Cannabinoids, broadly speaking, are a class of biological compounds that bind to cannabinoid receptors. They are most frequently sourced from and associated with the plants of the Cannabis genus, including Cannabis sativa, Cannabis indica, and Cannabis ruderalis. The earliest known use of cannabinoids dates back 5,000 years ago in modern Romania, while the documentation of the earliest medical dates back to around 400 AD. However, formal extraction, isolation, and structural elucidation of cannabinoids have taken place rather recently in the late 19th and early 20th centuries . Since then, numerous advancements have been made in further isolating naturally occurring cannabinoids, synthesizing artificial equivalents, and discovering the endogenous the endocannabinoid system in mammals, reptiles, fish, and birds. Cannabinoids, in the context of medicine, come in three forms:
Of all known cannabinoids (hundreds of which have been isolated and identified), arguably the most commonly notable are the phytocannabinoids tetrahydrocannabinol (THC) and cannabidiol (CBD) - the former being responsible for Cannabis’s psychoactive effects. Throughout their storied history, cannabinoids have been renowned for their psychotropic and physiological effects. In tandem, the effects, as mentioned above, have made them the target of medical, cultural, and recreational uses, of which the former will be the focus of this article. Cannabinoids are frequently the targets of pharmaceutical innovation, with most being either structurally related to or mimicking the ligand-receptor activity of THC and CBD. These biochemical innovations have found extensive application in clinical studies for a variety of diseases, where cannabinoids have shown the mild to strong efficacy:
Clinical studies notwithstanding, in the United States (US), only a small number of cannabinoids have been approved for medical use by the Food and Drug Administration (FDA). Those are:
Finally, as a point of clarification for this review, Cannabis refers to the plants mentioned above of the Cannabis genus, marijuana refers to parts of Cannabis containing notable concentrations of THC, and hemp refers to cannabis plants often designated for industrial use containing less than legal threshold of THC in the US.
Cannabinoids function by stimulating two receptors, cannabinoid receptor type 1 (CB1) and type 2 (CB2) within the endocannabinoid system. This system is a complex network of organs throughout the body, expressing the cannabinoid receptors and plays a homeostatic role. Functions of the endocannabinoid system including pain, memory, movement, appetite, metabolism, lacrimation/salivation, immunity, and even cardiopulmonary function. It bears mentioning that the vast majority of end-effects from cannabinoids, including psychotropics, are from activation of CB1 with CB2 serving more important roles in immune and inflammatory functions.
Endogenously, endocannabinoids serve as neuro-regulatory modulators responsible for retrograde neurotransmission. Here, a post-synaptic neuron releases endocannabinoids that bind to predominantly CB1 receptors on the presynaptic neuron. This binding results in inhibited presynaptic calcium channel activation and subsequent presynaptic neurotransmitter release. If the presynaptic neurotransmitters are predominantly inhibitory such as GABA, the net effect is excitatory and vice versa.
Binding to the different parts of the central nervous system mediates different psychotropic properties of cannabinoids, in particular THC. These areas and end-effects include :
Other end-effects of CB1 activation peripherally include dry mouth, conjunctivitis, tachycardia, hypotension, and bradypnea.
Depending on the cannabinoid, the route of administration will vary. Medical cannabinoids are generally administered orally as a capsule or liquid suspension. Dronabinol is available as a capsule in 2.5mg, 5mg, and 10mg strengths in addition to an oral 5mg/mL formulation. The medication is generally taken twice daily an hour before meals with titration from the initial dose performed gradually based on tolerability and response. Nabilone is available as a 1mg capsule and may be taken 2 to 3 times daily, depending on the provider and patient preference. Finally, cannabidiol is available as an oral solution at 100 mg/mL and may be taken twice daily, starting at 2.5 mg/kg/day and titrated as patient response and tolerability dictate.
