Marijuana, the dried leaves of the Cannabis sativa plant, has long been used both recreationally and as a medicine. (Although more than one species of Cannabis can be used for its psychoactive properties [such as C. afghanica or indica, used to make hashish2] for the purposes of this document, the term “cannabis” will be used to mean Cannabis sativa.) Its use in the United States was curtailed in the early 20th century, first by various state laws and then in 1937 by the Marihuana Tax Act, a federal law. Since that time, although the specific applicable law has changed, the manufacture, importation, possession, use, and distribution of marijuana has remained illegal under federal law. At this time, the US Drug Enforcement Administration lists marijuana and its cannabinoids as Schedule I controlled substances, which means that they cannot legally be prescribed under federal law. Schedule I drugs are said to: 1) have a high potential for abuse; 2) have no currently accepted medical use in treatment in the United States; and 3) have a lack of accepted safety for use under medical supervision. Other Schedule I drugs include heroin and 3,4-methylenedioxy-N-methylamphetamine (MDMA or ecstasy), whereas cocaine is a Schedule II controlled substance. Although cannabinoids from marijuana are Schedule I substances, some synthetic cannabinoids are not (these are discussed later).
Because marijuana is a Schedule I controlled substance, physicians and other health care professionals who write prescriptions for it can be prosecuted under federal law. A number of states have passed laws allowing for the medical use of marijuana. In those states, a health care practitioner provides an “authorization” for that use that, based on previous court action, is considered by the federal courts to be protected physician-patient communication.
Marijuana can be used to make hashish and hash oil, which contain concentrated cannabinoids (cannabinoids are discussed below). Both marijuana and hash oil can be consumed by inhalation (smoking and vaporizing) and by mouth (drinking it as a tea or eating after it is mixed into foods, such as baked goods).
In addition to the cannabinoids responsible for its psychoactive effects, marijuana smoke contains many of the same chemical constituents as tobacco smoke. Some of these, such as 4-aminobiphenyl, arsenic, benzene, cadmium, formaldehyde, and lead, are known human carcinogens (for some of these, marijuana smoke contains more or less than the smoke of tobacco cigarettes). The smoke also contains toxicants such as ammonia, carbon monoxide, hydrogen cyanide, and tar. Unlike tobacco smoke, marijuana smoke does not contain nicotine or tobacco-specific nitrosamines (which are derived from nicotine). Although in mutagenicity assays marijuana smoke condensates had comparable or even somewhat less mutagenicity than tobacco smoke condensates, smoking marijuana is linked to higher carboxyhemoglobin levels, inhaled tar, and tar retained in the lungs compared with smoking filter-tipped cigarettes. This may be due to observed differences in smoking behavior, such as puff volume, depth of inhalation, and breath holding.[6, 7]
Vaporizing marijuana by heating it to temperatures between 180°C and 200°C releases substantial amounts of cannabinoids with only trace amounts of a few other chemicals.[8, 9] Vaporization has become an alternative to smoking as a means of inhaling marijuana.
Cannabinoid Receptors and Cannabinoids
Cannabis sativa contains a number of chemical compounds, some of which are classified as cannabinoids. “Cannabinoid” was the term originally used for C21 terpenophenolic compounds originally found in this plant. These compounds were found to activate cannabinoid receptors in the brain, and now this term is also used to describe other compounds that activate those receptors, even if they do not have a similar chemical structure. Two major types of cannabinoid receptors have been characterized: CB1 and CB2. CB1 receptors are found mainly in central and peripheral neurons, whereas CB2 receptors are found most often in immune cells. Nevertheless, CB1 receptors can be found in immune cells, whereas CB2 receptors can be found in neurons. These receptors, along with endogenous cannabinoid receptor agonists (endocannabinoids, molecules naturally found in and produced by the body that activate these receptors), are known collectively as the endocannabinoid system.
Although there are more than 60 cannabinoids in marijuana, 2 in particular have been the subjects of most studies examining medicinal uses: delta-9-tetrahydrocannabinol (Δ9-THC, often referred to just as THC) and cannabidiol (CBD).
THC is often called the major psychoactive component of marijuana because it appears to be responsible for the feeling of “high” reported by consumers of marijuana. In addition to euphoriant properties, it also has analgesic, antiemetic, antiinflammatory, and antioxidant properties.
CBD is another major cannabinoid found naturally in the marijuana plant. Although CBD has low affinity for CB1 and CB2 receptors, at low concentrations it can antagonize CB1/CB2 agonists and may even behave as an inverse agonist. Although in the past it was called “nonpsychoactive,” CBD has anxiolytic and antipsychotic properties. It also has anticonvulsive properties and can counteract some of the psychoactive effects of THC.[10, 12] It also has reported efficacy in the treatment of pain, although this may be due more to its anticonvulsive effects than an antinociceptive effect.
Based on a study of marijuana seized in California, the content of THC in marijuana by weight has increased over time, with a median potency increasing from 4.18% in 1996 to 13.95% in 2008. In contrast, the CBD content has gone down, with a resultant increase in the THC:CBD ratio. Strains of marijuana with high CBD content and low THC content have been cultivated and have been used by some to treat forms of refractory childhood epilepsy.[14, 15] Formal clinical trials of this, however, are lacking.
Because marijuana is a Schedule I controlled substance, marijuana used for research must be obtained through the National Institute of Drug Abuse (NIDA). Any limits in terms of the strains available through the NIDA limits the research that can be conducted. In July 2014, a representative from the NIDA reported that the THC content in the strains of marijuana currently available for clinical trials ranged from 0.001% to 13%. None of the marijuana available at that time through the NIDA had a “high CBD content,” and was not expected to be available until 2015 (H. Singh, personal communication, July 2014).
