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CB 2 is principally associated with cells governing immune function, although it may also be expressed in the central nervous system. AEA and 2-AG are released upon demand from cell membrane phospholipid precursors. Entourage compounds include N-palmitylethanolamide PEA , N-oleoylethanolamide SEA , and cisoctadecenoamide OEA or oleamide and may represent a novel route for molecular regulation of endogenous cannabinoid activity. Additional noncannabinoid targets are also linked to cannabis.
G-protein—coupled receptors provide noncompetitive inhibition at mu and delta opioid receptors as well as norepinephrine, dopamine, and serotonin. Ligand-gated ion channels create allosteric antagonism at serotonin and nicotinic receptors, and enhance activation of glycine receptors.
THC is known to be the major psychoactive component of cannabis mediated by activation of the CB 1 receptors in the central nervous system; however, this very mechanism limits its use due to untoward adverse effects.
It is now accepted that other phytocannabinoids with weak or no psychoactivity have promise as therapeutic agents in humans. The cannabinoid that has sparked the most interest as a nonpsychoactive component is CBD. Several activities give CBD a high potential for therapeutic use, including antiepileptic, anxiolytic, antipsychotic, anti-inflammatory, and neuroprotective effects. And, some states have passed legislation to allow for the use of majority CBD preparations of cannabis for certain pathological conditions, despite lack of standardization of CBD content and optimal route of administration for effect.
Finally, preliminary clinical trials suggest that high-dose oral CBD — mg per day may exert a therapeutic effect for epilepsy, insomnia, and social anxiety disorder. Nonetheless, such doses of CBD have also been shown to cause sedation. The three most common methods of administration are inhalation via smoking, inhalation via vaporization, and ingestion of edible products.
The method of administration can impact the onset, intensity, and duration of psychoactive effects; effects on organ systems; and the addictive potential and negative consequences associated with use. Cannabinoid pharmacokinetic research has been challenging; low analyte concentrations, rapid and extensive metabolism, and physicochemical characteristics hinder the separation of compounds of interest from biological matrices and from each other. The net effect is lower drug recovery due to adsorption of compounds of interest to multiple surfaces.
In a randomized controlled trial conducted by Huestis and colleagues, THC was detected in plasma immediately after the first inhalation of marijuana smoke, attesting to the efficient absorption of THC from the lungs. THC levels rose rapidly and peaked prior to the end of smoking. Vaporization provides effects similar to smoking while reducing exposure to the byproducts of combustion and possible carcinogens and decreasing adverse respiratory syndromes.
THC is highly lipophilic, distributing rapidly to highly perfused tissues and later to fat. After oral THC, the onset of clinical effects was slower and lasted longer, but effects occurred at much lower plasma concentrations than they did after the other two methods of administration.
Cannabinoids are usually inhaled or taken orally; the rectal route, sublingual administration, transdermal delivery, eye drops, and aerosols have been used in only a few studies and are of little relevance in practice today. The pharmacokinetics of THC vary as a function of its route of administration. Inhalation of THC causes a maximum plasma concentration within minutes and psychotropic effects within seconds to a few minutes. These effects reach their maximum after 15 to 30 minutes and taper off within two to three hours.
Following oral ingestion, psychotropic effects manifest within 30 to 90 minutes, reach their maximum effect after two to three hours, and last for about four to 12 hours, depending on the dose. Within the shifting legal landscape of medical cannabis, different methods of cannabis administration have important public health implications.
A survey using data from Qualtrics and Facebook showed that individuals in states with medical cannabis laws had a significantly higher likelihood of ever having used the substance with a history of vaporizing marijuana odds ratio [OR], 2. Longer duration of medical cannabis status and higher dispensary density were also significantly associated with use of vaporized and edible forms of marijuana.
Medical cannabis laws are related to state-level patterns of utilization of alternative methods of cannabis administration. Metabolic and pharmacodynamic interactions may exist between medical cannabis and other pharmaceuticals. Much of what is known about the adverse effects of medicinal cannabis comes from studies of recreational users of marijuana. A systematic review of published trials on the use of medical cannabinoids over a year period was conducted to quantify adverse effects of this therapy.
