Nitrous Oxide: A Psychotogenic
Agent
Lewis Brodsky and Jorge Zuniga
T
HE LITERATURE is noticeably lacking in information on the psychological effects of nitrous oxide. There is obvious heuristic value in exploring this because (1) nitrous oxide is widely used for general anesthesia and (2) there appears to be an increase in the abuse of nitrous oxide by people seeking psychodelic effects.’ Bergstrom and Bernstein2 have noted and studied psychic reactions following nitrous oxide anesthesia used for cesarean section. Although their study lacked the statistical validity that would have derived from a larger number of patients, they reported psychotic reactions in all patients studied who were given nitrous oxide analgesia (80%) alone, as opposed to patients being given barbiturates preoperatively. Four of the 6 patients given nitrous oxide alone still exhibited serious sequelae (perhaps what could be termed psychotic sequelae) 1 year after the anesthetic event. None of the 11 patients receiving barbiturate premeditation developed any psychotic symptoms. Of paramount importance in their study was the finding that the premorbid personality of the patient played no role in the outcome. Most current data on the sequelae of nitrous oxide point to its relative safety and noncumulative effects.‘v3 It has been said that were it a better muscle relaxant it would be the ideal anesthetic.3 Although a single case report does not provide opportunity for in-depth scrutiny of a hypothesis, it may help to bring to light what is likely to become a medical-psychiatric-social problem in the future. CASE PRESENTATION Dr. X is a 32-year-old
white married
male whom we first saw as a result of his feeling confused,
his
inability to carry out his dental practice, and his belief that he was being observed by people sent to gather evidence in order to revoke his license. He believed that his assistant was stealing from him, and he felt he was the victim of a conspiracy initiated by the licensing body that governed his right to practice. Until 6 months prior to his hospitalization, the patient had never given evidence of confusion or psychotic symptoms (such as delusions and hallucinations) nor had any difficulty functioning. In fact, his performance both at work and socially was judged to be above average. Through our patient (the medium being open-ended psychiatric interview) and the social history provided by his family we became aware of several factors that helped to explain his abuse of nitrous oxide. His premorbid history gave evidence of a dependent character structure within a depressive core.* *The following is one illustration to lend credence to the formulation that we have presented in summary fashion: The patient had always had low self-esteem. There was a history of intense sibling rivalry with an older brother who was extremely successful. By contrast, the patient saw himself failing. His parents were extremely achievement-oriented and would accuse the patient of “being lazy.” From the Department ofpsychiatry. Sinai Hospital of Detroir. Detroit. Mich. Lewis Brodsky, M.D.: Chief, Crisis Intervention Center, Departmenr of P.rychiatry. Sinai Hospital of Detroit; Assisrant Clinical Professor, Michigan State University. East Lansing, Mich.: Instructor. Wayne State University, Delroit. Mich. Jorge Zuniga, M.D.: Third- Year Resident. Department oj Psw-hiatry, Sinai Hospital of Detroit. [L!197.5 hy Grune & Stratton, Inc. Comprehensive Psychiatry, Vol. 16. No. 2 IMarch/Aprtl).
1975
185
186
BRODSKY
AND ZUNIGA
His recently initiated practice, the serious illness of his mother, and the birth of his first child set the stage for his increasing use of nitrous oxide on a daily basis during the 6 months prior to his hospitalization. The nitrous oxide helped him to feel better and placed him in a somnolent state of bliss. He could “relax.” The paranoid delusions appeared approximately 3 months after he had begun using the nitrous oxide (NPO concentration ranging from 45% to 65%). The inhalation would often take place several times per day. In the 4 or 5 days prior to his hospitalization the patient’s paranoid symptoms had become more intense. His delusional system had begun to incorporate all of the people with whom he had any kind of contact. For example, his newly hired secretary was really “sent to spy on me so that they would have evidence that I am incompetent.” During those last 4 or 5 days he had become increasingly confused. He suffered recent memory loss, often forgetting scheduled activities. At the time of his hospitalization his retention and recall had become impaired and his synthetic and integrative functions were seriously impaired. He was suffering from a nominal dysphasia and was beginning to experience visual hallucinations and bilateral paresthesia. The hallucinations were nor the systematized, dynamically rich projections frequently seen in a schizophrenic process. For example, on one occasion the patient saw a funnel-shaped whirlwind in front of him. It is also significant that they were always visual. Not only was he suffering from paranoid delusions, but also delusions of guilt. He began to assess his practice in an overly scrupulous fashion, blaming himself for shortcomings, and feeling that he deserved to be punished. It is important to note that tangential thinking existed at this time. Psychological testing, which included the Wechsler Adult Intelligence Scale, the Minnesota Multiphasic Personality inventory, the Tactual Performance Test of the