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Cannabinoids

Cannabinoids are a class of compounds interacting with cannabinoid receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors. The 3 types of cannabinoids are phytocannabinoids (naturally derived from flora), endocannabinoids (endogenous), and synthetic cannabinoids (artificially produced). Endocannabinoids are endogenous neuropeptide neurotransmitters found in the human nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. Nervous System: Anatomy, Structure, and Classification. Cannabinoids have a psychotropic effect, which leads to frequent recreational use, but the unique effects of cannabinoids on the CNS also provide pharmacological indications. Prescription cannabinoids treat pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways, nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics, vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia, and seizure disorders and also serve as appetite stimulants Stimulants Stimulants are used by the general public to increase alertness and energy, decrease fatigue, and promote mental focus. Stimulants have medical uses for individuals with ADHD and sleep disorders, and are also used in combination with analgesics in pain management. Stimulants.

Last updated: 24 Jan, 2022

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Chemistry and Pharmacodynamics

Chemistry

Tetrahydrocannabinol (THC) is the psychoactive component of cannabis:

  • THC is a lipid.
  • Aromatic terpenoid (modified terpene with a removed methyl group or added oxygen atom)
Structure of thc

The structure of tetrahydrocannabinol (THC): the psychoactive component of cannabis

Image: “THC” by Harbin. License: Public Domain

Mechanism of action

  • Cannabinoid receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors are metabotropic (G-protein coupled) and act through secondary messengers to elicit cellular responses.
  • Cannabinoids bind BIND Hyperbilirubinemia of the Newborn and activate cannabinoid receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors type 1 Type 1 Spinal Muscular Atrophy (CB1) and cannabinoid receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors type 2 Type 2 Spinal Muscular Atrophy (CB2):
    • CB1 receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors: regulate glutamate Glutamate Derivatives of glutamic acid. Included under this heading are a broad variety of acid forms, salts, esters, and amides that contain the 2-aminopentanedioic acid structure. Synthesis of Nonessential Amino Acids and GABA GABA The most common inhibitory neurotransmitter in the central nervous system. Receptors and Neurotransmitters of the CNS neurotransmission Neurotransmission The communication from a neuron to a target (neuron, muscle, or secretory cell) across a synapse. In chemical synaptic transmission, the presynaptic neuron releases a neurotransmitter that diffuses across the synaptic cleft and binds to specific synaptic receptors, activating them. The activated receptors modulate specific ion channels and/or second-messenger systems in the postsynaptic cell. In electrical synaptic transmission, electrical signals are communicated as an ionic current flow across electrical synapses. Synapses and Neurotransmission (located in CNS and peripheral tissues)
    • CB1 receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors: most widely expressed Gαi-protein coupled receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors in the brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification:
      • Gαi → α α Alpha is the chance of testing positive by a diagnostic test among those without the condition, causing a type I error or a “false positive.” Statistical Power subunit of G protein inhibits adenylyl cyclase
      • ꞵ and 𝛾 subunits released from Gαi: activate K+ channels Channels The Cell: Cell Membrane, inhibit Ca CA Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts)2+ channels Channels The Cell: Cell Membrane 
    • CB2 receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors: regulate pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways and emesis (located in immune cells) 
    • CB receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors activation causes ↓ neurotransmitter release Release Release of a virus from the host cell following virus assembly and maturation. Egress can occur by host cell lysis, exocytosis, or budding through the plasma membrane. Virology through the following mechanisms:
      • Inhibition of presynaptic adenylyl cyclase → inactivation of presynaptic protein kinase A Protein kinase A A group of enzymes that are dependent on cyclic amp and catalyze the phosphorylation of serine or threonine residues on proteins. Included under this category are two cyclic-amp-dependent protein kinase subtypes, each of which is defined by its subunit composition. Glycogen Metabolism (PKA) 
      • Activation of presynaptic mitogen-activated protein kinase Protein kinase A family of enzymes that catalyze the conversion of ATP and a protein to adp and a phosphoprotein. Interferons (MAPK)
      • Inhibition of presynaptic voltage-gated Ca CA Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts)2+ channels Channels The Cell: Cell Membrane → ↓ Ca CA Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts)2+ influx
      • Activation of presynaptic inward-rectifier K+ channels Channels The Cell: Cell Membrane → ↑ K+ efflux 

Tetrahydrocannabinol (THC)

