Cannabis Use Disorder

Definition and Epidemiology

Definition

Cannabis use disorder (CUD) is defined as chronic (> 12 months) maladaptive use of cannabis. 

• Intoxication:
  • Heightened sensitivity to stimuli 
  • Derealization Derealization Derealization is a persistent subjective sense of detachment or unreality of the surrounding world often described by the patient as unreal, dreamlike, foggy, lifeless, or visually distorted reality. Depersonalization/Derealization Disorder and 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 with higher dosage Dosage Dosage Calculation
  • Motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology skills are impaired for up to 8–12 hours after ingestion.
  • Delirium Delirium Delirium is a medical condition characterized by acute disturbances in attention and awareness. Symptoms may fluctuate during the course of a day and involve memory deficits and disorientation. Delirium and cannabis-induced psychotic disorders may also occur.
• Withdrawal:
  • Development of a substance-specific syndrome due to the cessation (or reduction) of substance use
  • Very mild for cannabis and other inhalants/hallucinogen-type drugs
• Tolerance Tolerance Pharmacokinetics and Pharmacodynamics:
  • The need to increase the dose of the substance to achieve desired effect (diminished effect if using the same amount of the substance)
  • Evidence for physiological dependence is not strong for cannabis.

Epidemiology

• Cannabis is the most widely used illicit substance.
• Used by an estimated 228 million people worldwide 
• About 13 million individuals worldwide suffer from moderate-to-severe cannabis use disorder.
• Prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency of CUD declines with increase in age. 
• Men are more than twice as likely to have CUD as women.

Pharmacology

Pharmacologic properties

• Cannabis is consumed from both naturally occuring and agriculture-selected strains (which have increased potency). 
• Synthetic formulations available (e.g., “spice,” “K2”)  
• Common ways of consumption:
  • Smoking Smoking Willful or deliberate act of inhaling and exhaling smoke from burning substances or agents held by hand. Interstitial Lung Diseases (most widespread) 
  • Vaporizers 
  • Baked into cookies or other sweets
  • Tea
• THC ( tetrahydrocannabinol Tetrahydrocannabinol It is the psychoactive component of cannabis. Cannabinoids):
  • The main active and most potent psychoactive component in cannabis 
  • 50% of THC enters the bloodstream via the alveoli Alveoli Small polyhedral outpouchings along the walls of the alveolar sacs, alveolar ducts and terminal bronchioles through the walls of which gas exchange between alveolar air and pulmonary capillary blood takes place. Acute Respiratory Distress Syndrome (ARDS) in the lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs: Anatomy rapidly after inhalation. 
  • THC binds to 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 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’s reward system → results in feelings of 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 
  • Synthetic cannabinoids Synthetic Cannabinoids Cannabinoids have active compounds that are more potent than THC.
• 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 inhibitory G 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 →  inhibit adenylate cyclase → decreases cAMP cAMP An adenine nucleotide containing one phosphate group which is esterified to both the 3′- and 5′-positions of the sugar moiety. It is a second messenger and a key intracellular regulator, functioning as a mediator of activity for a number of hormones, including epinephrine, glucagon, and acth. Phosphodiesterase Inhibitors
• Cannabinoids Cannabinoids Cannabinoids are a class of compounds interacting with cannabinoid receptors. The 3 types of cannabinoids are phytocannabinoids (naturally derived from flora), endocannabinoids (endogenous), and synthetic cannabinoids (artificially produced). Cannabinoids are lipophilic → can remain in the body in detectable levels for days to weeks

Medical uses of cannabis

Indications:

• Treatment of 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, appetite stimulation:
  • Chemotherapy Chemotherapy Osteosarcoma
  • Multiple sclerosis Sclerosis A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. Wilms Tumor
  • AIDS
  • 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 patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship
• Decreasing intraocular pressure Intraocular Pressure The pressure of the fluids in the eye. Ophthalmic Exam in glaucoma Glaucoma Glaucoma is an optic neuropathy characterized by typical visual field defects and optic nerve atrophy seen as optic disc cupping on examination. The acute form of glaucoma is a medical emergency. Glaucoma is often, but not always, caused by increased intraocular pressure (IOP). Glaucoma
• Childhood 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 and refractory 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

Pharmaceutical forms:

• Dronabinol Dronabinol A psychoactive compound extracted from the resin of cannabis sativa (marihuana, hashish). The isomer delta-9-tetrahydrocannabinol (thc) is considered the most active form, producing characteristic mood and perceptual changes associated with this compound. Cannabinoids
• Nabilone Nabilone Cannabinoids
• Rimonabant

Clinical Presentation and Diagnosis

To make the diagnosis of cannabis intoxication or withdrawal, a detailed history of cannabis use should be obtained. Urine drug screen aids in confirming the diagnosis. Signs and symptoms are listed below.

