Nicotine Use Disorder

Overview

Definition

Nicotine Nicotine Nicotine is highly toxic alkaloid. It is the prototypical agonist at nicotinic cholinergic receptors where it dramatically stimulates neurons and ultimately blocks synaptic transmission. Nicotine is also important medically because of its presence in tobacco smoke. Stimulants use disorder is defined as the chronic (> 12 months) maladaptive use of tobacco.

• Most common substances: cigarettes, chewing tobacco
• Intoxication:
  • Much milder symptoms than are present in intoxication with other substances
  • Presents with mild restlessness/ anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder and increased GI motility GI Motility The primary functions of the GI tract are digestion and absorption, which require coordinated contractions of the smooth muscles present in the GI tract. Peristaltic waves, segmentation contractions, and the migrating motor complex are all important contraction patterns that help to mix contents, get them in contact with the intestinal walls, and propel material down the tract at appropriate times and in appropriate amounts. Gastrointestinal Motility 
• Withdrawal:
  • Development of a substance-specific syndrome due to the cessation (or reduction) of substance use
  • Mild physical symptoms:
    • Weight gain
    • Poor concentration
  • Mild psychological symptoms:
    • Depression
    • Perceived need to use the substance 
• Tolerance Tolerance Pharmacokinetics and Pharmacodynamics: need to increase the dose of the substance to achieve desired effect (diminished effect if using the same amount of the substance)

Epidemiology

• Tobacco use is the leading cause of preventable deaths worldwide. 
• 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:
  • 15% of adults in the United States smoke regularly.
  • Higher in those with other comorbid psychiatric disorders such as bipolar Bipolar Nervous System: Histology disorder (70%), 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 (90%), or other substance use disorders (70%) 
  • Cigarette smoking Smoking Willful or deliberate act of inhaling and exhaling smoke from burning substances or agents held by hand. Interstitial Lung Diseases rates among young people in the United States are decreasing, while e-cigarette use is increasing. 
• Level of education is a protective factor in tobacco use.

Pharmacology

Nicotine Nicotine Nicotine is highly toxic alkaloid. It is the prototypical agonist at nicotinic cholinergic receptors where it dramatically stimulates neurons and ultimately blocks synaptic transmission. Nicotine is also important medically because of its presence in tobacco smoke. Stimulants is the main psychoactive component of tobacco:

• Agonist at the nicotinic subtype of acetylcholine Acetylcholine A neurotransmitter found at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. Receptors and Neurotransmitters of the CNS 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 central nervous system Central nervous system The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. Nervous System: Anatomy, Structure, and Classification
• Activates the dopaminergic pathway from the ventral tegmental area to the cerebral cortex Cerebral cortex The cerebral cortex is the largest and most developed part of the human brain and CNS. Occupying the upper part of the cranial cavity, the cerebral cortex has 4 lobes and is divided into 2 hemispheres that are joined centrally by the corpus callosum. Cerebral Cortex: Anatomy to produce its rewarding effects 
• Leads to increasing circulation Circulation The movement of the blood as it is pumped through the cardiovascular system. ABCDE Assessment of the following neurotransmitters:
  • 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
  • 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
  • Beta-endorphin
  • Adrenocorticotropic hormone Adrenocorticotropic hormone An anterior pituitary hormone that stimulates the adrenal cortex and its production of corticosteroids. Acth is a 39-amino acid polypeptide of which the n-terminal 24-amino acid segment is identical in all species and contains the adrenocorticotropic activity. Upon further tissue-specific processing, acth can yield alpha-msh and corticotropin-like intermediate lobe peptide (clip). Adrenal Hormones
  • Cortisol Cortisol Glucocorticoids

Only 25% of inhaled nicotine Nicotine Nicotine is highly toxic alkaloid. It is the prototypical agonist at nicotinic cholinergic receptors where it dramatically stimulates neurons and ultimately blocks synaptic transmission. Nicotine is also important medically because of its presence in tobacco smoke. Stimulants enters the bloodstream, but it reaches 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 in 15 seconds.