  • Presynaptic CB1 agonism 
  • THC prolongs activation of CB1 receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors causing continuous inhibition of neurotransmitter release Release Release of a virus from the host cell following virus assembly and maturation. Egress can occur by host cell lysis, exocytosis, or budding through the plasma membrane. Virology from GABAergic and glutamatergic presynaptic nerve terminals expressing CB1 receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors
  • THC binds to CB1 receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors on inhibitory GABAergic interneurons in the VTA (ventricular tegmental area), causing decreased GABA GABA The most common inhibitory neurotransmitter in the central nervous system. Receptors and Neurotransmitters of the CNS release Release Release of a virus from the host cell following virus assembly and maturation. Egress can occur by host cell lysis, exocytosis, or budding through the plasma membrane. Virology and disinhibition of dopaminergic neurons Neurons The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. Nervous System: Histology → ↑ dopamine Dopamine One of the catecholamine neurotransmitters in the brain. It is derived from tyrosine and is the precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. Receptors and Neurotransmitters of the CNS 

Physiologic effects

Cannabinoids bind BIND Hyperbilirubinemia of the Newborn to peripheral and central receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors:

  • Peripheral receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors activation leads to: 
    • Dry mouth
    • Tachycardia Tachycardia Abnormally rapid heartbeat, usually with a heart rate above 100 beats per minute for adults. Tachycardia accompanied by disturbance in the cardiac depolarization (cardiac arrhythmia) is called tachyarrhythmia. Sepsis in Children 
    • Hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension 
    • Decreased respiratory effort 
  • Cannabinoids bind BIND Hyperbilirubinemia of the Newborn to CB receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors in various areas of the CNS causing:
    • Hippocampus: impairment of short-term memory Memory Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. Psychiatric Assessment
    • Neocortex Neocortex The largest portion of the cerebral cortex in which the neurons are arranged in six layers in the mammalian brain: molecular, external granular, external pyramidal, internal granular, internal pyramidal and multiform layers. Cerebral Cortex: Anatomy: impairment of judgement and changes in sensation
    • Hypothalamus Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. Hypothalamus: increase in appetite
    • Amygdala Amygdala Almond-shaped group of basal nuclei anterior to the inferior horn of the lateral ventricle of the temporal lobe. The amygdala is part of the limbic system. Limbic System: Anatomy: paranoia 
    • Brainstem: antiemetic effect
    • Spinal cord Spinal cord The spinal cord is the major conduction pathway connecting the brain to the body; it is part of the CNS. In cross section, the spinal cord is divided into an H-shaped area of gray matter (consisting of synapsing neuronal cell bodies) and a surrounding area of white matter (consisting of ascending and descending tracts of myelinated axons). Spinal Cord: Anatomy: analgesic effect
Cannabinoids form a connection with cannabinoid receptors

Cannabinoids form a connection with cannabinoid receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors:
Neurotransmitters (including dopamine Dopamine One of the catecholamine neurotransmitters in the brain. It is derived from tyrosine and is the precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. Receptors and Neurotransmitters of the CNS) flood into the synaptic cleft Synaptic cleft Synapses and Neurotransmission, causing calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes to be pumped into the postsynaptic neuron Postsynaptic neuron Synapses and Neurotransmission at higher levels than observed in healthy natural stimuli. The higher amount of neurotransmitters gives the “high” associated with cannabis. Acting through cannabinoid receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors, THC activates the reward system of the brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification. Tetrahydrocannabinol also disrupts functioning of the cerebellum Cerebellum The cerebellum, Latin for “little brain,” is located in the posterior cranial fossa, dorsal to the pons and midbrain, and its principal role is in the coordination of movements. The cerebellum consists of 3 lobes on either side of its 2 hemispheres and is connected in the middle by the vermis. Cerebellum: Anatomy and basal ganglia Basal Ganglia Basal ganglia are a group of subcortical nuclear agglomerations involved in movement, and are located deep to the cerebral hemispheres. Basal ganglia include the striatum (caudate nucleus and putamen), globus pallidus, substantia nigra, and subthalamic nucleus. Basal Ganglia: Anatomy, which regulate balance, posture, coordination Coordination Cerebellar Disorders, and reaction time.
The 1st diagram shows normal activity and the 2nd diagram shows activity with the addition of THC.
A: THC
B: CB1 receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors
C: neurotransmitters
D: postsynaptic receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors
E: cannabinoid

Image by Lecturio.

