the top of the nail and the dabber can inhale the vapor through the mouthpiece at the upper left. The user must adjust time, temperature, and air flow so that the dab produces a grayish vapor to be inhaled but does not destroy all the THC in the dab. Dabbing uses a product of up to 80% THC and gives an immediate hit to the user. The rigs come in many sizes and designs and may be used for consuming flower product, as well.
Sublingual (tinctures and oils): This method requires that the THCA be decarboxylated to THC by heat prior to placing in an oil or tincture (alcohol base). The desired dose of THC or CBD is placed under the tongue and held for a time until the material is absorbed.
Edibles (oral): Edible products containing active THC have increased in popularity. The products available vary widely from gummy candies, truffles, and the more traditional cookies, brownies, and sauces (Fig. 1.6). The edibles are generally baked or cooked to activate the drugs. The consumption of edibles produces a delayed effect, and the phytocannabinoids are subject to first-pass metabolism in the liver. The difficulty with edibles is that the delayed effect makes titration of the dose very difficult and easily produces overdose conditions.
Sidestream smoke: The combustion products emanating from smoked marijuana that are not inhaled by the user contain THC and CBD and may be inhaled by persons in the vicinity of the user. Sidestream marijuana smoke has been found to contain polycyclic aromatic hydrocarbons at a higher concentration than found in the mainstream smoke [30].
Rectal: Use of suppositories or insertion of extracts of liquid extracts reduces first-pass metabolism and essentially doubles bioavailability over oral ingestion [31].
Secondhand smoke: Secondhand smoke is exhaled following use of combusted or vaporized marijuana and contains THC that is not absorbed by the inhalation process. Cone et al. [32] have thoroughly investigated the inhalation of secondhand smoke, although the THC concentrations in materials smoked in the studies were not as high as those of today’s marijuana.
Passive or unknowing exposure: Passive inhalation may occur if a person is in the vicinity of a smoker and inhaling secondhand or sidestream smoke. Unknowing inhalation is relatively rare because most adults are aware of the odor of smoked marijuana. Passive inhalation is more significant in the case of children in a household where smoking occurs. Unknowing ingestion of marijuana may occur by adults, children, or pets when an edible product containing marijuana is consumed without knowledge of the contents. A Massachusetts poison control center recently reported the more than doubling of cannabis-related calls following the implementation of medical marijuana [33]. Of interest is that the increase in calls was not in young children but in the 15–19 year age group, indicating that additional efforts must be made by adults, caregivers, and others to prevent access to marijuana by teens.
A water pipe rig used for dabbing and identified as a “dab rig” or oil rig and designed specifically for the use of waxes, oils, honey, budder, or shatter (dabs). The user must learn to adjust THC material, times, temperature, and air flow to achieve their desired effect. Dabbing does allow titration of the dose although the THC concentration in the materials used is very high and may approach 80% THC. (Photo used by extended license #142300664 from Adobe Stock)
Edible products containing marijuana come in many forms. Representative examples are shown and include cookies, truffles, gummy drops, and brownies. In addition are body creams and lotions
Metabolism
The absorption, metabolism, and pharmacokinetic profile of the THC vary with route of administration and the formulation; the time course of drug effects and metabolism for THC is quite different than for sublingual and edibles. Smoked or dabbed THC has a more immediate effect than THC consumed as an edible.
As shown in Fig. 1.1, the active THC is metabolized to the primary inactive metabolite delta-9-tetrahydrocannabinol-9-carboxylic acid (THC-COOH) and to a psychoactive substance 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC) and other metabolites, as well. The THC-COOH is more polar than the THC and can be excreted in the urine, although the excreted THC-COOH makes up a relatively small percentage of the total dose of THC administered. Approximately one third of the smoked THC dose is eliminated in the feces [34]. The presence of THC-COOH in the urine cannot be used to show impairment, but can only be used to demonstrate exposure of the individual to THC.
