Cannabis and Anandamide - The Endocannabinoid System

What Is Anandamide?

• 1964: Isolation of THC from cannabis
• 1988: CB1 cannabinoid receptors identified in the brain
• 1990: CB1 receptor cloned
• 1992: Anandamide discovered as the first endogenous brain endocannabinoid
• 1993: CB2 receptor identified

The Endocannabinoid System

How THC Hijacks the Endocannabinoid System

• Anandamide is a partial agonist at CB1/CB2 and is rapidly broken down by the enzyme fatty acid amide hydrolase (FAAH)
• THC is also a partial agonist but is not degraded by FAAH, so its effects last much longer
• CBD (cannabidiol) is an isomer of THC but is relatively inactive at CB1 and CB2 - it is non-psychoactive, and its mechanism is not fully understood; it may even be antipsychotic and anxiolytic

Effects of Cannabis (via CB1 Activation)

• Sense of well-being, relaxation
• Friendliness, euphoria
• Loss of temporal awareness
• Appetite stimulation
• Mild analgesia

• Hallucinations, delusions
• Anxiety, memory impairment
• Precipitation of psychosis in vulnerable individuals

Anandamide as a Target

• Stahl's Essential Psychopharmacology, Neuroscientific Basis, Cannabis section
• Katzung's Basic and Clinical Pharmacology, 16th Ed., Chapter 21 - Endocannabinoids
• Kaplan and Sadock's Synopsis of Psychiatry, Table 33-5 (cannabinoid timeline)

Cannabis Toxicity

1. General Lethality

2. Acute Toxicity - Clinical Features

From Smoking/Vaping (rapid onset, 2-4 hours duration)

From Edibles (delayed onset up to 4 hours, duration 6-12+ hours)

• Users re-dose while waiting for effects to begin
• Dose is difficult to estimate
• Effects are unpredictable in naive or infrequent users
• "Cannabis tourists" and children are especially vulnerable

3. Pediatric Toxicity

• Hypothermia, ataxia, nystagmus, tremor
• Tachycardia, injected conjunctiva, labile affect
• Drowsiness, hypotonia, lethargy
• Seizures (less common)
• Coma and airway obstruction requiring intubation in large ingestions

4. Neuropsychiatric Toxicity

• Severe anxiety and panic attacks (especially with high-THC products)
• Acute psychosis - can occur even without prior psychiatric history
• Worsening of pre-existing psychotic disorders
• Cannabis hyperemesis syndrome (CHS): cyclic severe nausea, vomiting, abdominal pain in chronic heavy users - often relieved by hot showers
• Cognitive impairment, especially with adolescent use
• High-potency cannabis (more THC, less CBD) carries the greatest psychosis risk

5. Cardiovascular Toxicity

1. Combustion products - similar toxicity profile to cigarette smoke
2. Direct sympathomimetic effects - acute heart rate increase of 20-100%, supine hypertension, systemic catecholamine release causing coronary constriction and platelet activation
3. Indirect effects - extreme anxiety, hallucinations, psychosis

• Myocardial infarction (especially in middle-aged adults with pre-existing disease)
• Stroke, arrhythmias, sudden death
• Increased myocardial oxygen demand with inadequate compensatory coronary blood flow
• Orthostatic hypotension - risk in elderly patients
• Case reports of serious cardiovascular events in young, heavy daily cannabis smokers
• Hospital data (1990-2014) showed increased cardiac-related deaths after medical cannabis policy passage, especially in older men

6. Pulmonary Toxicity

• Cannabis smoke delivers more carboxyhemoglobin and inhaled tar per cigarette than tobacco smoke
• Deep inhalation with breath-holding increases exposure
• Deep inhalation at near-total lung capacity can cause barotrauma - pneumothorax and pneumomediastinum
• Chronic symptoms: laryngitis, wheezing, chronic cough, sputum production
• Pulmonary fungal infections in immunocompromised cannabis smokers (diabetes, leukemia, chronic steroid use)
• EVALI (e-cigarette/vaping associated lung injury): Severe acute hypoxemic respiratory failure/ARDS with ground-glass opacities on CT (subpleural sparing), linked to vitamin E acetate in illicit THC vape pens - first described in 2019
• Cannabis smoking has not been clearly linked to lung cancer, likely due to lower frequency of use compared to tobacco