Pharmacokinetics

Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption

  • Cannabinoid kinetics differ based on the route of administration and formulation.
  • Kinetics vary for cannabinoids not approved by the FDA (e.g., smoking Smoking Willful or deliberate act of inhaling and exhaling smoke from burning substances or agents held by hand. Interstitial Lung Diseases cannabis, edible cannabis): 

Metabolism

  • Metabolized in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy
  • Some cannabinoid is stored in fatty tissue.
  • Often metabolized by the cytochrome P450 Cytochrome P450 A superfamily of hundreds of closely related hemeproteins found throughout the phylogenetic spectrum, from animals, plants, fungi, to bacteria. They include numerous complex monooxygenases (mixed function oxygenases). In animals, these p450 enzymes serve two major functions: (1) biosynthesis of steroids, fatty acids, and bile acids; (2) metabolism of endogenous and a wide variety of exogenous substrates, such as toxins and drugs (biotransformation). They are classified, according to their sequence similarities rather than functions, into cyp gene families (>40% homology) and subfamilies (>59% homology). For example, enzymes from the cyp1, cyp2, and cyp3 gene families are responsible for most drug metabolism. Drug-induced Liver Injury system (particularly CYP2C9 CYP2C9 A cytochrome p-450 subtype that has specificity for acidic xenobiotics. It oxidizes a broad range of important clinical drugs that fall under the categories of nonsteroidal anti-inflammatory agents; hypoglycemic agents; anticoagulants; and diuretics. Anticoagulants):
    • CYP2C9 CYP2C9 A cytochrome p-450 subtype that has specificity for acidic xenobiotics. It oxidizes a broad range of important clinical drugs that fall under the categories of nonsteroidal anti-inflammatory agents; hypoglycemic agents; anticoagulants; and diuretics. Anticoagulants inhibitors prevent metabolism.
    • CYP2C9 CYP2C9 A cytochrome p-450 subtype that has specificity for acidic xenobiotics. It oxidizes a broad range of important clinical drugs that fall under the categories of nonsteroidal anti-inflammatory agents; hypoglycemic agents; anticoagulants; and diuretics. Anticoagulants inhibitor use leads to prolonged intoxication.
  • Hydrocarbons produced from combustion of marijuana inhibit CYP1A2.
  • Dronabinol is heavily bound to plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis (may affect Affect The feeling-tone accompaniment of an idea or mental representation. It is the most direct psychic derivative of instinct and the psychic representative of the various bodily changes by means of which instincts manifest themselves. Psychiatric Assessment other protein-bound drugs).
  • THC is a substrate Substrate A substance upon which the enzyme acts. Basics of Enzymes of CYP2C9 CYP2C9 A cytochrome p-450 subtype that has specificity for acidic xenobiotics. It oxidizes a broad range of important clinical drugs that fall under the categories of nonsteroidal anti-inflammatory agents; hypoglycemic agents; anticoagulants; and diuretics. Anticoagulants and CYP3A4 CYP3A4 Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers).
  • Cannabidiol ( CBD CBD Atypical Parkinsonian Syndromes) is a substrate Substrate A substance upon which the enzyme acts. Basics of Enzymes of CYP2C19 and CYP3A4 CYP3A4 Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers).
  • Drugs metabolized by CYP1A2 are more quickly metabolized after consumption of cannabinoids (e.g., olanzapine Olanzapine A benzodiazepine derivative that binds serotonin receptors; muscarinic receptors; histamine h1 receptors; adrenergic alpha-1 receptors; and dopamine receptors. It is an antipsychotic agent used in the treatment of schizophrenia; bipolar disorder; and major depressive disorder; it may also reduce nausea and vomiting in patients undergoing chemotherapy. Second-Generation Antipsychotics).

Excretion

  • Cannabinoids are excreted in the feces and urine Urine Liquid by-product of excretion produced in the kidneys, temporarily stored in the bladder until discharge through the urethra. Bowen Disease and Erythroplasia of Queyrat.
  • Cannabinoids are excreted after hydroxylation and carboxylation.
  • The majority of cannabinoids are excreted after 5 days of consumption.