Cannabis intoxication

• No deaths have ever been documented from cannabis intoxication alone. 
• General: 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 or feeling relaxed, inappropriate laughter
• CNS: psychomotor retardation, impairment in motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology function
• Ophthalmologic: conjunctival injection or “reddening” of the conjunctives
• GI: increased appetite, dry mouth
• Urine drug screen:
  • Detects the major inactive metabolite 11-Nor-9-carboxy THC
  • Single use can cause detectable levels for up to 3 days. 
  • Chronic use can cause detectable levels for ≥ 30 days.

Cannabis withdrawal

• General: mood changes, slight increase in irritability
• CNS: 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
• 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, decreased appetite

Management and Complications

Management of cannabis intoxication and withdrawal

• Intoxication:
  • Supportive
  • Reassurance Reassurance Clinician–Patient Relationship, dim lights, reduce stimulation
  • 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 and antipsychotics may be used for anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder and agitation Agitation A feeling of restlessness associated with increased motor activity. This may occur as a manifestation of nervous system drug toxicity or other conditions. St. Louis Encephalitis Virus due to severe intoxication.
• Withdrawal:
  • Supportive
  • Psychosocial interventions (e.g., contingency management, groups, etc ETC The electron transport chain (ETC) sends electrons through a series of proteins, which generate an electrochemical proton gradient that produces energy in the form of adenosine triphosphate (ATP). Electron Transport Chain (ETC).)
  • Medications for significant symptoms:
    • Dronabinol Dronabinol A psychoactive compound extracted from the resin of cannabis sativa (marihuana, hashish). The isomer delta-9-tetrahydrocannabinol (thc) is considered the most active form, producing characteristic mood and perceptual changes associated with this compound. Cannabinoids or nabiximols
    • Gabapentin Gabapentin A cyclohexane-gamma-aminobutyric acid derivative that is used for the treatment of partial seizures; neuralgia; and restless legs syndrome. Second-Generation Anticonvulsant Drugs
    • Sedatives (e.g., zolpidem) for sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep disturbances

Management of cannabis use disorder

• Psychotherapy Psychotherapy Psychotherapy is interpersonal treatment based on the understanding of psychological principles and mechanisms of mental disease. The treatment approach is often individualized, depending on the psychiatric condition(s) or circumstance. Psychotherapy: cognitive behavioral therapy Cognitive behavioral therapy A directive form of psychotherapy based on the interpretation of situations (cognitive structure of experiences) that determine how an individual feels and behaves. It is based on the premise that cognition, the process of acquiring knowledge and forming beliefs, is a primary determinant of mood and behavior. The therapy uses behavioral and verbal techniques to identify and correct negative thinking that is at the root of the aberrant behavior. Psychotherapy (CBT) or motivational enhancement 
• Medications:
  • No strong evidence for any medications 
  • If psychotherapy Psychotherapy Psychotherapy is interpersonal treatment based on the understanding of psychological principles and mechanisms of mental disease. The treatment approach is often individualized, depending on the psychiatric condition(s) or circumstance. Psychotherapy alone is not effective, adding N-acetylcysteine N-Acetylcysteine Acetaminophen Overdose (if adolescent/young adult) or gabapentin Gabapentin A cyclohexane-gamma-aminobutyric acid derivative that is used for the treatment of partial seizures; neuralgia; and restless legs syndrome. Second-Generation Anticonvulsant Drugs (adults) may be helpful.

Complications of cannabis use disorder

• Cannabis-induced psychotic disorder:
  • Psychotic disorder in the setting of cannabis use 
  • More commonly presents with transient paranoid delusions 
  • Chronic cannabis use has been linked with the development of 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 later in life.
• Amotivational syndrome:
  • Associated with long-term severe cannabis use
  • Can be confounded with underlying mood disorder 
  • Adolescent use of cannabis is linked with use of other substances (gateway drug).