Cannabinoids may also be administered orally via incorporation in consumed food products such as infused teas or oils or via inhalation by smoking cannabis or marijuana. Products containing THC are almost always illicit, carrying a Schedule I classification by the US Drug Enforcement Agency (DEA) and are therefore are available only on black markets. CBD, however, has in recent years has gained popularity and is available over the counter. Although smoking cannabis is traditionally the most common method of cannabinoid administration, vaporization with e-cigarettes is continuing to become more popular, offering a more rapid, less carcinogenic method of delivering cannabinoids from the lungs into the bloodstream. Finally, although sublingual, rectal, ocular, transdermal, and aerosol deliveries have seen research, a paucity of literature regarding their use have mitigated their practical application.
Adverse effects of cannabinoids exist on a spectrum, ranging from mild to lethal, and vary on the mode associated risks of administration. The most frequently encountered side effects of cannabinoids are generally those from recreational sources. Over the short-term, mild effects include euphoria, anxiolysis, tachycardia, visuotemporal distortion, sensory amplification, tachycardia, postural hypotension, conjunctivitis, hunger, and dry throat, mouth, and eyes . More severe symptoms include panic attacks, myoclonus, psychosis, hyperemesis, inhalation burns, acute respiratory distress syndrome (ARDS), and bronchospasm – any one of which may result in hospitalization or the necessity of emergency medical services.
Over the long-term, heavy cannabinoid abuse has correlated in numerous adverse health conditions, including:
In addition to the above, other adverse effects of cannabinoids include hypersensitivity reactions to active cannabinoids in specific formulations or constituent components (e.g., capsules or inactive additives) or disulfiram reaction (nausea, vomiting, abdominal cramping, and headache) with concurrent disulfiram or metronidazole use.
Contraindications to cannabinoids are few but include hypersensitivity to specific medications, cannabinoids generally, constituent components of specific formulations (e.g., sesame seed oil in capsules  or other inactive ingredients), and recent administration of products containing disulfiram or metronidazole within two weeks. Some have also posited that concurrent anxiety or mood disorders or personal/family history of psychotic disorders such as schizophrenia may also be a contraindication.
Cannabinoids are generally not monitored regularly except for some patients who require routine drug screening or present with suspicion of drug overdose or abuse. The most common diagnostic test for cannabinoid detection is the urine drug screen (UDS), which detects THC and CBD metabolites. Otherwise, due to differences in metabolism, mode of administration detection, and frequency of use may cause detection times to vary significantly between patients. Besides UDS, monitoring is otherwise largely based on symptoms of intoxication and overdose.
In the event of cannabinoid drug toxicity, as described above, treatment and management are largely supportive and focused on symptom relief. Psychosis and agitation should have treatment with benzodiazepines and antipsychotics, preferably of the second-generation or atypical class due to their lower risk of extrapyramidal effects. An electrocardiogram can rule out myocardial ischemia or dysrhythmias, and if present, the clinician should start empiric therapy with rate-controlling agents. Hyperemesis should receive appropriate medication with antiemetics provided that the risk of dysrhythmias is sufficiently low. Clinicians need to address seizure activity with benzodiazepines and/or anticonvulsant agents as tolerated. Finally, signs of pulmonary compromised should necessitate supportive measures such as oxygen via nasal cannula, positive airway pressure ventilation, and endotracheal intubation if severe enough.
Cannabinoids have served numerous roles in medicine, culture, and recreation for almost as long as recorded human history. With pharmaceutical and illicit forms available to patients, healthcare providers must be equipped with the knowledge to identify symptoms of cannabinoid abuse and toxicity and take steps to mitigate adverse outcomes. However, medical professionals must also be equally understanding of medical conditions that may respond to treatment with appropriately dosed and administered cannabinoids. As a result, all members of today's integrated, interprofessional health team must demonstrate full engagement regarding the entire spectrum of cannabinoids' ability to help and harm patients so that they can achieve an optimal balance. [Level 5]
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