Cannabis, Cannabinoids and Methamphetamine

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Cannabis and Cannabinoids

• Cannabis and cannabinoids function as partial agonists of CB1 receptors in the neuroaxis.
• Partial agonism of CB1 receptors in the ventral tegmental area (VTA) and pre-frontal cortex (PFC) results in increased dopaminergic function.
• Increased dopamine (DA) binding to the D2 receptor leads to euphoria and decreased anxiety.
• Impure products or long-term abuse can potentiate norepinephrine release, leading to anxiety, hallucinations, and delusions.
• Conservative management includes abstinence from THC products or using more pure products to avoid cutting agents.

Methamphetamine-Based Drugs

• Methamphetamines are sympathomimetic agents that increase dopamine release and activity in the brain.
• Increased dopaminergic activity causes tactile hallucinations (feeling bugs crawling on skin), delusions, severe paranoia, and repetitive movements.
• Increased norepinephrine (NE) activity leads to aggression, hyper-exaggeration to small stimuli, severe anxiety, and insomnia.
• Acute management involves IV benzodiazepines (lorazepam, midazolam) for severe agitation or violence.
• Chronic abusers may benefit from atypical antipsychotics like Quetiapine and monitoring for extra-neurological effects.

Ketamine and PCP

• Ketamine and PCP act as NMDA receptor antagonists.
• NMDA receptor antagonism reduces GABA release onto dopaminergic neurons, increasing DA release.
• Increased DA activity causes hallucinations (out-of-body experiences, visual distortions) and delusions due to thalamic involvement.
• Ketamine typically requires conservative management, while PCP requires a higher level of care due to its stronger effects.

MDMA (Ecstasy)

• MDMA is a sympathomimetic drug that highly stimulates dopamine and serotonin release by blocking serotonin reuptake.
• Causes tactile and visual hallucinations (flashing/strobe lights) and delusions.
• Patients feel extremely close to others and experience increased SNS activity, leading to hypertension, hyperthermia, and constant thirst.
• Persistent thirst can cause primary polydipsia, leading to dilutional hyponatremia and increased seizure risk.
• After 24-48 hours, patients experience a "comedown" phase with fatigue and agitation.
• Management includes conservative measures, monitoring electrolytes, and watching for seizures if hyponatremia is suspected.

Bath Salts (Flakka)

• Bath salts cause significant NE upregulation, along with moderate serotonin and dopamine upregulation.
• Serotonin and dopamine cause hallucinations and delusions.
• Increased NE suppresses frontal lobe areas involved with conscious awareness and behavior control, resulting in severe aggression, anger, agitation, and violent urges.
• Permanent cognitive impairment can occur even after the first experience.

Opioids

• Most neurologically active opioids are mu receptor agonists.
• Mu receptor agonism increases DA release from the VTA, hippocampus, and PFC.
• Patients may feel "dissociated" and experience increased libido due to DA release.

Sensation of Taste

• Facial Nerve (VII) mediates taste from the anterior 2/3 of the tongue
• Glossopharyngeal Nerve (IX) mediates taste from the posterior 1/3 of tongue

Dysgeusia

• Dysgeusia is the technical term for a loss/dysfunction in taste.
• Infectious causes include: Sinusitis, Rhinitis, Dental Caries, Viral Infections affecting the oropharynx or nasopharynx (COVID-19, Influenza, Colds)
• latrogenic causes include: Antibiotics (especially Metronidazole), chemotherapy agents (methotrexate, doxorubicin), radiation therapy
• Vitamin Deficiency causes include: B12, Niacin
• Alcohol, Tobacco use can cause it
• Inflammatory/Autoimmune causes include: GERD, various autoimmune diseases

Esophageal Dysmotility

• Neuromuscular diseases can cause it: myasthenia gravis, severe forms of multiple sclerosis, Parkinson’s Disease, mitochondrial myopathies
• Ischemic Strokes—particular brainstem ischemic strokes can cause it