Clinical Presentation

Active nicotine Nicotine Nicotine is highly toxic alkaloid. It is the prototypical agonist at nicotinic cholinergic receptors where it dramatically stimulates neurons and ultimately blocks synaptic transmission. Nicotine is also important medically because of its presence in tobacco smoke. Stimulants use

• Immediate effects of nicotine Nicotine Nicotine is highly toxic alkaloid. It is the prototypical agonist at nicotinic cholinergic receptors where it dramatically stimulates neurons and ultimately blocks synaptic transmission. Nicotine is also important medically because of its presence in tobacco smoke. Stimulants include improved 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 elevated mood.
• Usually, there are no severe intoxication symptoms from tobacco use.
• Nicotine Nicotine Nicotine is highly toxic alkaloid. It is the prototypical agonist at nicotinic cholinergic receptors where it dramatically stimulates neurons and ultimately blocks synaptic transmission. Nicotine is also important medically because of its presence in tobacco smoke. Stimulants intoxication:
  • 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 
  • 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
  • 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, elevated blood pressure 
  • Tremor Tremor Cyclical movement of a body part that can represent either a physiologic process or a manifestation of disease. Intention or action tremor, a common manifestation of cerebellar diseases, is aggravated by movement. In contrast, resting tremor is maximal when there is no attempt at voluntary movement, and occurs as a relatively frequent manifestation of parkinson disease. Myotonic Dystrophies
  • Cold sweats
• Note: Nicotine Nicotine Nicotine is highly toxic alkaloid. It is the prototypical agonist at nicotinic cholinergic receptors where it dramatically stimulates neurons and ultimately blocks synaptic transmission. Nicotine is also important medically because of its presence in tobacco smoke. Stimulants is a CNS stimulant but a skeletal muscle relaxant.

Nicotine Nicotine Nicotine is highly toxic alkaloid. It is the prototypical agonist at nicotinic cholinergic receptors where it dramatically stimulates neurons and ultimately blocks synaptic transmission. Nicotine is also important medically because of its presence in tobacco smoke. Stimulants withdrawal

• Intense craving
• Dysphoria
• Anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder
• Poor concentration
• Increased appetite
• Weight gain
• Irritability
• Restlessness
• 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

Management and Complications

Pharmacotherapy for nicotine Nicotine Nicotine is highly toxic alkaloid. It is the prototypical agonist at nicotinic cholinergic receptors where it dramatically stimulates neurons and ultimately blocks synaptic transmission. Nicotine is also important medically because of its presence in tobacco smoke. Stimulants use disorder

Nicotine-replacement therapy:

• 1st-line treatment
• Doubles chances of cessation
• Available in multiple formulations:
  • Transdermal patch Patch Nonpalpable lesion > 1 cm in diameter Generalized and Localized Rashes
  • Gum
  • Lozenge
  • Nasal spray
  • Inhaler

Nicotine Nicotine Nicotine is highly toxic alkaloid. It is the prototypical agonist at nicotinic cholinergic receptors where it dramatically stimulates neurons and ultimately blocks synaptic transmission. Nicotine is also important medically because of its presence in tobacco smoke. Stimulants cessation:

