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‘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 and Answer the challenge questions . 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 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 . 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 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, . 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. 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 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 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- and negative for amphet- ers called “whippits” that can be legally vitamin B12 amines, , , and . 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 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 ,

N2O, also known as “laughing gas,” is rou- including macrocytosis, depression, and tinely used by dentists and pediatric anes- (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, , 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 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 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- as an NMDA ,

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. Other ally for a long time, and his Cannabis potential contributing factors are premorbid

use acutely escalated with use of N2O. hyperthymic temperament, a possible pro- Long-term use of Cannabis alone is a risk pensity to psychotic thinking under stress, factor for psychotic illness.22 Combined the sudden death of his wife, acute grief, Current Psychiatry 50 November 2017 abuse of Cannabis and N2O has been the potentiating role of Cannabis, dehydra- Cases That Test Your Skills

Figure

Identifying vitamin B12 deficiency

Strong suspicion of cobalamin deficiency with objective parameters eg, anemia, glossitis, paresthesia (confirm normal folate status)

Serum cobalamin within reference range Serum cobalamin <148 pmol/L (>148 pmol/L; >200 ng/L) (<200 ng/L) ie, probable deficiency ie, possible cobalamin deficiency (falsely normal cobalamin) Clinical Point

Check anti-intrinsic factor antibody Combined abuse of

Check anti-intrinsic factor antibody Check MMA, tHcy, or HoloTC Cannabis and N2O Start treatment with cobalamin Start empirical cobalamin treatment has been reported to while waiting results of second- line tests provoke psychiatric illness

No biochemical evidence of (i) Elevated MMA deficiency (“normal” or tHcy, or reduced secondary tests) Anti-intrinsic HoloTC factor antibody Unlikely to Anti-intrinsic factor (ii) or definite negative have cobalamin antibody positive objective clinical deficiency Lifelong treatment If clinical response response present: But consider as pernicious Lifelong treatment as continuation of anemia Lifelong treatment pernicious anaemia treatment if anti- as AbNegPA (anti-intrinsic factor intrinsic factor antibody positive) positive or good or AbNegPA objective response to initial treatment

ABNegPA: antibodynegative pernicious; HoloTC: holotranscobalamin; MMA: methylmalonic acid; tHcy: total homocysteine Source: Reference 21

tion, and general malnutrition. The death of and what caused it, but frank delusional ide- a loved one is associated with an increased ation has clearly receded. He still shows some risk of developing substance use disorders.27 signs of grief. Mr. M is advised to stop using

During a 15-day psychiatric hospitaliza- Cannabis and N2O and about the potential tion, Mr. M is given , increased to consequences of continued use.

15 mg/d and oral vitamin B12, 1,000 mcg/d for 4 days, then IM cyanocobalamin for 7 days. Mr. M’s symptoms steadily improve, with nor- The authors’ observations malization of sleep and near-total resolution For patients with vitamin B12 deficiency, of delusions. On hospital Day 14, his vitamin B12 guidelines from the National Health Service levels are within normal limits (844 pg/mL). in the United Kingdom and the British At discharge, Mr. M shows residual mild Society for Haematology recommend treat- Current Psychiatry grandiosity, with limited insight into his illness ment with IM hydroxocobalamin, 1,000 IU, Vol. 16, No. 11 51 Cases That Test Your Skills

