Cases That Test Your Skills ‘Self-anesthetizing’ to cope with grief Reiko J. Emtman, MD, James R. Basinski, MD, and Brian D. Poeschla, MD Mr. M, age 51, stops eating and develops delusions after his wife How would you handle this case? dies. He has been using increasing amounts of Cannabis and Answer the challenge questions nitrous oxide. What could be causing his symptoms? at CurrentPsychiatry.com and see how your colleagues responded CASE Grieving, delusional insight and immediately relapses into psy- Mr. M, age 51, is brought to the emergency chotic thinking. Over several hours in the ED, department (ED) because of new-onset delu- he is tearful and sad about his wife’s death. sions and decreased self-care over the last Mr. M recalls a similar experience of grief after 2 weeks following the sudden death of his his mother died when he was a teenager, but wife. He has become expansive and gran- at that time he did not abuse substances or diose, with pressured speech, increased have psychotic symptoms. He is fully alert, energy, and markedly reduced sleep. Mr. M is fully oriented, and has no significant deficits preoccupied with the idea that he is “the first of attention or memory. to survive a human reboot process” and says that his and his wife’s bodies and brains had What could be causing Mr. M’s symptoms? been “split apart.” Mr. M has limited his food a) acute grief and fluid intake and lost 15 lb within the past b) psychotic depression 2 to 3 weeks. c) mania Mr. M has no history of any affective, d) substance-induced psychosis psychotic, or other major mental disorders or treatment. He reports that he has regu- larly used Cannabis over the last 10 years, The authors’ observations and a few years ago, he started occasionally Grief was a precipitating event, but by itself using nitrous oxide (N2O). He says that in the grief cannot explain psychosis. Psychotic week following his wife’s death, he used N2O depression is a possibility, but Mr. M’s almost daily and in copious amounts. In an psychotic features are incongruent with attempt to “self-anesthetize” himself after his mood. Mania would be a diagnosis of his wife’s funeral, he isolated himself in his exclusion. Mr. M had no prior history of Discuss this article at bedroom and used escalating amounts of major affective illness. Mr. M was abusing www.facebook.com/ Cannabis and N2O, while continually work- CurrentPsychiatry ing on a book about their life together. Dr. Emtman is Geriatric Psychiatry Fellow, Cambridge Health At first, Mr. M shows little emotion and Alliance, Cambridge, Massachusetts. Dr. Basinski is Clinical Assistant Professor of Psychiatry, and Dr. Poeschla is Associate Professor of describes his situation as “interesting and Psychiatry, University of Washington, Seattle, Washington. fascinating.” He mentions that he thinks he Disclosures might have been “psychotic” the week after The authors report no financial relationships with any company Current Psychiatry whose products are mentioned in this article or with manufacturers 48 November 2017 his wife’s death, but he shows no sustained of competing products. Cases That Test Your Skills Cannabis, which might independently con- Table 1 tribute to psychosis1; however, he had been Causes of vitamin B12 deficiency using it recreationally for 10 years without Folate deficiency psychiatric problems. N2O, however, can cause symptoms consistent with Mr. M’s Malnutrition presentation. Gastric bypass surgery Pernicious anemia Nitrous oxide use In a patient who has been abusing N2O, what metabolic abnormalities should be Alcohol use considered? HIV a) thiamine deficiency Helicobacter pylori Source: Reference 2 b) cobalamin (vitamin B12) deficiency c) pyridoxine deficiency Clinical Point d) vitamin D deficiency N2O may cause use of N2O for pain control in the ED and during colonoscopies.3,4 neurologic EVALUATION Laboratory tests In the 2013 U.S. National Survey on and psychiatric Mr. M’s physical examination is notable Drug Use and Health, 16% of respondents dysfunction via toxic 5,6 only for an elevated blood pressure of reported lifetime illicit use of N2O. It is effects on the CNS 196/120 mm Hg. Neurologic examina- readily available in tanks used in medi- or by inactivating tion is normal. Toxicology is positive for cine and industry and in small dispens- cannabinoids and negative for amphet- ers called “whippits” that can be legally vitamin B12 amines, cocaine, opiates, and phencyclidine. purchased. Acute effects of N2O include Chemistries are normal except for a potas- euphoric mood, numbness, feeling of sium of 3.4 mEq/L (reference range, 3.7 to warmth, dizziness, and auditory halluci- 7 5.2 mEq/L) and a blood urine nitrogen of nations. The anesthetic effects of N2O are 25 mg/dL (reference range, 6 to 20 mg/dL), linked to endogenous release of opiates, which are consistent with reduced food and and recent research links