• Varenicline Varenicline A benzazepine derivative that functions as an alpha4beta2 nicotinic receptor partial agonist. It is used for smoking cessation. Cholinomimetic Drugs: 
  • Partial agonist to the alpha-4 beta-2 (α4β2) nicotinic cholinergic 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 
  • Mimics the action of nicotine Nicotine Nicotine is highly toxic alkaloid. It is the prototypical agonist at nicotinic cholinergic receptors where it dramatically stimulates neurons and ultimately blocks synaptic transmission. Nicotine is also important medically because of its presence in tobacco smoke. Stimulants
  • Reduces the rewarding effects of nicotine Nicotine Nicotine is highly toxic alkaloid. It is the prototypical agonist at nicotinic cholinergic receptors where it dramatically stimulates neurons and ultimately blocks synaptic transmission. Nicotine is also important medically because of its presence in tobacco smoke. Stimulants
  • Prevents withdrawal symptoms
  • Side effects:
    • Sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep disturbance
    • Depressed mood
• Bupropion Bupropion A propiophenone-derived antidepressant and antismoking agent that inhibits the uptake of dopamine. Other Antidepressants:
  • Inhibitor 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 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 reuptake
  • Helps reduce cravings and withdrawal symptoms
  • Side effects:
    • 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
    • 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
    • Headaches
    • 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 bulimic patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship (contraindicated in this group)

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 and preventive measures for nicotine Nicotine Nicotine is highly toxic alkaloid. It is the prototypical agonist at nicotinic cholinergic receptors where it dramatically stimulates neurons and ultimately blocks synaptic transmission. Nicotine is also important medically because of its presence in tobacco smoke. Stimulants use disorder

• Behavioral counseling:
  • Includes:
    • Face-to-face or phone sessions
    • Print materials
    • Software programs 
  • The goal is to help eliminate cues for smoking Smoking Willful or deliberate act of inhaling and exhaling smoke from burning substances or agents held by hand. Interstitial Lung Diseases.
• Motivational interviewing Motivational interviewing It is a client-centered, directive method for eliciting intrinsic motivation to change using open-ended questions, reflective listening, and decisional balancing. This nonjudgmental, nonconfrontational interviewing style is designed to minimize a patient’s resistance to change by creating an interaction that supports open discussion of risky or problem behavior. Psychotherapy:
  • Offered by providers to patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship to uncover internal reasons for tobacco cessation 
  • The 1st step is to set a “quit date.”
• Address barriers to quitting:
  • Fear of withdrawal symptoms or weight gain
  • Common triggers
  • Cost
• Prevention and education are recommended in school-aged children and adolescents. 
• Public health policies such as a ban on public smoking Smoking Willful or deliberate act of inhaling and exhaling smoke from burning substances or agents held by hand. Interstitial Lung Diseases

Management of nicotine Nicotine Nicotine is highly toxic alkaloid. It is the prototypical agonist at nicotinic cholinergic receptors where it dramatically stimulates neurons and ultimately blocks synaptic transmission. Nicotine is also important medically because of its presence in tobacco smoke. Stimulants withdrawal

• Symptomatic treatment 
• Supportive, psychosocial interventions:
  • Contingency management
  • Support groups

