A patient presents with low mood one month after heavy nitrous‑oxide (N₂O) abuse; what is the likely cause and how should it be evaluated and managed?

Low Mood After Nitrous Oxide Abuse: Vitamin B12-Mediated Neuropsychiatric Toxicity

The low mood one month after heavy nitrous oxide abuse is most likely caused by functional vitamin B12 deficiency resulting from N₂O's irreversible inactivation of vitamin B12, which disrupts neurotransmitter synthesis and myelin production—this requires immediate evaluation of B12 levels, homocysteine, and neurological examination, followed by aggressive B12 replacement therapy. 1, 2, 3

Pathophysiology of N₂O-Induced Psychiatric Symptoms

Nitrous oxide irreversibly binds and inactivates vitamin B12, which serves as a critical cofactor in metabolic pathways involved in DNA synthesis, myelin production, and neurotransmitter metabolism. 2 This functional B12 deficiency can develop rapidly—even within one month of heavy use—and manifests as neuropsychiatric complications including depression, emotional indifference, personality changes, hallucinations, and cognitive impairment. 4, 3

Critical insight: Psychiatric symptoms can occur without accompanying neurological symptoms in approximately half of cases, and vitamin B12 concentrations may appear within the hospital's reference range despite functional deficiency. 1 This makes the diagnosis easily missed if clinicians rely solely on B12 levels or wait for classic neurological signs like paresthesias or ataxia.

Essential Diagnostic Evaluation

Laboratory Assessment

• Vitamin B12 level: Even if within "normal" range, levels below 211 pg/mL are concerning; one case series showed B12 as low as 78 pg/mL. 4
• Homocysteine level: All 16 patients in one recent series had hyperhomocysteinemia, making this a more sensitive marker than B12 alone. 3
• Complete blood count: Look for megaloblastic anemia, though this may be absent early. 5, 2
• Methylmalonic acid: Elevated in functional B12 deficiency even when serum B12 appears normal. 2

Neurological Examination

Look specifically for:

• Sensory symptoms: Paresthesias in extremities (fingers, toes, all four limbs). 5, 3
• Motor symptoms: Lower extremity weakness, unsteady gait, difficulty ambulating. 4, 3
• Cognitive assessment: Memory impairment, disorientation, acute cognitive changes. 5, 3
• Cranial nerve involvement: Diplopia (double vision) has been reported. 4

Neuroimaging Considerations

If neurological symptoms are present, MRI of the cervical and thoracic spine may show abnormal high T2-weighted signal with the characteristic inverted "V" sign in axial view, involving the posterior columns. 3 However, brain and spinal cord MRI can be completely normal despite significant symptoms. 4

Management Protocol

Immediate Treatment

Initiate intramuscular vitamin B12 replacement immediately—do not wait for laboratory confirmation if clinical suspicion is high. 4, 3

• Acute phase: Intramuscular cyanocobalamin or hydroxocobalamin (typical dosing: 1000 mcg IM daily for 1-2 weeks, then weekly). 4
• Maintenance: Transition to long-term oral or IM supplementation after acute phase. 4
• Cessation of N₂O use: Absolute requirement for recovery; continued use will perpetuate toxicity. 3

Expected Clinical Course

The clinical response to vitamin B12 supplementation combined with cessation of nitrous oxide use is generally good, with neuropsychiatric symptoms improving in all cases in recent series. 3 However, recovery may be partial rather than complete, particularly if treatment is delayed. 4

Critical Clinical Pitfalls

Don't Miss Isolated Psychiatric Presentations

The most dangerous pitfall is dismissing new-onset psychiatric symptoms (depression, mood changes, personality changes) as primary psychiatric illness without asking about nitrous oxide use. 1 Approximately 50% of patients with N₂O-induced psychiatric symptoms do not have neurological symptoms at presentation. 1

Don't Rely on "Normal" B12 Levels

Vitamin B12 concentrations are often within the hospital's reference range despite functional deficiency. 1 Use homocysteine and methylmalonic acid as more sensitive markers. 3

Don't Underestimate Rapidity of Onset

Severe vitamin B12 deficiency with neuropsychiatric symptoms can develop after just one month of heavy use (a few times daily). 4 This is much faster than dietary B12 deficiency, which typically takes years to develop.

Risk Stratification by Usage Pattern

Heavy/Sustained Use (High Risk)

• Daily or near-daily use for weeks to months
• Large volume per session (>10 balloons)
• Highest risk for functional B12 deficiency and neuropsychiatric complications 5, 3

Moderate Use (Lower Risk)

• Most recreational users take <10 balloons per episode
• Approximately 80% have <10 episodes per year
• Lower but not absent risk for complications 5

Patient Demographics

Young adults aged 17-25 years are predominantly involved, with recreational N₂O being the second most popular drug after cannabis in some regions. 5, 3 The patient population includes university students who obtain N₂O from whipped cream chargers. 4