In the randomized trials, the median duration of cannabinoid exposure was two weeks, with a range between eight hours and 12 months. Of patients assigned to active treatment in these trials, a total of 4, adverse effects were reported; The most common serious adverse effects included relapsing MS 9. No significant differences in the rates of serious adverse events between individuals receiving medical cannabis and controls were identified relative risk, 1.
The most commonly reported non-serious adverse event was dizziness, with an occurrence rate of Other negative adverse effects reported with acute cannabis use include hyperemesis syndrome, impaired coordination and performance, anxiety, suicidal ideations or tendencies, and psychotic symptoms, whereas chronic effects may include mood disturbances, exacerbation of psychotic disorders, cannabis use disorders, withdrawal syndrome, and neurocognitive impairments, as well as cardiovascular and respiratory conditions.
Cannabis and cannabinoid agents are widely used to alleviate symptoms or treat disease, but their efficacy for specific indications is not well established. For chronic pain, the analgesic effect remains unclear. A systematic review of randomized controlled trials was conducted examining cannabinoids in the treatment of chronic noncancer pain, including smoked cannabis, oromucosal extracts of cannabis-based medicine, nabilone, dronabinol, and a novel THC analogue.
Fifteen of the 18 included trials demonstrated a significant analgesic effect of cannabinoids compared with placebo. Cannabinoid use was generally well tolerated; adverse effects most commonly reported were mild to moderate in severity. Overall, evidence suggests that cannabinoids are safe and moderately effective in neuropathic pain with preliminary evidence of efficacy in fibromyalgia and rheumatoid arthritis. While there is not enough evidence to suggest routine use of medicinal cannabis for alleviating chemotherapy-related nausea and vomiting by national or international cancer societies, therapeutic agents based on THC e.
Only recently has the efficacy and safety of cannabis-based medicines in managing nausea and vomiting due to chemotherapy been evaluated. In a review of 23 randomized, controlled trials, patients who received cannabis-based products experienced less nausea and vomiting than subjects who received placebo. In crossover trials in which patients received cannabis-based products and conventional antiemetics, patients preferred the cannabis-based medicines.
Cannabis-based medications may be useful for treating chemotherapy-induced nausea and vomiting that responds poorly to conventional antiemetics. However, the trials produced low to moderate quality evidence and reflected chemotherapy agents and antiemetics that were available in the s and s.
With regard to the management of neurological disorders, including epilepsy and MS, a Cochrane review of four clinical trials that included 48 epileptic patients using CBD as an adjunct treatment to other antiepileptic medications concluded that there were no serious adverse effects associated with CBD use but that no reliable conclusions on the efficacy and safety of the therapy can be drawn from this limited evidence.
In older patients, medical cannabinoids have shown no efficacy on dyskinesia, breathlessness, and chemotherapy-induced nausea and vomiting. Some evidence has shown that THC might be useful in treatment of anorexia and behavioral symptoms in patients with dementia. The most common adverse events reported during cannabinoid treatment in older adults were sedation-like symptoms. Despite limited clinical evidence, a number of medical conditions and associated symptoms have been approved by state legislatures as qualifying conditions for medicinal cannabis use.
Table 1 contains a summary of medicinal cannabis indications by state, including select disease states and qualifying debilitating medical conditions or symptoms. A total of 28 states, the District of Columbia, Guam, and Puerto Rico now allow comprehensive public medical marijuana and cannabis programs. Medicinal Cannabis Indications for Use by State 10 , 60 , Table adapted with permission from the Marijuana Policy Project; 60 table is not all-encompassing and other medical conditions for use may exist.
The reader should refer to individual state laws regarding medicinal cannabis for specific details of approved conditions for use. In addition, states may permit the addition of approved indications; list is subject to change. Some of the most common policy questions regarding medical cannabis now include how to regulate its recommendation and indications for use; dispensing, including quality and standardization of cultivars or strains, labeling, packaging, and role of the pharmacist or health care professional in education or administration; and registration of approved patients and providers.
The regulation of cannabis therapy is complex and unique; possession, cultivation, and distribution of this substance, regardless of purpose, remain illegal at the federal level, while states that permit medicinal cannabis use have established individual laws and restrictions on the sale of cannabis for medical purposes. In a U. Department of Justice memorandum to all U.