Holstead battery, the Reitan-Indiana Aphasia Screening Test, the Purdue Pegboard, the Reitan Trailmaking Test, and the Rorschach, was conducted following the commencement of therapy in the hospital. Testing revealed a very mild disruption of mental abilities. There appeared to be a mild bilateral disturbance of temporal-lobe functions. Immediate memory was impaired, probably as a result of cerebra1 dysfunction. There was questionable dysgraphia of the right hand. Evidence of a mild bilateral motor uncoordination, maxima1 in the right hand (hence involvement of the left motor cortex) was documented. Visual motor speed, though normal, was not as good as expected for his intellectual level. Perseverate response elicited on the Rorschach provided further evidence of a toxic state at the time of the examination. The impression following psychological testing was that there was a mild residual of toxic cerebral dysfunction. It was also felt, as a result of the testing, that the patient was experiencing much more in the way of somatic symptomatology than he was willing to admit. Within 1 week of hospitalization the secondary psychotic symptoms had disappeared. Treatment modalities employed included milieu therapy, psychotherapy, and chemotherapy. The antipsychotic agent utilized was trifluoperazine (IO mg q 12 hr). This was selected because of the value of an alerting, nonsedative antipsychotic agent in the presence of organic involvement.3 By the end of 112 weeks this dose was decreased (5 mg q I2 hr). At the time of discharge all of the toxic symptoms found on mental-status examination had disappeared. The patient was maintained on a small dose of trifluoperazine (2 mg q 12 hr) until I week posthospitalization. At this point all medications were discontinued. During the first week posthospitalization, the patient endured one night in which he experienced recurrence of some of his paranoid thinking. An l8-month follow-up had shown the patient to be free of any delusional thinking, or psychotic symptomatology in general. DISCUSSION
We have ruled out the possibility of the patient having been psychotic prior to his use of nitrous oxide. There is no question that at the very least a decompensation was precipitated by the nitrous oxide inhalation. In the absence of psychological testing it would be more difficult for us to distinguish between what may be termed a paranoid schizophrenic decompensation, merely precipitated by nitrous oxide, and a toxic psychosis. However, we are fortunate in being able to document specific areas of cerebral dysfunction that cannot be accounted for on a “functional” basis. In addition, we see no evidence premorbidly of a pre-
NITROUS
OXIDE
187
schizophrenic matrix. We are also able to appease those who would subscribe to a genetic hypothesis of schizophrenia by pointing to the absence of anything remotely resembling schizophrenia in the patient’s immediate family over the last two generations. We have the additional benefit of the results of psychological testing conducted on this patient as a university undergraduate, approximately 6 years prior to this episode. At that time there was no evidence of any cerebral dysfunction or of a paranoid matrix. Now it becomes incumbent upon us to postulate a mechanism by which the chronic use of nitrous oxide produced a disruption in cerebral function and a clinical picture of a toxic psychosis. We are aware of the fact that nitrous oxide inhalation in high concentrations does produce a state of cerebral anoxia; as a consequence methemoglobinemia, low arterial PO*, and acidosis (which produces a shift in the oxyhemoglobin dissociation curve) develop.4 We believe that the potential for a nitrous oxide psychosis is universal. We can draw an analogy to the other psychotomimetic agents. For our purposes we will make the comparison with amphetamines: Although chronic use would appear to have the better potential for inducing a psychosis, potential exists also with acute use. In effect we would then have to consider the influence of nitrous oxide (its effective dosage) coupled with constitutional factors. The possibility may exist that nitrous oxide favors the metabolism of biogenic amines along aberrant pathways, ultimately producing psychotomimetic transmethylated derivatives. This could take place either through enhancement of these pathways directly or indirectly through blocking the enzyme [email protected]* In vitro and in vivo studies of the action of nitrous oxide on neuronal metabolism, e.g., tryptophan transport ratio, biogenic amine levels, dopamine$hydroxylase, etc., should be emphasized in order to formulate an accurate mechanism. The need for more careful evaluation of nitrous oxide from both physiologic and psychologic vantage points is apparent in view of current clinical and psychedelic use.
SUMMARY
1. In the presence of increased abuse of nitrous oxide for its psychedelic effects, the absence of studies dealing with its psychological sequelae was noted. 2. A case was presented of a patient who developed psychotic and “toxic organic” features following 6 months of almost daily inhalation of nitrous oxide. 3. The mental-status examination and psychological testing pointed strongly toward an organic substrate. 4. A mechanism for the psychotogenic effect of nitrous oxide was postulated. 5. The need for more intensive follow-up studies involving the psychological effects of nitrous oxide was emphasized.
*This is a current hypothesis elucidating
a biochemical
etiology of schizophrenia.