7. Synthetic Cannabinoids ("Spice," "K2")

8. Management

9. Special Populations at Highest Risk

• Children - accidental edible ingestion
• Cannabis-naive users and tourists - unfamiliar with edible dosing and delayed onset
• Elderly - orthostatic hypotension, cardiovascular risk
• Patients with cardiovascular disease - MI, arrhythmia risk
• Immunocompromised - pulmonary fungal infections
• Pregnant women - fetal neurodevelopmental effects, cognitive deficits in offspring
• Adolescents - neurodevelopmental harm, higher risk of psychosis

• Harrison's Principles of Internal Medicine 22E (2025) - Acute & Chronic Toxicity
• Rosen's Emergency Medicine - Clinical Features, Differential Diagnosis
• Murray & Nadel's Textbook of Respiratory Medicine - Pulmonary & Cardiovascular Toxicity
• Kaplan & Sadock's Comprehensive Textbook of Psychiatry - Pharmacology of Cannabinoids

Unilateral Toe (Digit) Swelling - Differential Diagnosis & Approach

Key Concept: The "Sausage Digit" (Dactylitis)

• Flexor tenosynovitis
• Soft tissue edema
• Bone edema
• Synovitis

Dactylitis of the second toe with associated nail changes - Rheumatology, 2-Volume Set (Elsevier)

Differential Diagnosis - Organized by Likelihood

1. GOUT (Podagra) - Most Common Cause

• Involved in 70-90% of gout cases (the 1st MTP joint)
• Flares often begin at night or early morning
• Joint becomes warm, red, tender, and substantially swollen
• Can mimic cellulitis (pseudocellulitis)
• Flares self-resolve within 1-2 weeks without treatment
• Triggered by: purine-rich food, alcohol, diuretics, dehydration, trauma

2. Psoriatic Arthritis (PsA) - Dactylitis

• Dactylitis occurs in 30-40% of PsA patients
• Most commonly involves 1-2 digits at a time
• Feet affected more than hands
• Associated with DIP joint involvement and nail changes (pitting, onycholysis)
• Long-term non-inflammatory swelling with loss of mobility can persist after the flare resolves
• Look for skin psoriasis plaques elsewhere

3. Other Spondyloarthropathies Causing Dactylitis

4. Septic Arthritis / Osteomyelitis

• Bacterial infection of the joint or bone
• Hot, swollen, exquisitely tender single joint
• Fever, elevated WBC, raised CRP/ESR
• Risk factors: diabetes, immunosuppression, penetrating injury, IV drug use
• Medical emergency - requires urgent joint aspiration and antibiotics

5. Trauma / Fracture

• History of injury (dropping object, stubbing toe)
• Stress fractures (less severe, insidious onset)
• Bruising may appear the next day
• Confirm with X-ray

6. Ingrown Toenail (Onychocryptosis)

• Nail edge grows into periungual skin
• Redness, swelling, pain at the nail fold
• Can become secondarily infected (paronychia)
• Usually affects the great toe

7. Cellulitis / Soft Tissue Infection

• Spreading erythema, warmth, swelling of the toe/foot
• No joint effusion on examination
• May follow a small wound, insect bite, or tinea pedis
• Can co-exist with or be confused with gout

8. Calcium Pyrophosphate Deposition (CPPD / Pseudogout)

• Similar presentation to gout but first MTP rarely involved
• More commonly knee or wrist
• Diagnosed by joint aspiration (rhomboid crystals vs. needle-shaped in gout)

9. Chronic Tophaceous Gout

• Painless subcutaneous tophi (chalky deposits) in and around toe joints
• Occurs after years of untreated hyperuricemia
• Bony destruction and deformity on X-ray