Cole noted that despite the enactment of state laws authorizing marijuana production and sale having a regulatory structure that is counter to the usual joint efforts of federal authorities working together with local jurisdictions, prosecution of individuals cultivating and distributing marijuana to seriously ill individuals for medicinal purpose has not been identified as a federal priority.
There are, however, other regulatory implications to consider based on the federal restriction of cannabis. Medical cannabis expenses are not reimbursable through government medical assistance programs or private health insurers. As previously described, the Schedule I listing of cannabis according to federal law and DEA regulations has led to difficulties in access for research purposes; nonpractitioner researchers can register with the DEA more easily to study substances in Schedules II—V compared with Schedule I substances.
For example, the Center for Medicinal Cannabis Research at the University of California—San Diego had access to funding, marijuana at different THC levels, and approval for a number of clinical research trials, and yet failed to recruit an adequate number of patients to conduct five major trials, which were subsequently canceled. The limited availability of clinical research to support or refute therapeutic claims and indications for use of cannabis for medicinal purposes has frequently left both state legislative authorities and clinicians to rely on anecdotal evidence, which has not been subjected to the same rigors of peer review and scrutiny as well-conducted, randomized trials, to validate the safety and efficacy of medicinal cannabis therapy.
Furthermore, although individual single-entity pharmaceutical medications, such as dronabinol, have been isolated, evaluated, and approved for use by the FDA, a plant cannot be patented and mass produced by a corporate entity. The Schedule I designation of cannabis causes hospitals and other care settings that receive federal funding, either through Medicare reimbursement or other federal grants or programs, to pause to consider the potential for loss of these funds should the federal government intercede and take action if patients are permitted to use this therapy on campus.
Similarly, licensed practitioners registered to certify patients for state medicinal cannabis programs may have comparable concerns regarding jeopardizing their federal DEA registrations and ability to prescribe other controlled substances as well as jeopardizing Medicare reimbursements. Attorney General Eric Holder recommended that enforcement of federal marijuana laws not be a priority in states that have enacted medicinal cannabis programs and are enforcing the rules and regulations of such a program; despite this, concerns persist.
The argument for or against the use of medicinal cannabis in the acute care setting encompasses both legal and ethical considerations, with the argument against use perhaps seeming obvious on its surface. States adopting medical cannabis laws may advise patients to utilize the therapy only in their own residence and not to transport the substances unless absolutely necessary.
Canada has adopted national regulations to control and standardize dried cannabis for medical use. The argument can be made that an herb- or plant-based entity cannot be identified by pharmacy personnel as is commonly done for traditional medicines, although medicinal cannabis dispensed through state programs must be labeled in accordance with state laws. Dispensing and storage concerns, including an evaluation of where and how this product should be stored e.
Inpatient use of medicinal cannabis also carries implications for nursing and medical staff members. The therapy cannot be prescribed, and states may require physicians authorizing patient use to be registered with local programs. Despite the complexities in the logistics of continuing medicinal cannabis in the acute care setting, proponents of palliative care and continuity of care argue that prohibiting medicinal cannabis use disrupts treatment of chronic and debilitating medical conditions.
Patients have been denied this therapy during acute care hospitalizations for reasons stated above. Legislation in Minnesota, as one example, has been amended to permit hospitals as facilities that can dispense and control cannabis use; similar legislative actions protecting nurses from criminal, civil, or disciplinary action when administering medical cannabis to qualified patients have been enacted in Connecticut and Maine.
Despite lingering controversy, use of botanical cannabis for medicinal purposes represents the revival of a plant with historical significance reemerging in present day health care. Legislation governing use of medicinal cannabis continues to evolve rapidly, necessitating that pharmacists and other clinicians keep abreast of new or changing state regulations and institutional implications. Ultimately, as the medicinal cannabis landscape continues to evolve, hospitals, acute care facilities, clinics, hospices, and long-term care centers need to consider the implications, address logistical concerns, and explore the feasibility of permitting patient access to this treatment.
Whether national policy—particularly with a new presidential administration—will offer some clarity or further complicate regulation of this treatment remains to be seen.
The authors report no commercial or financial interests in regard to this article. National Center for Biotechnology Information , U. Journal List P T v. Author information Copyright and License information Disclaimer.
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5 Best Practices for Using Cannabis Topicals
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