THC is highly lipophilic and is water insoluble. It is rapidly absorbed into the blood from inhaled marijuana smoke, with plasma levels becoming detectable within seconds and peak plasma levels noted in fewer than 10 minutes. Peak plasma levels are directly related to the THC content of the marijuana that is smoked. The bioavailability of THC from smoking marijuana varies based on depth of inhalation, puff, and breath-holding duration, and is estimated to be between 10% to 35%, with higher systemic bioavailability for heavy users than occasional users. Smoking marijuana through a pipe instead of a cigarette can result in higher THC absorption because this results in less THC loss in sidestream smoke.
A human study of vaporization of marijuana found that this delivery method yielded similar plasma THC levels compared with marijuana smoking, with lower carbon monoxide levels.
Characterization of absorption of THC after oral administration has largely been based on studies of the pharmaceutical dronabinol (see below), although there have been a few studies of marijuana in baked goods. Absorption after oral administration has been described as “slow and erratic,” resulting in “low and irregular” plasma levels. THC can be degraded by acid, which could potentially lower the amount available to be absorbed by the stomach. It is known to undergo extensive first-pass metabolism. After oral ingestion, plasma levels usually peak after 60 to 120 minutes, although in some subjects it can take as long as 4 hours or more to observe peak plasma levels. Some subjects can even have more than one peak after a single oral dose. Bioavailability after oral ingestion is approximately 6%, but with high variability between subjects.
THC can also be administered via the oral mucosa. Mean plasma levels reached the threshold of detection at 45 minutes after sublingual administration of a whole-plant cannabis extract containing THC (range, 30-120 minutes; the mean peak plasma levels were noted 100-130 minutes after administration [higher concentration drops showed a later peak]). In a study comparing the pharmacokinetics of oral THC with those of THC in a whole-plant cannabis extract (nabiximols), the time to maximal concentration was increased in the latter, although the difference was not statistically significant. Delivery via the oral mucosa resulted in slightly increased bioavailabilty compared with ingestion. The bioavailability of THC, in terms of peak plasma level and area under the curve, is increased if the oral mucosal spray is administered during a fed state.
In the blood, 90% of THC is distributed to the plasma, and is mainly bound to plasma proteins such as lipoproteins and albumin. Approximately 10% of THC in the blood is distributed in red blood cells. THC rapidly penetrates highly vascularized tissues including the liver, heart, fat, lung, jejunum, kidney, spleen, mammary gland, placenta, adrenal cortex, muscle, thyroid, and pituitary gland. Only approximately 1% of a dose of THC given intravenously is found in the brain at the time when the psychoactive effects are peaking. Oxidative metabolism of THC yields an active metabolite, 11-hydroxy-delta 9-tetrahydrocannabinol (11-OH-THC). Over time, THC accumulates in less vascularized tissues and finally in body fat, although the exact composition in body fat is not known and may include hydroxyl metabolites and fatty acid conjugates.
When marijuana is smoked, THC levels peak within 6 to 10 minutes, whereas 11-OH-THC levels peak within 9 to 23 minutes. After inhalation, maximal psychotropic effects occur after 20 to 30 minutes and continue for 45 to 60 minutes or longer depending on the THC concentration of the marijuana.
Levels differ after oral ingestion, with peak THC levels occurring hours after ingestion and 11-OH-THC levels that can exceed THC levels. Psychotropic effects are noted within 30 to 90 minutes, peak within 2 to 4 hours, and decline to low levels after 6 hours.
THC crosses the placenta and can be found in small amounts in breast milk.
CBD is also highly lipophilic. The absorption and kinetics of CBD from inhaled marijuana smoke have been described as being similar to those of THC, with an average systemic bioavailability of 31% in marijuana smokers (range, 11%-45%). Again, similar to THC, CBD oral bioavailability is poor, in the range of 13% to 19%. Peak plasma levels in one study occurred after 1.3 hours. Peak plasma levels are similar when CBD is administered as an oral mucosal spray along with THC; however, the time to maximal concentration is longer. The bioavailability of CBD, in terms of peak plasma level and area under the curve, is increased if the oral mucosal spray is administered during a fed state.
Pharmaceutical Forms of Cannabinoids
Two cannabinoids are approved by the FDA and therefore can be legally prescribed in the United States according to federal law. One, dronabinol, contains the trans isomer of THC dissolved in sesame oil contained within a gelatin capsule. The THC for this drug is synthetically derived. This drug is approved by the FDA approved for 2 indications: 1) chemotherapy-induced nausea and vomiting (CINV); and 2) anorexia associated with weight loss in patients with the acquired immunodeficiency syndrome. The second, nabilone, is a synthetic cannabinoid that mimics the action of THC. It is approved by the FDA to treat CINV. Both drugs are only available as capsules. Nabilone is classified as a Schedule II controlled substance, whereas dronabinol is classified as a Schedule III controlled substance. The usefulness of these drugs for treating acute nausea and vomiting is hampered by the need for oral administration and absorption from the stomach, as well as the length of time to reach peak plasma levels.
Another cannabinoid pharmaceutical of note is nabiximols. Nabiximols is a whole-plant extract of marijuana, and contains THC and CBD in a 1.08:1.00 ratio. It is administered as an oral mucosal spray. This drug is currently in clinical trials in the United States for the treatment of pain, and is approved for use in Canada and parts of Europe for the treatment of spasticity from multiple sclerosis. It is also approved in Canada under the Notice of Compliance with Conditions program for the treatment of some types of pain.
A liquid containing cannabidiol without THC will also soon become available in the United States through a clinical trial to treat Lennox-Gastaut syndrome and Dravet syndrome, rare forms of childhood-onset epilepsy. A phase 2 clinical trial of this drug in patients with schizophrenia is currently ongoing.