Cannabis or N2O, and he discontinues olan- Related Resource zapine following this visit. Two weeks later, • Tips for teens on . https://store.samhsa.gov/shin/ Mr. M shows no psychotic or affective symp- content/PHD631/PHD631.pdf. toms other than grief, which is appropriately Drug Brand Names expressed. His insight has improved. He com- Olanzapine • Zyprexa Hydroxocobalamin • Cyanokit Cyanocobalamin • Nascobal mits to not using Cannabis, N2O, or any other illicit substances. Mr. M is referred back to his long-standing primary care provider with the 3 times weekly, for 2 weeks.21,28 For patients understanding that if any psychiatric symp- with neurologic symptoms, the British toms recur he will see a psychiatrist again. National Foundation recommends treat- ment with IM hydroxocobalamin, 1,000 IU, References 1. Semple DM, McIntosh AM, Lawrie SM. Cannabis as a risk Clinical Point on alternative days until there is no further factor for psychosis: systematic review. J Psychopharmacol. improvement.21 2005;19(2):187-194. By chemically 2. Lindenbaum J, Healton EB, Savage DG, et al. This case is a reminder for clinicians to Neuropsychiatric disorders caused by cobalamin deficiency inactivating screen for use, specifically N O, in the absence of anemia or macrocytosis. N Engl J Med. 2 1988;318(26)1720-1728. vitamin B12, which can precipitate vitamin B12 deficiency 3. Herres J, Chudnofsky CR, Manur R, et al. The use of inhaled with psychiatric symptoms as the only pre- nitrous oxide for analgesia in adult ED patients: a pilot N2O causes a rapid study. Am J Emerg Med. 2016;34(2):269-273. functional deficiency senting concern. Clinicians should consider 4. Aboumarzouk OM, Agarwal T, Syed Nong Chek SA, et al. measuring vitamin B levels in psychiatric Nitrous oxide for colonoscopy. Cochrane Database Syst Rev. 12 2011;(8):CD008506. patients at risk of deficiency of this nutri- 5. National Institute on Drug Abuse. Drug facts: inhalants. ent, including older adults, vegetarians, http://www.drugabuse.gov/publications/drugfacts/ inhalants. Updated February 2017. Accessed September 30, and those with alimentary disorders.29,30 2017. 6. SAMHSA, Center for Behavioral Health Statistics and Dietary sources of vitamin B12 include meat, Quality, National Survey on Drug Use and Health 2012 milk, egg, fish, and shellfish.31 The body can and 2013: Table 1.88C. https://www.samhsa.gov/data/ sites/default/files/NSDUH-DetTabs2013.pdf. Published store a total of 2 to 5 mg of vitamin B12; thus, September 4, 2017. Accessed September 30, 2017.

it takes 2 to 5 years to develop vitamin B12 7. Brouette T, Anton R. Clinical review of inhalants. Am J deficiency from malabsorption and can take Addict. 2001;10(1):79-94. 8. Emmanouil DE, Quock RM. Advances in understanding the as long as 20 years to develop vitamin B12 actions of nitrous oxide. Anesth Prog. 2007;54(1):9-18. deficiency from vegetarianism.32 However, 9. Garakani A, Jaffe RJ, Savla D, et al. Neurologic, psychiatric, and other medical manifestations of nitrous oxide abuse: by chemically inactivating vitamin B12, N2O a systematic review of the case literature. Am J Addict. causes a rapid functional deficiency, as was 2016;25(5):358-369. 10. Hathout L, El-Saden S. Nitrous oxide-induced B12 deficiency seen in our patient. myelopathy: perspectives on the clinical biochemistry of

vitamin B12. J Neurol Sci. 2011;301(1-2):1-8. 11. van Tonder SV, Ruck A, van der Westhuyzen J, et al. Dissociation of methionine synthetase (EC 2.1.1.13) activity OUTCOME and impairment of DNA synthesis in bats (Rousettus Improved insight aegyptiacus) with nitrous oxide-induced vitamin B12 At a 1-week follow-up appointment with a deficiency. Br J Nutr. 1986;55(1):187-192. psychiatrist, Mr. M has no evident psychotic 12. Schrier SL, Mentzer WC, Tirnauer JS. Diagnosis and treatment of vitamin B12 and folate deficiency. UpToDate. https:// symptoms. He reports that he has not used www.uptodate.com/contents/clinical-manifestations-and- Bottom Line