Differential Diagnosis

• 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: a chronic mental health disorder that is characterized by both positive (delusions, hallucinations Hallucinations Subjectively experienced sensations in the absence of an appropriate stimulus, but which are regarded by the individual as real. They may be of organic origin or associated with mental disorders. Schizophrenia, disorganized speech or behavior) and negative symptoms (flat affect, avolition Avolition Lack of initiative. Schizophrenia, anhedonia Anhedonia Inability to experience pleasure due to impairment or dysfunction of normal psychological and neurobiological mechanisms. It is a symptom of many psychotic disorders (e.g., depressive disorder, major; and schizophrenia). Schizophrenia, poor attention Attention Focusing on certain aspects of current experience to the exclusion of others. It is the act of heeding or taking notice or concentrating. Psychiatric Assessment, and alogia Alogia Poverty of speech. Schizophrenia). The disorder is associated with a decline in functioning lasting over 6 months. The use of cannabis may result in psychosis and symptoms similar to 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 in the acute phase Acute phase Short Bowel Syndrome. Management of 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 is with antipsychotics. 
• Cocaine Cocaine An alkaloid ester extracted from the leaves of plants including coca. It is a local anesthetic and vasoconstrictor and is clinically used for that purpose, particularly in the eye, ear, nose, and throat. It also has powerful central nervous system effects similar to the amphetamines and is a drug of abuse. Cocaine, like amphetamines, acts by multiple mechanisms on brain catecholaminergic neurons; the mechanism of its reinforcing effects is thought to involve inhibition of dopamine uptake. Local Anesthetics use disorder: cocaine Cocaine An alkaloid ester extracted from the leaves of plants including coca. It is a local anesthetic and vasoconstrictor and is clinically used for that purpose, particularly in the eye, ear, nose, and throat. It also has powerful central nervous system effects similar to the amphetamines and is a drug of abuse. Cocaine, like amphetamines, acts by multiple mechanisms on brain catecholaminergic neurons; the mechanism of its reinforcing effects is thought to involve inhibition of dopamine uptake. Local Anesthetics is an indirect sympathomimetic Sympathomimetic Sympathomimetic drugs, also known as adrenergic agonists, mimic the action of the stimulators (α, β, or dopamine receptors) of the sympathetic autonomic nervous system. Sympathomimetic drugs are classified based on the type of receptors the drugs act on (some agents act on several receptors but 1 is predominate). Sympathomimetic Drugs that blocks the reuptake of 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, epinephrine Epinephrine The active sympathomimetic hormone from the adrenal medulla. It stimulates both the alpha- and beta- adrenergic systems, causes systemic vasoconstriction and gastrointestinal relaxation, stimulates the heart, and dilates bronchi and cerebral vessels. Sympathomimetic Drugs, and norepinephrine Norepinephrine Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers, and of the diffuse projection system in the brain that arises from the locus ceruleus. Receptors and Neurotransmitters of the CNS from the synaptic cleft Synaptic cleft Synapses and Neurotransmission. This process causes a stimulating effect ( 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, increased energy, irritability, psychosis, decreased appetite, weight loss Weight loss Decrease in existing body weight. Bariatric Surgery, and hypersomnia Hypersomnia Disorders characterized by hypersomnolence during normal waking hours that may impair cognitive functioning. Subtypes include primary hypersomnia disorders (e.g., idiopathic hypersomnolence; narcolepsy; and kleine-levin syndrome) and secondary hypersomnia disorders where excessive somnolence can be attributed to a known cause (e.g., drug affect, mental disorders, and sleep apnea syndrome). Whipple’s Disease) similar to but more pronounced than cannabis. Withdrawal symptoms include severe depression and 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. Management is very similar to cannabis in that there is no direct medication that can be used for cocaine Cocaine An alkaloid ester extracted from the leaves of plants including coca. It is a local anesthetic and vasoconstrictor and is clinically used for that purpose, particularly in the eye, ear, nose, and throat. It also has powerful central nervous system effects similar to the amphetamines and is a drug of abuse. Cocaine, like amphetamines, acts by multiple mechanisms on brain catecholaminergic neurons; the mechanism of its reinforcing effects is thought to involve inhibition of dopamine uptake. Local Anesthetics use disorder. 
• Inhalant intoxication: the abuse of inhalant substances such as glue, paint, or lighter fluid. In order to reach euphoric effects, patients administer inhalants through the mouth (commonly known as “huffing”) or sniff substances through the nose Nose The nose is the human body’s primary organ of smell and functions as part of the upper respiratory system. The nose may be best known for inhaling oxygen and exhaling carbon dioxide, but it also contributes to other important functions, such as tasting. The anatomy of the nose can be divided into the external nose and the nasal cavity. Nose Anatomy (External & Internal). The effect lasts only for several minutes. Signs of acute intoxication range from transient 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 up to a loss of consciousness. Inhalants result in central nervous inhibition and cardiac arrhythmia. Treatment is supportive, and sedative drugs should be avoided as they tend to worsen intoxication.