Complications

• Smoking Smoking Willful or deliberate act of inhaling and exhaling smoke from burning substances or agents held by hand. Interstitial Lung Diseases increases the risk for several types of cancers:
  • Lung cancer Lung cancer Lung cancer is the malignant transformation of lung tissue and the leading cause of cancer-related deaths. The majority of cases are associated with long-term smoking. The disease is generally classified histologically as either small cell lung cancer or non-small cell lung cancer. Symptoms include cough, dyspnea, weight loss, and chest discomfort. Lung Cancer: Tobacco smoking Smoking Willful or deliberate act of inhaling and exhaling smoke from burning substances or agents held by hand. Interstitial Lung Diseases is the most common risk factor for the most deadly form of cancer in the United States.
  • Chronic obstructive pulmonary disease Pulmonary disease Diseases involving the respiratory system. Blastomyces/Blastomycosis ( COPD COPD Chronic obstructive pulmonary disease (COPD) is a lung disease characterized by progressive, largely irreversible airflow obstruction. The condition usually presents in middle-aged or elderly persons with a history of cigarette smoking. Signs and symptoms include prolonged expiration, wheezing, diminished breath sounds, progressive dyspnea, and chronic cough. Chronic Obstructive Pulmonary Disease (COPD)): 90% of cases of COPD COPD Chronic obstructive pulmonary disease (COPD) is a lung disease characterized by progressive, largely irreversible airflow obstruction. The condition usually presents in middle-aged or elderly persons with a history of cigarette smoking. Signs and symptoms include prolonged expiration, wheezing, diminished breath sounds, progressive dyspnea, and chronic cough. Chronic Obstructive Pulmonary Disease (COPD) can be attributed to tobacco smoking Smoking Willful or deliberate act of inhaling and exhaling smoke from burning substances or agents held by hand. Interstitial Lung Diseases.
  • Esophageal cancer Esophageal cancer Esophageal cancer is 1 of the most common causes of cancer-related deaths worldwide. Nearly all esophageal cancers are either adenocarcinoma (commonly affecting the distal esophagus) or squamous cell carcinoma (affecting the proximal two-thirds of the esophagus). Esophageal Cancer
  • Gastric cancer Gastric cancer Gastric cancer is the 3rd-most common cause of cancer-related deaths worldwide. The majority of cases are from adenocarcinoma. The modifiable risk factors include Helicobacter pylori infection, smoking, and nitrate-rich diets. Gastric Cancer
  • Renal cell carcinoma Renal cell carcinoma Renal cell carcinoma (RCC) is a tumor that arises from the lining of the renal tubular system within the renal cortex. Renal cell carcinoma is responsible for 80%-85% of all primary renal neoplasms. Most RCCs arise sporadically, but smoking, hypertension, and obesity are linked to its development. Renal Cell Carcinoma
  • Transitional cell carcinoma
  • Salivary gland Salivary gland Glands that secrete saliva in the mouth. There are three pairs of salivary glands (parotid gland; sublingual gland; submandibular gland). Diseases of the Salivary Glands tumors
  • Cervical cancer Cervical cancer Cervical cancer, or invasive cervical carcinoma (ICC), is the 3rd most common cancer in women in the world, with > 50% of the cases being fatal. In the United States, ICC is the 13th most common cancer and the cause of < 3% of all cancer deaths due to the slow progression of precursor lesions and, more importantly, effective cancer screening. Cervical Cancer
• Cardiovascular diseases:
  • Atherosclerosis Atherosclerosis Atherosclerosis is a common form of arterial disease in which lipid deposition forms a plaque in the blood vessel walls. Atherosclerosis is an incurable disease, for which there are clearly defined risk factors that often can be reduced through a change in lifestyle and behavior of the patient. Atherosclerosis
  • Ischemic heart disease Ischemic heart disease Coronary heart disease (CHD), or ischemic heart disease, describes a situation in which an inadequate supply of blood to the myocardium exists due to a stenosis of the coronary arteries, typically from atherosclerosis. Coronary Heart Disease
• Vasculitis Vasculitis Inflammation of any one of the blood vessels, including the arteries; veins; and rest of the vasculature system in the body. Systemic Lupus Erythematosus (Buerger disease)
• Pregnancy-related complications:
  • Low birth weight
  • Preterm labor Preterm labor Preterm labor refers to regular uterine contractions leading to cervical change prior to 37 weeks of gestation; preterm birth refers to birth prior to 37 weeks of gestation. Preterm birth may be spontaneous due to preterm labor, preterm prelabor rupture of membranes (PPROM), or cervical insufficiency. Preterm Labor and Birth
  • Placental problems
  • Intrauterine growth restriction 
  • Sudden infant death syndrome Sudden Infant Death Syndrome Sudden infant death syndrome (SIDS) describes the sudden death of an otherwise healthy infant (< 1 year of age) with no identifiable cause. Sudden infant death syndrome is the leading cause of death in children between 1 and 12 months of age in the United States. Sudden Infant Death Syndrome (SIDS)
  • Ectopic pregnancy Ectopic pregnancy Ectopic pregnancy refers to the implantation of a fertilized egg (embryo) outside the uterine cavity. The main cause is disruption of the normal anatomy of the fallopian tube. Ectopic Pregnancy
• Secondhand smoke
  • Refers to involuntary exposure to tobacco smoke 
  • Similar complications as above although in lower numbers