Synthetic Cannabinoids and Cannabimimetics
There are two classes of synthetic cannabinoids. One class includes substances such as dronabinol and nabilone that are created by chemical methods and approved for use as pharmaceuticals; both have been commercially available since 1985. Dronabinol is structurally identical to THC; nabilone is related to the THC structure and is more efficacious than dronabinol. Dronabinol is used to treat anorexia (as in AIDS conditions) and both dronabinol and nabilone are used to treat severe nausea and vomiting caused by chemotherapy, usually after traditional medications have been tried without success. The second class of the synthetic cannabinoids (cannabimimetics) are being used as alternatives to marijuana and are marketed as “incense” or similar product with no list of contents or active components. The packages are often marked as “not for human consumption.” These materials are advertised as legal and are thought to achieve the effects of THC but are of concern due to their potential toxicity. The origin of this second class of cannabinoids began with pharmaceutical research to find substances with medical benefit, such as analgesia, but without the psychotropic effects of THC [35]. Auwarter et al. [36] identified a series of cannabimimetics in various “Spice” products and did not find THC in the products. The synthetic cannabimimetics are included in Schedule I of the CSA.
Hemp
Traditionally hemp has been grown for fiber and seeds; Canada, China, and North Korea are the world leaders in hemp production. The seeds may be pressed for oil that is polyunsaturated and used in cooking or for food for humans and animals or processed into cosmetics. The seed cake is protein rich and included in animal feed and fiber is used for paper or animal bedding. Recent technological advances use the fiber for production of plastics, 3D printer filaments, oil absorbent materials, and construction concrete. Hemp has become a crop of increasing interest, and Colorado is currently the leading producer of hemp in the U.S. The primary purpose of hemp in the U.S. is the production of CBD and the price is dependent on the concentration and varies from around $2.50/g to $10.00/g for CBD in flower materials [37].
Extracts of hemp will generally contain both CBD and THC. For example, an extract of 1000 pounds of hemp containing 0.3% THC (as allowed) and 6.0% CBD will contain 3 pounds of THC, 60 pounds of CBD, other phytocannabinoids, and oils and waxes from the plant. In this example, the THC represents about a 5% contamination of the CBD since these organic type molecules are extracted in an essentially similar manner. The significant point is that an extract of hemp that is not purified will certainly contain some concentration of THC. The THC may be removed; however, of interest in Colorado is that no regulation appears to control the THC that is removed from the hemp in the production of CBD. Colorado is in the process of developing a hemp advancement and management plan to be published in 2020 [38].
Hemp seeds, in and of themselves, do not contain THC or CBD [13, 18]; however, the processing often contaminates the seeds and produces great variability in the concentration of THC in the hemp seed oil. Yang et al. [39] found wide variation in the THC content of hemp seed oils, with a high of 125 ug/g hemp seed. This concentration raises the possibility of psychotropic effects of hemp seed oil and points out the requirement for appropriate analytical methods to be used before releasing hemp seed oil to the consumer. Other reports have reported on the potential presence of THC in hemp seed oil and the impact on consumers [40–43].
CBD
CBD is being widely advertised as a medication and a dietary supplement, although currently available CBD products do not meet normal expectations for a pharmaceutical [44]. The cannabis industry, having successfully legalized THC in many jurisdictions, has pivoted to the promotion of hemp and marketing of CBD. Many of the industry claims concerning quality, concentrations, and benefits of CBD are misleading or unsubstantiated [45]. Although the 2018 Farm Bill removed hemp and extracts of hemp from Schedule I of the CSA [46], the legislation specifically preserved the U.S. Food and Drug Administration’s (FDA) responsibility over such products. The FDA has determined that CBD is to be treated as a drug [47] and has committed to assessing the science behind the use of CBD [48]. Also, the FDA has determined CBD does not meet the definition of a supplement for nutritional purposes [49]. On May 31, 2019, the FDA held a public hearing on CBD to begin the regulatory process and has published the full transcript of the hearings [50].
