Does vitamin B12 deficiency explain psychiatric symptoms in recreational nitrous oxide users? A narrative review

Figures & data

Figure 1. Strobe diagram of screened cases.

Table 1. Overview of case reports reviewed.

Case	Origin of paper	Age (sex)	Amount of nitrous oxide use	Period of nitrous oxide use	Other illicit substance use	B12 level upon admission	Reference range^a	Remarks
1 [18]	Australia	37 (F)	20 whippets per day	Several years		130 pmol/L	140 − 700	Medical history: depression, variable B12 deficiency during 3 years
2 [19]	Australia	21 (F)	200 whippets per week	Unknown		56 ng/L	200 − 1000
3 [20]	USA	32 (M)	Several times per day	6 months		Unknown
4 [21]	China	19 (M)	1) 400 whippets per day 2) 1000 whippets per day	1) 6 months 2) Last month		602 pmol/L	Unknown
5 [22]	Taiwan	32 (F)	Unknown	Daily during 10 years	Alcohol, ketamine, MDMA			Medical history: MDD
6 [22]	Taiwan	33 (M)	Unknown	Daily during 1 year	Ketamine, MDMA			Medical history: MDD
7 [22]	Taiwan	24 (F)	Unknown	Daily during 1 year	Ketamine, cannabis			Medical history: MDD
8 [22]	Taiwan	32 (M)	Unknown	2-3/week during 4 months
9 [22]	Taiwan	21 (F)	Unknown	Daily during 10 months	Alcohol, ketamine			Medical history: MDD, anorexia nervosa
10 [22]	Taiwan	24 (F)	Unknown	Daily during 6 years	Methamfetamine, ketamine, MDMA, alcohol			Medical history: MDD
11 [22]	Taiwan	27 (M)	Unknown	Daily during 7 years	Ketamine, MDMA, alcohol, cannabis			Medical history: bipolar I disorder
12 [23]	USA	38 (M)	Unknown	5 years, recent increase in use	Alcohol abuse	193 pg/mL	Unknown	Medical history: generalized anxiety disorder, major depressive disorder, social phobia
13 [24]	Belgium	24 (M)	"Several cases"	Unknown	Cannabis	171 pg/mL	197 − 866
14 [13]	USA	22 (M)	100 whippets per day	9 months	Cannabis (1 joint/week)	144 pg/mL	180 − 914
15 [25]	USA	22 (M)	20-pound canister	Once	Alcohol	Unknown
16 [26]	Australia	45 (M)	480 whippets per occasion	Unknown		97 pmol/L	140 − 650	Medical history: nitrous oxide- induced psychosis
17 [27]	United Kingdom	27 (F)	24 whippets per occasion	Unknown		83 ng/L	187 − 833	Patient from Ethiopia Medical history: brief psychotic episode in context of nitrous oxide abuse
18 [28]	USA	55 (M)	Unknown	Many years		121 μg/L	190 − 930	Medical history: obsessive compulsive disorder, intermitting gait disturbance, vitamin B12 deficiency
19 [29]	Australia	21 (F)	300 whippets per week	One year, increased use in last month		44 pmol/L	150 − 700
20 [30]	Korea	22 (F)	250 whippets per day	One month		136 pg/mL	211 − 911
21 [31]	USA	21 (F)	Several times per day	One month		78 pg/mL	211 − 911	Patient from China
22 [32]	China	18 (F)	1 whippet per day	5 months, increased use in last 4 days		<1500 pmol/L	Unknown	Patient resided in Australia during nitrous oxide abuse
23 [8]	Canada	20 (F)	100 whippets per day	Unknown		"Normal"		Patient from Asia
24 [33]	USA	21 (F)	600 whippets per day	Several weeks		"Normal"		Patient from China, 11 weeks pregnant Medical history: multiple abortions
25 [34]	USA	24 (M)	100 whippets per day	2 years	Alcohol	254 pg/mL	210–920	Biological father had bipolar disorder
26 [11]	USA	33 (M)	Unknown	Daily during 4 weeks		202 pg/mL	180–900	Patient from India
27 [15]	United Kingdom	37 (F)	144 "cases"	Once		193 ng/L	180–1000	Patient from Somalia
28 [35]	USA	28 (M)	Continuously	4-6 months	Marijuana	383 pg/mL	300–1000
29 [36]	USA	20 (F)	Hundreds of whippets	Several weeks	Hydroxymorphone, oxymorphone, marijuana	"Deficit"		Pregnant
30 [37]	Netherlands	26 (M)	2 liters per week	6 months		56 pmol/L	148–550
31 [38]	Canada	30-40 (M)	3 times per two weeks	Years		148 pmol/L	156–672	Exact age unknown

MDD: Major Depressive Disorder.

^aReference range reported in the article.

Table 2. Number of psychiatric symptoms (n = 31) reported and the presence of neurologic symptoms (n = 16).

Category	Symptoms	Number of cases	Distribution of neurologic symptoms
			Yes	No
Thinking disturbances		19	11	8
	Disturbances in thought contents	7	5	2
	Delusions	11	6	5
	Paranoia	11	8	3
	Suicidal thoughts	1	1	0
Disturbances of perception		16	10	6
	Hallucinations	16	10	6
Disturbances of consciousness		8	4	4
	Disturbances of orientation	4	3	1
	Attention deficit	5	2	3
	Derealization	1	0	1
Disturbances of memory		8	6	2
Disturbances of cognition		5	4	1
Disturbances of mood		8	4	4
	Depression	3	2	1
	Affective/emotional instability	6	3	3
Anxiety disorders		5	4	1
	Anxiety	5	4	1
	Panic attacks	1	1	0
Somatic disturbances in psychiatric illness		16	7	9
	Sleep disturbances	3	2	1
	Dreams/nightmares	1	1	0
	Lethargia	1	0	1
	Aggression/Irritability	6	2	4
	Agitation	6	4	2
	Self-mutilation	1	1	0
	Suicide attempt	3	0	3

Figure 2. Type of treatment (n = 31) of patients with and without neurologic symptoms. Symptomatic treatments (e.g., benzodiazepines) were not taken into account in this figure.

Figure 3. Metabolic reactions involving vitamin B12. Vitamin B12, or cobalamin, affects two metabolic pathways through its active forms adenosylcobalamin and methylcobalamin. They are cofactors for reactions in which methylmalonyl coenzyme A mutase and methionine synthase are substrates. Without vitamin B12, coenzyme A is converted to methylmalonic acid (MMA) and homocysteine is not metabolized, leading to elevated serum concentrations of MMA and homocysteine. The black arrows represent the physiological process. The grey arrow represents the process in absence of vitamin B12.

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