its anxiolytic fluid intake. Mr. M shows no signs of anemia. activity to the facilitation of GABAergic Hematocrit is 42% and mean corpuscular inhibitory and N-methyl-d-aspartic acid volume is 90 fL. Syphilis screen is negative; a (NMDA)-mediated transmission.8 Abuse head CT scan is unremarkable. of N2O has been the presumptive cause of Further workup reveals a cobalamin (vita- death in 29 cases.9 min B12) level of 82 pg/mL (reference range, N2O may cause neurologic and psychiat- 180 to 900 pg/mL) and a methylmalonic acid ric dysfunction by 2 main routes: direct toxic level of >5 (reference range, <0.3). Mr. M’s CNS effects and inactivating vitamin B12. folate level is normal (>22 ng/mL). Because the Putative mechanisms of action of vitamin acute onset of symptoms corresponded with B12 deficiency–induced neuronal dysfunc- a sudden increase in N2O use, further workup tion include dysregulation of cytokine and 10 for other causes of vitamin B12 deficiency growth factor levels in the CSF. By irre- 2 (Table 1 ) is not pursued. versible oxidation of its cobalt ion, N2O inactivates vitamin B12 and causes func- 11 tional deficiency. Vitamin B12 deficiency The authors’ observations can cause various signs and symptoms, N2O, also known as “laughing gas,” is rou- including macrocytosis, depression, and tinely used by dentists and pediatric anes- hallucinations (Table 2, page 50).2,12 Several thesiologists, and has other medical uses. case reports have linked abuse of N2O Current Psychiatry Some studies have examined an adjunctive with vitamin B12 deficiency and reported Vol. 16, No. 11 49 Cases That Test Your Skills Table 2 reported to provoke psychotic illness. In a case report of a 22-year-old male who Vitamin B12 deficiency: Signs and symptoms was treated for paranoid delusions, using Cannabis and 100 cartridges of N2O daily Signs Anemia, macrocytosis (mean was associated with low vitamin B and corpuscular volume >100 fL), 12 hypersegmented neutrophils, elevated homocysteine and methylmalo- idiopathic pancytopenia, elevated nic acid levels.23 methylmalonic acid levels,a Cannabis use may have played a role elevated homocysteine levels in Mr. M’s escalating N O use. In a study Symptoms Weakness, ataxia, paresthesia, 2 memory loss, depression, comparing 9 active Cannabis users with 9 hypomania, psychosis, non-using controls, users rated the subjec- hallucinations tive effects of N2O as more intense than aCommon in patients with renal insufficiency non-users.24 In our patient’s case, Cannabis Clinical Point Source: References 2,12 may have played a role in both sustaining Vitamin B12 his escalating N2O abuse and potentiating deficiency can cause its psychotomimetic effects. various signs and psychotic symptoms as the sole presenting It also is possible that Mr. M may have symptoms, including abnormalities, with an absence of other been “self-medicating” his grief with N2O. 13-16 macrocytosis, signs and symptoms. In a recent placebo-controlled crossover Beginning with a 1960 report of a series trial of 20 patients with treatment-resistant depression, and of patients with “megaloblastic madness,”17 depression, Nagele et al25 found a signifi- hallucinations there have been calls for increased awareness cant rapid and week-long antidepressant of the potential for vitamin B12 deficiency– effect of subanesthetic N2O use. A model induced psychiatric disorders, even in the involving NMDA receptor activation has absence of other hematologic or neurologic been proposed.25,26 Zorumski et al26 further sequelae that would alert clinicians of the reviewed possible antidepressant mecha- deficiency. In a case series of 141 patients nisms of N2O. They compared N2O with with a broad array of neurologic and psychi- ketamine as an NMDA receptor antagonist, atric symptoms associated with vitamin B12 but also noted its distinct effects on gluta- deficiency, 40 (28%) patients had no anemia minergic and GABAergic neurotransmitter or macrocytosis.2 systems as well as other receptors and chan- 26 Vitamin B12-responsive psychosis has nels. However, illicit use of N2O poses tox- been reported as the sole manifestation of icity dangers and has no current indication illness, without associated neurologic or for psychiatric treatment. hematologic symptoms, in only a few case reports. Vitamin B12 levels in these cases ranged from 75 to 236 pg/mL (reference TREATMENT Supplementation range, 160 to 950 pg/mL).18-20 In all of these Mr. M is diagnosed with substance-induced cases, the vitamin B12 deficiency was traced psychotic disorder. His symptoms were pre- to dietary causes. The clinical evaluation of cipitated by an acute increase in N2O use, suspected vitamin B12 deficiency is outlined which has been shown to cause vitamin B12 in the Figure21 (page 51). deficiency, which we consider was likely a pri- Mr. M had used Cannabis recreation- mary contributor to his presentation.