Following conversion of CBDA to CBD by heat, the CBD may be ingested in a variety of ways. The CBD is prepared as oils, tinctures, or edibles. The oils may be purchased as the full extract of the whole plant containing whatever substances were included in that hemp and extract by the particular company. The advantage as advertised by the industry is the potential entourage effect of interactions of the full spectrum of phytocannabinoids and terpenes substances extracted and included [51]. In addition, the industry offers “purified” and “THC-free” products. A quick internet search will find CBD products such as gummy candies, tinctures, protein bars, vape oils, dried fruit, and pet products [52]. The CBD, like THC, is metabolized and excreted in a variety of ways. Much of administered CBD is excreted unchanged or as a glucuronide. The metabolites produced by phase 1 metabolism are predominantly hydroxylated 7-COOH derivatives that are excreted intact or as glucuronides [2]. A recent study by Arkell et al. found that CBD content in vaporized cannabis does not prevent THC-induced impairment in driving [53].
Phytocannabinoids such as CBD are being appropriately investigated to identify and document actual benefits as medicinals. The benefit may come from the full extract of phytocannabinoids or just CBD. One example is Epidiolex® which was approved in 2018 by the FDA [54] as a pharmaceutical and is an essentially pure CBD oral formulation that is produced by GW Pharmaceuticals in the U.K. and marketed by their U.S. operating subsidiary, Greenwich Biosciences Inc. This CBD formulation was approved for the treatment of two rare, severe forms of epilepsy (Lennox-Gastaut Syndrome and Dravet Syndrome) [55]. As is appropriate for a medicine, the Epidiolex® is of known purity and concentration and the efficacy has been evaluated by studies presented to and approved by the FDA. For a CBD pharmaceutical to be included in Schedule V of the CSA, the pharmaceutical must contain no more than 0.1% THC and must be approved by the FDA as a drug [56]. The prescribing information warns of hepatocellular damage, suicidal ideation, and sedation, along with other concerns. These patients will be under the care of a physician that will monitor and determine efficacy of the treatment. Epidiolex® is also being evaluated as treatment for certain other medical diagnoses.
The hemp industry is working to have CBD approved as an additive to food or as a supplement, as well as FDA-approved medications. The use of CBD as a food additive is of concern. Although FDA has viewed CBD as a drug based on the initial investigations as a pharmaceutical, the FDA does have authority to provide an exemption to the drug status and allows the substance to be marketed as a food or supplement that is widely used. A significant concern is that many CBD products are widely advertised using unsubstantiated claims, improper labeling, and CBD concentration that are not correct. Two warning letters from FDA are informative as to types of claims that were made initially by companies producing CBD. In one case on October 31, 2017, the FDA, Division of Pharmaceutical Quality Operations IV, issued a warning letter to Stanley Brothers Social Enterprises to correct the claims that the products are drugs and intended to diagnose, cure, mitigate, treat, or prevent disease [57]. In addition to being new drugs, the products were misbranded. The second letter was issued to That’s Natural, also a Colorado company, on the same date, concerning misbranding of CBD [58]. The FDA has issued similar letters concerning misbranding of CBD to other CBD producers.
Following the Letters of Warning, Colorado passed House Bill 18-1295 into law. This bill is significant because it is intended to establish, with no scientific analysis, that products are not (cannot be) adulterated or misbranded if they contain industrial hemp. HB 18-1295 defines “industrial hemp product” as a finished product containing industrial hemp that is a cosmetic, food, food additive, or herb and is for human use or consumption and contains … any part of the hemp plant (including extracts) but the finished product contains THC at a concentration less than 0.3% [59]. Of great significance is that the 0.3% limitation removes any restriction on a dose of THC per serving of product – that dose depends on the quantity of finished product consumed. For example, if a baked product weighing 1 ounce (28.3 g) contains the allowed concentration of 0.3% THC, the actual total dose of THC in the baked item is 85 mg. Having been baked, the THC would be in active form and is many times the dose that may cause impairment and is a danger to an unsuspecting consumer, since the product is sold as containing hemp or CBD and not THC. This law protecting edible hemp products is of particular significance in light of the prescribing information provided for Epidiolex® (essentially pure CBD) which warns of potential liver damage, developmental toxicity, and other adverse effects that should be monitored by a physician [55].