Benefits of smoking Smoking Willful or deliberate act of inhaling and exhaling smoke from burning substances or agents held by hand. Interstitial Lung Diseases cessation

Short-term benefits (< 12 months):

• Lowered heart rate Heart rate The number of times the heart ventricles contract per unit of time, usually per minute. Cardiac Physiology and blood pressure
• Return of blood carbon monoxide Carbon monoxide Carbon monoxide (CO). A poisonous colorless, odorless, tasteless gas. It combines with hemoglobin to form carboxyhemoglobin, which has no oxygen carrying capacity. The resultant oxygen deprivation causes headache, dizziness, decreased pulse and respiratory rates, unconsciousness, and death. Carbon Monoxide Poisoning level to normal
• Improved circulation Circulation The movement of the blood as it is pumped through the cardiovascular system. ABCDE Assessment and lung function 
• Decreased coughing and shortness of breath Shortness of breath Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea 
• Women who stop smoking Smoking Willful or deliberate act of inhaling and exhaling smoke from burning substances or agents held by hand. Interstitial Lung Diseases during the 1st trimester reduce their risk of low birth weight to that of women who never smoked.

Long-term benefits (> 12 months):

• Increased life expectancy Life expectancy Based on known statistical data, the number of years which any person of a given age may reasonably expected to live. Population Pyramids 
• Decreased risk of:
  • Myocardial infarction Myocardial infarction MI is ischemia and death of an area of myocardial tissue due to insufficient blood flow and oxygenation, usually from thrombus formation on a ruptured atherosclerotic plaque in the epicardial arteries. Clinical presentation is most commonly with chest pain, but women and patients with diabetes may have atypical symptoms. Myocardial Infarction
  • Cerebrovascular diseases 
  • Cancer:
    • Oropharyngeal
    • Bladder Bladder A musculomembranous sac along the urinary tract. Urine flows from the kidneys into the bladder via the ureters, and is held there until urination. Pyelonephritis and Perinephric Abscess
    • Cervical
    • Lung
    • Pancreatic

Differential Diagnosis

• Organophosphate poisoning: chemicals commonly found in insecticides Insecticides Pesticides designed to control insects that are harmful to man. The insects may be directly harmful, as those acting as disease vectors, or indirectly harmful, as destroyers of crops, food products, or textile fabrics. Trypanosoma cruzi/Chagas disease, classified as irreversible cholinesterase Cholinesterase Liver Function Tests inhibitors. When these chemicals are ingested in toxic amounts, symptoms include salivation, lacrimation, urination, 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, GI upset, and emesis. These symptoms are similar to nicotine Nicotine Nicotine is highly toxic alkaloid. It is the prototypical agonist at nicotinic cholinergic receptors where it dramatically stimulates neurons and ultimately blocks synaptic transmission. Nicotine is also important medically because of its presence in tobacco smoke. Stimulants intoxication. However, the severity of symptoms observed in organophosphate poisoning is unlikely to occur from excessive tobacco consumption. 
• Cannabis use disorder Cannabis use disorder Cannabis use disorder (CUD) is characterized by the pathologic consumption of cannabis, which is the most commonly used illicit substance worldwide. While cannabis has some beneficial medical uses, it also has the potential to cause intoxication characterized by psychosis or cognitive impairment, especially in chronic use. Cannabis Use Disorder: cannabis is the most commonly used illicit substance worldwide. Intoxication symptoms include 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, laughter, 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, impaired reaction time, conjunctival injection, and increased appetite. Withdrawal symptoms include irritability, anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder, 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, and decreased appetite. While the withdrawal symptoms of irritability and anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder are similar in cannabis and tobacco use, appetite is usually increased during withdrawal from tobacco use. Careful history taking of the substance ingested will also help distinguish the diagnosis.