Drug interactions

Additional potential drug interactions with cannabinoids include: 

  • Warfarin Warfarin An anticoagulant that acts by inhibiting the synthesis of vitamin K-dependent coagulation factors. Warfarin is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, pulmonary embolism, and atrial fibrillation with embolization. It is also used as an adjunct in the prophylaxis of systemic embolism after myocardial infarction. Warfarin is also used as a rodenticide. Anticoagulants: increased risk of bleeding
  • Clobazam: increased risk of benzodiazepine toxicity Toxicity Dosage Calculation
  • Depressant medications: excessive sedation, depression

Classification

  • 3 forms of cannabinoids:
  • FDA-approved cannabinoid medications: 
  • Legal considerations:
    • Marijuana and cannabinoid are classified as Schedule I controlled substances by the United States FDA and the United States Drug Enforcement Administration (DEA).
    • Recreational and medical marijuana regulations differ between state and federal laws.
    • Many states have legalized or decriminalized marijuana.
Table: Prescription cannabinoid formulations and indications
Drug Notes on formulations Indications
Dronabinol:
  • Oral capsule Capsule An envelope of loose gel surrounding a bacterial cell which is associated with the virulence of pathogenic bacteria. Some capsules have a well-defined border, whereas others form a slime layer that trails off into the medium. Most capsules consist of relatively simple polysaccharides but there are some bacteria whose capsules are made of polypeptides. Bacteroides Marinol®
  • Oral solution Syndros®
  • Marinol® contains sesame oil (solvent) → impedes extraction and purification of tetrahydrocannabinol (THC) for abuse
  • Syndros® contains 50% ethanol Ethanol A clear, colorless liquid rapidly absorbed from the gastrointestinal tract and distributed throughout the body. It has bactericidal activity and is used often as a topical disinfectant. It is widely used as a solvent and preservative in pharmaceutical preparations as well as serving as the primary ingredient in alcoholic beverages. Ethanol Metabolism.
  • Cachexia in individuals with AIDS AIDS Chronic HIV infection and depletion of CD4 cells eventually results in acquired immunodeficiency syndrome (AIDS), which can be diagnosed by the presence of certain opportunistic diseases called AIDS-defining conditions. These conditions include a wide spectrum of bacterial, viral, fungal, and parasitic infections as well as several malignancies and generalized conditions. HIV Infection and AIDS
  • Refractory chemotherapy Chemotherapy Osteosarcoma-induced nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics and vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia (CINV)
  • The American Society of Clinical Oncology (ASCO) recommends dronabinol or nabilone over medical marijuana.
Nabilone: oral capsule Capsule An envelope of loose gel surrounding a bacterial cell which is associated with the virulence of pathogenic bacteria. Some capsules have a well-defined border, whereas others form a slime layer that trails off into the medium. Most capsules consist of relatively simple polysaccharides but there are some bacteria whose capsules are made of polypeptides. Bacteroides Cesamet® /
  • Refractory CINV
  • ASCO recommends dronabinol or nabilone over medical marijuana.
Cannabidiol: oral solution Epidiolex® Refractory childhood-onset seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures in individuals ≥ 2 years of age due to:

Methods of ingestion

  • Pills and capsules
  • Hash oils
  • Gums
  • Dabbing
  • Pens
  • Tetrahydrocannabinolic acid (THCA) crystals
  • Bongs
  • Vapes
  • Canna oils
  • Bowls/bubblers
  • Sprays
  • THC soda
  • Joints/blunts
  • Drinks
  • Syrups
  • Tinctures
  • Creams
  • Bath soaks
  • Edibles
  • Patches Patches Vitiligo
  • Decarb
  • Sols/butters