Conversion to THC
In recent years, the potential conversion of CBD to THC by gastric fluid has been investigated. That conversion has long been known to occur in acidic conditions in vitro [60, 61]; however, the in vivo conversion is a matter of interest. A study of metabolites of CBD in a single patient receiving a daily oral 600 mg dose found THC in the urine but did not identify the actual source [62]. The authors did not find the metabolite THC-COOH which argues against the in vivo conversion of CBD to THC. Additional study found delta-8-THC and delta-9-THC at 1.97 and 0.69% of extracted cannabinoids, respectively [63]. Watanabe et al. reported the conversion of CBD to delta-9-THC by artificial gastric fluid and that the metabolites demonstrated pharmacological effects in mice [64]. A similar conversion was also reported to occur over a 3-hour incubation in artificial gastric fluid, raising concerns about potential physiological responses to the products of degradation [65]. Grotenhermen et al. discount the conversion and the THC like effects of CBD being of clinical significance in humans [66]. Various studies have additional information on the conversion [67] and question the conversion of oral CBD to THC in humans [68].
CBD as a Quality Medicine
The view of CBD as a medicine that is demonstrated by the claims of the companies that are producing and selling CBD on a national scale is stunning. This acceptance of the wildly inflated claims of benefits, seemingly by a large percentage of the general population of this country, leads to the need for an assessment of the actual benefits and adverse consequences. The information for physicians prescribing Epidiolex® lists a number of potential adverse consequences, such as somnolence and sedation, suicidal ideation, hepatocellular injury, and drug-drug interactions [55]. In addition, a study of a CBD extract shows clear signs of hepatotoxicity [69].
A basic literature search of PUBMED displays numerous articles published in the last 25 years that propose a potential benefit of CBD as a medication for many purposes. That literature is too extensive to summarize here; however, a recent publication by S. Pisanti et al. provides extensive information and references pertaining to CBD [70]. A significant concern is the proposal to use CBD as medication to treat the opioid epidemic [71]. Colorado statistics show a concomitant increase in the opioid epidemic and the use of cannabinoids, but no decline in opioid use with the legalization of marijuana.
A 2017 study looking at market share of products by a cannabis investment group finds CBD is being used to replace traditional pharmaceuticals. The top conditions being treated included anxiety (67%), insomnia (60%), joint pain and inflammation (52%), and depression (43%). Respondents preferred CBD derived from cannabis to CBD derived from industrial hemp and only 9% of respondents indicated using hemp-derived CBD exclusively [72]. The preference for CBD from cannabis is significant because, without purification, the CBD extracted from cannabis will, most likely, contain a much higher percentage of THC than does CBD from hemp.
Discussion
Legalization of marijuana removes related criminal penalties and offers a new source of revenue with control expected from local and state government and collection of federal business and payroll taxes. The result has been the full commercialization of cannabis. Unfortunately, the legalization and liberalization of laws pertaining to marijuana have created a regulatory abyss that legislators appear unable or unwilling to fix, since control of production is very difficult. A second factor that is difficult to assess is the cost:benefit ratio of legalization. A state may tout the revenue; however, the costs to the state and to smaller jurisdictions within the state are not apparent and, in most cases, appear to not be considered. Only one report is available that completed any cost benefit analysis of legalization [73]. The report estimated costs as 4.5 times the benefits. The report may be subject to criticism; however, no other entity has attempted to assess the cost:benefit ratio. In any case, the real possibility is that the statewide costs of implementation and enforcement exceed the revenue. Every county, city, and town must establish marijuana rules and regulations and must cover the many social costs associated with legalization. These include law enforcement, social welfare, and medical care, in addition to the adverse effects on many individuals. The impact on generalized personal welfare and health cannot be assessed. In addition, the tax rates are fixed while costs of marijuana to consumers are not. As cannabinoid prices drop due to competition, sales volume must increase to maintain or increase state revenues. Marijuana, due to the ease of production, is quite different than tobacco and alcohol and is not easy to control and tax, especially when rules allow for growth by individuals at essentially any location. Cannabis growth by individuals and care givers is not taxed. In addition, the lax attitude toward marijuana has created a sanctuary for cartels and other illegal operations.