When consumed for recreational purposes, nitrous oxide (N2O) can rapidly cause

vitamin B12 deficiency. N2O can precipitate a broad array of psychiatric symptoms,

including psychotic syndromes, and although rare, psychosis related to vitamin B12 deficiency has been reported as the sole manifestation of illness, without associated Current Psychiatry 52 November 2017 neurologic or hematologic symptoms. Cases That Test Your Skills

diagnosis-of-vitamin-b12-and-folate-deficiency. Updated cyanocobalamin in a patient abusing nitrous oxide and September 30, 2011. Accessed September 8, 2015. cannabis. Psychosomatics. 2014;55(6):715-719. 13. Sethi NK, Mullin P, Torgovnick J, et al. Nitrous oxide 24. Yajnik S, Thapar P, Lichtor JL, et al. Effects of “whippit” abuse presenting with cobalamin responsive history on the subjective, psychomotor, and reinforcing psychosis. J Med Toxicol. 2006;2(2):71-74. effects of nitrous oxide in human. Drug Alcohol Depend. 14. Cousaert C, Heylens G, Audenaert K. Laughing gas abuse 1994;36(3):227-236. is no joke. An overview of the implications for psychiatric 25. Nagele P, Duma A, Kopec M, et al. Nitrous oxide for practice. Clin Neurol Neurosurg. 2013;115(7):859-862. treatment-resistant major depression: a proof-of-concept 15. Brodsky L, Zuniga J. Nitrous oxide: a psychotogenic agent. trial. Biol Psychiatry. 2015;78(1):10-18. Compr Psychiatry. 1975;16(2):185-188. 26. Zorumski CF, Nagele P, Mennerick S, et al. Treatment- 16. Wong SL, Harrison R, Mattman A, et al. Nitrous oxide resistant major depression: rationale for NMDA receptors

(N2O)-induced acute psychosis. Can J Neurol Sci. 2014;41(5): as targets and nitrous oxide as therapy. Front Psychiatry. 672-674. 2015;6:172. 17. Smith AD. Megaloblastic madness. Br Med J. 1960;2(5216): 27. Shear MK. Clinical practice. Complicated grief. N Engl J 1840-1845. Med. 2015;372(2):153-160. 18. Masalha R, Chudakov B, Muhamad M, et al. Cobalamin- 28. Knechtli CJC, Crowe JN. Guidelines for the investigation responsive psychosis as the sole manifestation of vitamin & management of vitamin B12 deficiency. Royal United B12 deficiency. Isr Med Associ J. 2001;3(9):701-703. Hospital Bath, National Health Service. http://www.ruh. 19. Kuo SC, Yeh SB, Yeh YW, et al. -like psychotic nhs.uk/For_Clinicians/departments_ruh/Pathology/ episode precipitated by cobalamin deficiency. Gen Hosp documents/haematology/B12_-_advice_on_investigation_ Clinical Point Psychiatry. 2009;31(6):586-588. management.pdf. Accessed June 14, 2016.

20. Raveendranathan D, Shiva L, Venkatasubramanian G, et al. 29. Jayaram N, Rao MG, Narashima A, et al. Vitamin B12 Screen for vitamin B12

Vitamin B12 deficiency masquerading as clozapine-resistant levels and psychiatric symptomatology: a case series. J psychotic symptoms in schizophrenia. J Neuropsychiatry Neuropsychiatry Clin Neurosci. 2013;25(2):150-152. levels in psychiatric Clin Neurosci. 2013;25(2):E34-E35. 30. Marks PW, Zukerberg LR. Case records of the Massachusetts patients at risk for 21. Devalia V, Hamilton MS, Molloy AM; British Committee for General Hospital. Weekly clinicopathological exercises. Standards in Haematology. Guidelines for the diagnosis and Case 30-2004. A 37-year-old woman with paresthesias of deficiency, including treatment of cobalamin and folate disorders. Br J Haematol. the arms and legs. N Engl J Med. 2004;351(13):1333-1341. 2014;166(4):496-513. 31. Watanabe F. Vitamin B12 sources and bioavailablility. Exp older adults, vegetarians, 22. Moore THM, Zammit S, Lingford-Hughes A, et al. Cannabis Biol Med (Maywood). 2007;232(10):1266-1274. use and risk of psychotic or affective mental health 32. Green R, Kinsella LJ. Current concepts in the diagnosis and those with outcomes: a systematic review. Lancet. 2007;370:319-328. of cobalamin deficiency. Neurology. 1995;45(8): 23. Garakani A, Welch AK, Jaffe RJ, et al. Psychosis and low 1435-1440. alimentary disorders