Indications

  • Medical marijuana in the United States is mainly authorized to treat:
    • Anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder
    • Spasticity Spasticity Spinal Disk Herniation in amyotrophic lateral sclerosis Amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a sporadic or inherited neurodegenerative disease of upper motor neurons (UMNs) and lower motor neurons (LMNs). ALS is the most common progressive motor neuron disease in North America, primarily affecting men and individuals of Caucasian ethnicity. Amyotrophic Lateral Sclerosis (Lou Gehrig disease) and multiple sclerosis Multiple Sclerosis Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease that leads to demyelination of the nerves in the CNS. Young women are more predominantly affected by this most common demyelinating condition. Multiple Sclerosis
    • Chronic pain Chronic pain Aching sensation that persists for more than a few months. It may or may not be associated with trauma or disease, and may persist after the initial injury has healed. Its localization, character, and timing are more vague than with acute pain. Pain Management/cancer pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways
    • Cachexia or wasting syndromes (e.g., HIV HIV Anti-HIV Drugs/ AIDS AIDS Chronic HIV infection and depletion of CD4 cells eventually results in acquired immunodeficiency syndrome (AIDS), which can be diagnosed by the presence of certain opportunistic diseases called AIDS-defining conditions. These conditions include a wide spectrum of bacterial, viral, fungal, and parasitic infections as well as several malignancies and generalized conditions. HIV Infection and AIDS, cancer)
    • Inflammatory bowel disease 
    • Insomnia Insomnia Insomnia is a sleep disorder characterized by difficulty in the initiation, maintenance, and consolidation of sleep, leading to impairment of function. Patients may exhibit symptoms such as difficulty falling asleep, disrupted sleep, trouble going back to sleep, early awakenings, and feeling tired upon waking. Insomnia 
    • Nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics 
    • Parkinson disease Parkinson disease Parkinson’s disease (PD) is a chronic, progressive neurodegenerative disorder. Although the cause is unknown, several genetic and environmental risk factors are currently being studied. Individuals present clinically with resting tremor, bradykinesia, rigidity, and postural instability. Parkinson’s Disease
    • Posttraumatic stress disorder Posttraumatic Stress Disorder Posttraumatic stress disorder is a psychiatric illness characterized by overwhelming stress and anxiety experienced after exposure to a life-threatening event. Symptoms last more than 1 month and involve re-experiencing the event as flashbacks or nightmares, avoiding reminders of the event, irritability, hyperarousal, and poor memory and concentration. Posttraumatic Stress Disorder (PTSD)
    • Seizure disorders
    • Pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways palliation in terminal illness 
  • Various cannabinoid medications with specific indications:
    • Nabiximol: pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways related to multiple sclerosis Multiple Sclerosis Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease that leads to demyelination of the nerves in the CNS. Young women are more predominantly affected by this most common demyelinating condition. Multiple Sclerosis and cancer
    • Dronabinol (Marinol):
      • Poor appetite
      • Sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep apnea
      • Anorexia Anorexia The lack or loss of appetite accompanied by an aversion to food and the inability to eat. It is the defining characteristic of the disorder anorexia nervosa. Anorexia Nervosa caused by HIV HIV Anti-HIV Drugs/ AIDS AIDS Chronic HIV infection and depletion of CD4 cells eventually results in acquired immunodeficiency syndrome (AIDS), which can be diagnosed by the presence of certain opportunistic diseases called AIDS-defining conditions. These conditions include a wide spectrum of bacterial, viral, fungal, and parasitic infections as well as several malignancies and generalized conditions. HIV Infection and AIDS
      • Chemotherapy Chemotherapy Osteosarcoma induced nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics and vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia
    • Epidiolex®: epilepsy Epilepsy Epilepsy is a chronic brain disorder marked by recurrent and unprovoked seizures. These seizures can be classified as focal or generalized and idiopathic or secondary to another condition. Clinical presentation correlates to the classification of the epileptic disorder. Epilepsy syndromes (Dravet syndrome, Lennox-Gastaut syndrome Lennox-Gastaut Syndrome Epilepsy)

Adverse Effects and Contraindications

Adverse effects

THC (Dronabinol and Nabilone):

  • CNS:
    • ↑ Appetite
    • Dizziness Dizziness An imprecise term which may refer to a sense of spatial disorientation, motion of the environment, or lightheadedness. Lateral Medullary Syndrome (Wallenberg Syndrome) 
    • Headache Headache The symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders. Brain Abscess
    • Euphoria Euphoria An exaggerated feeling of physical and emotional well-being not consonant with apparent stimuli or events; usually of psychologic origin, but also seen in organic brain disease and toxic states. Hepatic Encephalopathy 
    • Impaired concentration 
    • Somnolence
    • Increased pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways sensation
    • Ataxia Ataxia Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharynx, larynx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. Ataxia-telangiectasia
    • Depersonalization Depersonalization State in which an individual perceives or experiences a sensation of unreality concerning the self or the environment; it is seen in disorders such as schizophrenia, affection disorders, organic mental disorders, and personality disorders. Depersonalization/Derealization Disorder
  • GI:
    • Nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics 
    • Vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia
    • Abdominal pain Abdominal Pain Acute Abdomen

Cannabidiol (Epidiolex®):

  • CNS: 
    • ↓ Appetite 
    • Fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia
    • Lethargy Lethargy A general state of sluggishness, listless, or uninterested, with being tired, and having difficulty concentrating and doing simple tasks. It may be related to depression or drug addiction. Hyponatremia, sedation
  • GI:
    • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea 
    • Vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia 
  • Hepatic/metabolic: ↑ liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes

Cannabinoid hyperemesis syndrome (CHS)

  • Cyclic vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia syndrome due to cannabis use 
  • Symptoms include  nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics, vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia, and abdominal pain Abdominal Pain Acute Abdomen occurring on a cyclic basis in the setting of routine cannabis/marijuana use.
  • Seen in individuals using cannabis on a weekly basis for at least 1 year 
  • Pathophysiology unclear
  • Individuals compulsively take hot showers/baths to help relieve symptoms: 
    • Substance P is speculated to be involved in the pathophysiology.
    • Topical capsaicin cream depletes substance P after repeated application to skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions and is shown to alleviate symptoms.
  • Nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics and vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia treatment: 
    • Benzodiazepines Benzodiazepines Benzodiazepines work on the gamma-aminobutyric acid type A (GABAA) receptor to produce inhibitory effects on the CNS. Benzodiazepines do not mimic GABA, the main inhibitory neurotransmitter in humans, but instead potentiate GABA activity. Benzodiazepines ( lorazepam Lorazepam A benzodiazepine used as an anti-anxiety agent with few side effects. It also has hypnotic, anticonvulsant, and considerable sedative properties and has been proposed as a preanesthetic agent. Benzodiazepines) or haloperidol Haloperidol A phenyl-piperidinyl-butyrophenone that is used primarily to treat schizophrenia and other psychoses. It is also used in schizoaffective disorder, delusional disorders, ballism, and tourette syndrome (a drug of choice) and occasionally as adjunctive therapy in intellectual disability and the chorea of huntington disease. It is a potent antiemetic and is used in the treatment of intractable hiccups. First-Generation Antipsychotics appear more efficacious than conventional antiemetics Antiemetics Antiemetics are medications used to treat and/or prevent nausea and vomiting. These drugs act on different target receptors. The main classes include benzodiazepines, corticosteroids, atypical antipsychotics, cannabinoids, and antagonists of the following receptors: serotonin, dopamine, and muscarinic and neurokinin receptors. Antiemetics (e.g., ondansetron Ondansetron A competitive serotonin type 3 receptor antagonist. It is effective in the treatment of nausea and vomiting caused by cytotoxic chemotherapy drugs, including cisplatin, and has reported anxiolytic and neuroleptic properties. Antiemetics, metoclopramide Metoclopramide A dopamine d2 antagonist that is used as an antiemetic. Antiemetics).
    • Do not use opioids Opioids Opiates are drugs that are derived from the sap of the opium poppy. Opiates have been used since antiquity for the relief of acute severe pain. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Opioid Analgesics.
  • Cessation of cannabis is required to completely resolve the syndrome (may take weeks).
Phases of cannabinoid hyperemesis syndrome

Phases of cannabinoid hyperemesis syndrome (CHS)

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Contraindications Contraindications A condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks). Noninvasive Ventilation and drug interactions