Medical care providers that lack understanding of how cannabinoids may impact a patient or medical treatment.
Insufficient oversight by knowledgeable medical care providers of patients with critical illness that are using cannabinoids based on a recommendation.
Variable individual responses to the therapeutic use of cannabinoids.
Cannabis dispensary staff providing recommendations and assessment of medical conditions with no experience, training, or certification [76].
Variability of quality and concentrations of the desired cannabinoid in non-pharmaceutical products.
Improper labeling of products and contamination of the phytocannabinoid products by undesired or toxic constituents [77].
The quality and contents of both recreational and medical cannabis products are of concern. The intentional adulteration to enhance the psychotropic effects of THC with drugs such as opioids is recognized. Perhaps unrecognized are the problems of quality from contaminants in soil used to grow the cannabis, the improper use of pesticides, concentrations of phytocannabinoids that are either low or high and not consistent, the presence of many extracted natural products in the THC or CBD, and the presence of significant amounts of THC in CBD products. The involvement of many growers that have no knowledge of quality control in production of pharmaceuticals leads one to question how the plants are actually grown and how the products are treated during processing and marketing. Cannabis concentrates are of particular concern due to the potential concentrations of contaminants, along with the cannabinoid. A study of 57 concentrates from California found that over 80% were contaminated in some way including residual solvent and pesticides and had a very wide range in THC concentrations [78].
We have come to expect medications that are pure, of known and consistent efficacy, with a known mechanism, and from a manufacturer that is liable for the quality of the medication. Marijuana preparations are not consistent and vary from strain to strain and grower to grower or basement to basement. In addition, the effect and metabolism vary with the individual and the method of use [79].
All physicians must be aware of the potential impact of both THC and CBD on prescribed medications. The efficacy of THC or CBD for the many proposed therapeutic uses needs to be proven with legitimate, scientific, controlled studies. THC and CBD may place consumers, with no knowledge of the contents of the products, at risk. THC and CBD may also interact with or interfere in the metabolism of other medications [80] and may interfere with perioperative care [81]. In a recent address at the Institute of Cannabis Research, Dr. Di Marzo described research methods to assess the benefits of the phytocannabinoids as pharmaceuticals [82]. Pharmaceutical preparations of CBD may ultimately be useful; however, current motivation appears to be the financial reward to the CBD industry rather than the health and well-being of the consumer. The analysis of THC and CBD preparations for contaminants in the products being marketed to unsuspecting consumers is of great importance; however, that analysis is required to guarantee purity, safety, and the lack of psychotropic or intoxicant influences on other medications and human health.
Summary
THC has been widely investigated while the therapeutic potential of CBD has only come to the attention of the scientific community in more recent years. A quick search of PUBMED identified over 30,000 articles containing the word marijuana and 2300 articles containing the word cannabidiol that were published over the past decades [83]. The conclusions of the recent National Academy of Sciences review that there are few, if any, conditions that uniquely benefit from administration of THC indicate that the primary interest in THC is for the psychotropic effect. CBD, on the other hand, may be proven to be the phytocannabinoid of greatest pharmaceutical benefit; however, many persons are self-medicating with either or both THC and CBD products that are of suspect quality, concentration, and benefit. Few persons would choose to use pharmaceuticals from a drug company that were of questionable quality; however, many will obtain and use phytocannabinoids based on advice of persons with no scientific or medical training and with no assurance of quality or concentration. This creates a concern for the user, as well as any medical care provider. The impact of the use of THC and CBD on our society and, in particular, the practice of medicine remains to be understood. In addition, the absence of a true cost benefit analysis completed by an objective governmental agency is a critical issue that must be addressed. Regulatory decisions made without the benefit of actual costs results in inappropriate decisions and regulations.
The author would like to thank Ms. Kyong Smith, Library Technician, Evans Army Community Hospital, Lane Medical Library, Fort Carson, Colorado, for exceptional assistance with literature searches.