Distinguishing Features at a Glance

Investigations to Order

1. Serum uric acid - elevated in gout (note: can be normal during an acute flare)
2. FBC, CRP, ESR - elevated in infection/inflammation
3. X-ray foot - bony erosions, fractures, soft tissue swelling
4. Joint aspiration (arthrocentesis) - gold standard; crystals under polarized light microscopy
5. Ultrasound or MRI - if dactylitis suspected; shows tenosynovitis + synovitis extent
6. HLA-B27 - if spondyloarthropathy suspected
7. Skin examination - psoriasis plaques, nail changes
8. Blood cultures - if septic arthritis suspected

Red Flags Requiring Urgent Assessment

• High fever with hot swollen joint (septic arthritis - emergency)
• Rapidly spreading redness up the leg (necrotizing fasciitis)
• Diabetic foot with any wound/swelling
• Crepitus on palpation (gas-forming organisms)

• Harrison's Principles of Internal Medicine 22E (2025) - Gout, Clinical Manifestations
• Rheumatology, 2-Volume Set (Elsevier 2022) - Dactylitis in PsA
• Firestein & Kelley's Textbook of Rheumatology - Spondyloarthropathy features
• Miller's Review of Orthopaedics, 9th Ed. - Crystal deposition disease

Treatment of Unilateral Toe Swelling - by Cause

1. GOUT (Podagra) Treatment

Acute Flare Management

Important: Patients already on urate-lowering therapy (ULT) should continue it uninterrupted during a flare. ULT can also be safely started during an acute flare as long as anti-inflammatory cover is continued for several months.

Colchicine - Mechanism

Chronic Gout - Urate-Lowering Therapy (ULT)

• ≥2 gout flares per year
• Single flare with CKD stage ≥3 or serum urate ≥9 mg/dL
• Tophi present
• Kidney stones

Important: Starting ULT causes rapid shifts in serum urate which can precipitate an acute flare. Cover with low-dose colchicine, NSAIDs, or corticosteroids for at least 6 months after initiating ULT.

Lifestyle Modifications (ACR Recommendations)

2. Psoriatic Arthritis / Dactylitis Treatment

Step-Up Algorithm (EULAR/GRAPPA Guidelines)

• NSAIDs for peripheral arthritis and dactylitis
• Corticosteroid injections (with caution)

• Methotrexate - first-line; effective for skin, nails, arthritis. Monitor LFTs, blood counts, renal function. Folic acid 1 mg/day mandatory
• Leflunomide - effective for skin and arthritis
• Sulfasalazine - used for peripheral arthritis

Note: For enthesitis or spondylitis, skip straight to biologics - csDMARDs are not effective for these domains.

• Apremilast (PDE4 inhibitor) - effective for dactylitis and arthritis. SE: weight loss (10%), depression (1%)

3. Septic Arthritis Treatment

• Gram-positive cocci (most common - Staph aureus): IV flucloxacillin or vancomycin (if MRSA suspected)
• Gram-negative rods: IV cephalosporin or piperacillin-tazobactam
• Sexually active young adults: cover N. gonorrhoeae - IV ceftriaxone
• Duration: typically 4-6 weeks total (IV then oral)

4. Trauma / Fracture Treatment

5. Cellulitis / Soft Tissue Infection Treatment

6. Ingrown Toenail Treatment

Summary Treatment Ladder

Single hot swollen toe
        ↓
Is it septic arthritis? → YES → Admit, IV antibiotics + joint drainage
        ↓ NO
Is it gout? → YES → NSAIDs/colchicine/steroids (acute)
                      + ULT after flare (allopurinol)
        ↓ NO
Is it dactylitis (PsA)? → YES → NSAIDs → csDMARDs → Biologics
        ↓ NO
Trauma → Buddy strapping, rest, analgesia
Cellulitis → Antibiotics, elevation
Ingrown nail → Nail care, antibiotics if infected

• Goldman-Cecil Medicine - Gout treatment, treat-to-target
• Lippincott Illustrated Reviews: Pharmacology - Colchicine, acute gout
• Goodman & Gilman's Pharmacological Basis of Therapeutics - Febuxostat/allopurinol
• Fitzpatrick's Dermatology, 2-Volume Set - PsA treatment algorithm (EULAR/GRAPPA)
• Rosen's Emergency Medicine - Septic arthritis management