Table: Contraindications Contraindications A condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks). Noninvasive Ventilation and drug interactions of cannabinoids
Drugs Warnings Contraindications Contraindications A condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks). Noninvasive Ventilation Drug interactions
Dronabinol
  • Cardiovascular:
    • Syncope Syncope Syncope is a short-term loss of consciousness and loss of postural stability followed by spontaneous return of consciousness to the previous neurologic baseline without the need for resuscitation. The condition is caused by transient interruption of cerebral blood flow that may be benign or related to a underlying life-threatening condition. Syncope
    • Tachycardia Tachycardia Abnormally rapid heartbeat, usually with a heart rate above 100 beats per minute for adults. Tachycardia accompanied by disturbance in the cardiac depolarization (cardiac arrhythmia) is called tachyarrhythmia. Sepsis in Children
  • CNS:
    • Altered perception Perception The process by which the nature and meaning of sensory stimuli are recognized and interpreted. Psychiatric Assessment
    • Exacerbated mania Mania A state of elevated excitement with over-activity sometimes accompanied with psychotic symptoms (e.g., psychomotor agitation, inflated self esteem and flight of ideas). It is often associated with mental disorders (e.g., cyclothymic disorder; and bipolar diseases). Bipolar Disorder
    • Exacerbated schizophrenia Schizophrenia Schizophrenia is a chronic mental health disorder characterized by the presence of psychotic symptoms such as delusions or hallucinations. The signs and symptoms of schizophrenia are traditionally separated into 2 groups: positive (delusions, hallucinations, and disorganized speech or behavior) and negative (flat affect, avolition, anhedonia, poor attention, and alogia). Schizophrenia
    • Paranoia
    • Unmasked psychosis
  • GI:
    • Cannabinoid hyperemesis syndrome (CHS)
    • Severe nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics, vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia
  • Pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care and lactation Lactation The processes of milk secretion by the maternal mammary glands after parturition. The proliferation of the mammary glandular tissue, milk synthesis, and milk expulsion or let down are regulated by the interactions of several hormones including estradiol; progesterone; prolactin; and oxytocin. Breastfeeding: not recommended for women who are pregnant, breastfeeding Breastfeeding Breastfeeding is often the primary source of nutrition for the newborn. During pregnancy, hormonal stimulation causes the number and size of mammary glands in the breast to significantly increase. After delivery, prolactin stimulates milk production, while oxytocin stimulates milk expulsion through the lactiferous ducts, where it is sucked out through the nipple by the infant. Breastfeeding, or planning to become pregnant as cannabinoids cross the placenta Placenta A highly vascularized mammalian fetal-maternal organ and major site of transport of oxygen, nutrients, and fetal waste products. It includes a fetal portion (chorionic villi) derived from trophoblasts and a maternal portion (decidua) derived from the uterine endometrium. The placenta produces an array of steroid, protein and peptide hormones (placental hormones). Placenta, Umbilical Cord, and Amniotic Cavity
  • General:
    • Disorder of alcohol
    • Hypersensitivity to alcohol
    • Disorder of substance abuse
  • Dronabinol capsule Capsule An envelope of loose gel surrounding a bacterial cell which is associated with the virulence of pathogenic bacteria. Some capsules have a well-defined border, whereas others form a slime layer that trails off into the medium. Most capsules consist of relatively simple polysaccharides but there are some bacteria whose capsules are made of polypeptides. Bacteroides: allergic to sesame seed oil
  • Dronabinol oral solution: current or recent (within 14 days) therapy with products containing disulfiram or metronidazole Metronidazole A nitroimidazole used to treat amebiasis; vaginitis; trichomonas infections; giardiasis; anaerobic bacteria; and treponemal infections. Pyogenic Liver Abscess
  • Dronabinol may displace other highly protein-bound drugs → ↑ adverse effects (e.g., cyclosporine Cyclosporine A cyclic undecapeptide from an extract of soil fungi. It is a powerful immunosupressant with a specific action on T-lymphocytes. It is used for the prophylaxis of graft rejection in organ and tissue transplantation. Immunosuppressants, warfarin Warfarin An anticoagulant that acts by inhibiting the synthesis of vitamin K-dependent coagulation factors. Warfarin is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, pulmonary embolism, and atrial fibrillation with embolization. It is also used as an adjunct in the prophylaxis of systemic embolism after myocardial infarction. Warfarin is also used as a rodenticide. Anticoagulants)
  • CNS depressants:
    • Alcohol
    • Anticholinergics Anticholinergics Anticholinergic drugs block the effect of the neurotransmitter acetylcholine at the muscarinic receptors in the central and peripheral nervous systems. Anticholinergic agents inhibit the parasympathetic nervous system, resulting in effects on the smooth muscle in the respiratory tract, vascular system, urinary tract, GI tract, and pupils of the eyes. Anticholinergic Drugs
    • Efavirenz Efavirenz Anti-HIV Drugs
    • Hypnotics
    • Opioids Opioids Opiates are drugs that are derived from the sap of the opium poppy. Opiates have been used since antiquity for the relief of acute severe pain. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Opioid Analgesics
    • Sedatives (e.g., benzodiazepines Benzodiazepines Benzodiazepines work on the gamma-aminobutyric acid type A (GABAA) receptor to produce inhibitory effects on the CNS. Benzodiazepines do not mimic GABA, the main inhibitory neurotransmitter in humans, but instead potentiate GABA activity. Benzodiazepines, barbiturates Barbiturates A class of chemicals derived from barbituric acid or thiobarbituric acid. Many of these are gaba modulators used as hypnotics and sedatives, as anesthetics, or as anticonvulsants. Intravenous Anesthetics)
  • CYP2C9 CYP2C9 A cytochrome p-450 subtype that has specificity for acidic xenobiotics. It oxidizes a broad range of important clinical drugs that fall under the categories of nonsteroidal anti-inflammatory agents; hypoglycemic agents; anticoagulants; and diuretics. Anticoagulants inhibitors (may need to ↓ THC dose)
  • CYP2C9 CYP2C9 A cytochrome p-450 subtype that has specificity for acidic xenobiotics. It oxidizes a broad range of important clinical drugs that fall under the categories of nonsteroidal anti-inflammatory agents; hypoglycemic agents; anticoagulants; and diuretics. Anticoagulants inducers (may need to ↑ THC dose)
  • CYP3A4 CYP3A4 Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers) inhibitors (may need to ↓ THC dose)
  • CYP3A4 CYP3A4 Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers) inducers (may need to ↑ THC dose)
Nabilone /
  • Disorder of alcohol use
  • Disorder of substance abuse
CNS depressants
Cannabidiol ( CBD CBD Atypical Parkinsonian Syndromes) (Epidiolex®)
  • CNS: sedation, somnolence (diminishes with continued use)
  • Hepatotoxicity Hepatotoxicity Acetaminophen risk with:
    • Valproic acid Valproic acid A fatty acid with anticonvulsant and anti-manic properties that is used in the treatment of epilepsy and bipolar disorder. The mechanisms of its therapeutic actions are not well understood. It may act by increasing gamma-aminobutyric acid levels in the brain or by altering the properties of voltage-gated sodium channels. First-Generation Anticonvulsant Drugs
    • Clobazam
    • Hepatotoxic drugs
Allergic to sesame seed oil