Esophageal Strictures

• Esophageal strictures are scars/areas of fibrosis which result in narrowing of the esophagus.
• Ingestion of toxic substances
• Adults: usually suicidal/homicidal attempts with industrial grade chemicals (bleach, lye, detergents, motor oils/brake fluid/windshield wiper fluid/glass cleaner, pesticides, etc.)
• Children: most commonly due to lithium ion batteries from toys
• Hyperinflammation, and GERD usually lead to strictures in the lower esophagus
• Radiation therapy can cause it

Candidal Esophagitis

• Most common cause of esophagitis in the immunocompromised/immunodeficient patient populations (HIV/AIDS, patients on long-term immunosuppression, organ transplant patients, those with genetic immunodeficiency syndromes)
• Patients commonly present with fever, dysphagia (difficulty swallowing), pain while swallowing (odynophagia), and pain which is localized to just behind the sternum
• Commonly occurs in conjunction with fungal sepsis/fungemia (fungus in the bloodstream) SEVERE!

GERD (Gastroesophageal Reflux Disease)

• In GERD: repetitious acid exposure leads to cellular damage + attempted repair and proliferation of epithelial cells until mutations are accumulated, this results in metaplasia (conversion) of the stratified squamous epithelium to simple columnar epithelium with goblet cells (inclusion bodies which secrete mucus), this can further exacerbate acid production and inflammation of the lower esophagus
• Barrett’s Esophagus is a risk factor, predisposes to esophageal adenocarcinoma!

Risk factors for developing GERD

• Obesity and sedentary lifestyle
• Increased Adiposity/Size
• Dietary Factors: Spicy foods, Foods cooked in oils, fats with saturated fats, Citrus fruits, tomatoes (which increase the acidity of the stomach and esophagus), Chocolate, Caffeine, alcohol
• Smoking
• Pharmacologic Agents: Calcium Channel Blockers, Nitrates, Anticholinergics, Bisphosphonates (taken for osteoporosis)
• Asthma

Pharmacologic management of GERD

• Proton-Pump Inhibitors (PPI’s) block the H+/K+ ATPase channel in the parietal cells of the stomach, resulting in decreased HCl production in the stomach ("Prazole" drugs)
• H2 receptor antagonists block the H2 histaminergic receptor in the parietal cell, resulting in DECREASED cAMP production, DECREASED PKA activity, and DECREASED H+/K+ ATPase ACTIVITY ("Tidine" drugs)
• Alkaline agents help to neutralize the acidic pH of the stomach for rapid relief, be aware of tachyphylaxis, Calcium Carbonate, Magnesium Hydroxide, Bismuth Salicylate (teratogenic)
• Metoclopramide (D2 antagonist) results in increased lower esophageal sphincter contractility, beware of parkinsonian-like symptoms
• Sucralfate (Coating agent), coats the esophageal and gastric mucosa, protecting them from acid-based erosion, those who require acidity must remember to take before sucralfate

Hormonal Factors Promoting Acid Production

• Gastrin from "G cells" of stomach, stimulates the H+/K+ ATPase by upregulating the cAMP-PKA pathway
• Histamine (via H2 receptor) stimulates adenylyl cyclase, the enzyme which promotes cAMP formation, histamine increases the activation of the H+/K+ ATPase
• Acetylcholine (from the vagus nerve) same physiologic role as gastrin

Gastritis

• Gastritis is inflammation of the gastric mucosa, resulting in tissue damage and possible ulcer formation.
• Helicobacter Pylori infection, H. Pylori colonization can lead to the release of pro-inflammatory cytokines which downregulate urease activity and, therefore, promotes chronic inflammation
• Pharmacologic Causes: NSAID’s
• Alcohol, Smoking
• Biochemical stress (sepsis, severe inflammation), reduces perfusion to the gastric mucosa

Hematemesis

• Hematemesis is the term for vomiting blood within the scope of peptic ulcer disease.
• Dark hematemesis, emesis of darker, sometimes brown-tinged blood; usually a sign of a slowly bleeding, chronic ulcer, requires acid suppression therapy (PPI’s, H2 blockers, etc.) and conservative management
• Bright red hematemesis, emesis of bright red blood; usually a sign of acute, large-scale hemorrhaging ulcer may require emergent endoscopy with banding OR emergency surgery