References

  1. Fryer, A.D., Christopoulos, A., Nathanson, N.M. (Eds.) (2012). Muscarinic Receptors. Handbook of Experimental Pharmacology, vol 208. Springer: Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-23274-9 
  2. Curry, S.C., et al. (2019). Neurotransmitters and Neuromodulators. In Nelson, L.S., et al. (Eds.), Goldfrank’s Toxicologic Emergencies, 11e. New York, NY: McGraw-Hill.
  3. Lapoint, J.M. (2019). Cannabinoids. In Nelson, L.S., et al. (Eds.), Goldfrank’s Toxicologic Emergencies, 11e. New York, NY: McGraw-Hill.
  4. Gray, R.A., Whalley, B.J. (2020). The proposed mechanisms of action of CBD in epilepsy. Epileptic Disord. 22(S1), 10–15. https://pubmed.ncbi.nlm.nih.gov/32053110/
  5. Schmitz, N., Richert, L. (2020). Pharmacists and the future of cannabis medicine. J Am Pharm Assoc. 60(1), 207–211. https://doi.org/10.1016/j.japh.2019.11.007 
  6. Hesketh, P.J., et al. (2017). Antiemetics: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. 35, 3240–3261. https://doi.org/10.1200/JCO.2017.74.4789 
  7. Federation of State Medical Boards. (2016). Model guidelines for the Recommendation of Marijuana in Patient Care. https://www.fsmb.org/Media/Default/PDF/BRD_RPT_16-2_Marijuana_Model_Guidelines.pdf 
  8. The Marijuana Policy Project. (2020). Marijuana Policy Reform Legislation. https://www.mpp.org/issues/legislation/key-marijuana-policy-reform/ 
  9. Morano, A., et al. (2020). Cannabinoids in the Treatment of Epilepsy: Current Status and Future Prospects. Neuropsychiatr Dis Treat. 16, 381–396. https://doi.org/10.2147/ndt.s203782 
  10. Devinsky, O., et al. (2017). Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome. N Engl J Med. 376, 2011–2020. https://doi.org/10.1056/NEJMoa1611618 
  11. Lapoint, J., et al. (2018). Cannabinoid Hyperemesis Syndrome: Public Health Implications and a Novel Model Treatment Guideline. West J Emerg Med. 19(2), 380–386. https://doi.org/10.5811/westjem.2017.11.36368 
  12. Bahji, A., et al. (2020). Prevalence of Cannabis Withdrawal Symptoms Among People With Regular or Dependent Use of Cannabinoids: a systematic review and meta-analysis. JAMA Netw Open. 3(4), e202370. https://doi.org/10.1001/jamanetworkopen.2020.2370 
  13. McCracken, J.L., et al. (2017). Diagnosis and Management of Asthma in Adults: A Review. JAMA. 318(3), 279–290. https://doi.org/10.1001/jama.2017.8372 
  14. Mehta, G.R., et al. (2016). Chronic obstructive pulmonary disease: A guide for the primary care physician. Dis Mon. 62(6), 164–187. https://doi.org/10.1016/j.disamonth.2016.03.002

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