188
BRODSKY
AND ZUNIGA
REFERENCES 1. Bergstrom H, Bernstein K: Psychic reactions after analgesia with nitrous oxide for caesarean section. Lancet 7567:541-542, 1968 2. Brodsky L: Biochemical survey of schizophrenia. Can Psychiatr Assoc J 15:375388, 1970 3. Detre TP, Jarecki HJ: Modern Psychiatric Treatment. Philadelphia, JB Lippincott, 1971, pp 413-422
4. Dillon JB: Nitrous oxide inhalation as a fad. Calif Med 106444-446, 1967 5. Goth A: Textbook of Pharmacology (ed 7). St. Louis, CV Mosby, 1974 6. Meyler L, Herxheimer ML: Side effects of drugs, vol 7. Amsterdam, Excerpta Medica 1972, p 189 7. Stein L: Neurochemistry of reward and punishment. J Psychiatr Res8:345-361, 1971
Agent
Lewis Brodsky and Jorge Zuniga
T
HE LITERATURE is noticeably lacking in information on the psychological effects of nitrous oxide. There is obvious heuristic value in exploring this because (1) nitrous oxide is widely used for general anesthesia and (2) there appears to be an increase in the abuse of nitrous oxide by people seeking psychodelic effects.’ Bergstrom and Bernstein2 have noted and studied psychic reactions following nitrous oxide anesthesia used for cesarean section. Although their study lacked the statistical validity that would have derived from a larger number of patients, they reported psychotic reactions in all patients studied who were given nitrous oxide analgesia (80%) alone, as opposed to patients being given barbiturates preoperatively. Four of the 6 patients given nitrous oxide alone still exhibited serious sequelae (perhaps what could be termed psychotic sequelae) 1 year after the anesthetic event. None of the 11 patients receiving barbiturate premeditation developed any psychotic symptoms. Of paramount importance in their study was the finding that the premorbid personality of the patient played no role in the outcome. Most current data on the sequelae of nitrous oxide point to its relative safety and noncumulative effects.‘v3 It has been said that were it a better muscle relaxant it would be the ideal anesthetic.3 Although a single case report does not provide opportunity for in-depth scrutiny of a hypothesis, it may help to bring to light what is likely to become a medical-psychiatric-social problem in the future. CASE PRESENTATION Dr. X is a 32-year-old
white married
male whom we first saw as a result of his feeling confused,
his
inability to carry out his dental practice, and his belief that he was being observed by people sent to gather evidence in order to revoke his license. He believed that his assistant was stealing from him, and he felt he was the victim of a conspiracy initiated by the licensing body that governed his right to practice. Until 6 months prior to his hospitalization, the patient had never given evidence of confusion or psychotic symptoms (such as delusions and hallucinations) nor had any difficulty functioning. In fact, his performance both at work and socially was judged to be above average. Through our patient (the medium being open-ended psychiatric interview) and the social history provided by his family we became aware of several factors that helped to explain his abuse of nitrous oxide. His premorbid history gave evidence of a dependent character structure within a depressive core.* *The following is one illustration to lend credence to the formulation that we have presented in summary fashion: The patient had always had low self-esteem. There was a history of intense sibling rivalry with an older brother who was extremely successful. By contrast, the patient saw himself failing. His parents were extremely achievement-oriented and would accuse the patient of “being lazy.” From the Department ofpsychiatry. Sinai Hospital of Detroir. Detroit. Mich. Lewis Brodsky, M.D.: Chief, Crisis Intervention Center, Departmenr of P.rychiatry. Sinai Hospital of Detroit; Assisrant Clinical Professor, Michigan State University. East Lansing, Mich.: Instructor. Wayne State University, Delroit. Mich. Jorge Zuniga, M.D.: Third- Year Resident. Department oj Psw-hiatry, Sinai Hospital of Detroit. [L!197.5 hy Grune & Stratton, Inc. Comprehensive Psychiatry, Vol. 16. No. 2 IMarch/Aprtl).
1975
185
186
BRODSKY
AND ZUNIGA
His recently initiated practice, the serious illness of his mother, and the birth of his first child set the stage for his increasing use of nitrous oxide on a daily basis during the 6 months prior to his hospitalization. The nitrous oxide helped him to feel better and placed him in a somnolent state of bliss. He could “relax.” The paranoid delusions appeared approximately 3 months after he had begun using the nitrous oxide (NPO concentration ranging from 45% to 65%). The inhalation would often take place several times per day. In the 4 or 5 days prior to his hospitalization the patient’s paranoid symptoms had become more intense. His delusional system had begun to incorporate all of the people with whom he had any kind of contact. For example, his newly hired secretary was really “sent to spy on me so that they would have evidence that I am incompetent.” During those last 4 or 5 days he had become increasingly confused. He suffered recent memory loss, often forgetting scheduled activities. At the time of his hospitalization his retention and recall had become impaired and his synthetic and integrative functions were seriously impaired. He was suffering from a nominal dysphasia and was beginning to experience visual hallucinations and bilateral paresthesia. The hallucinations were nor the systematized, dynamically rich projections frequently seen in a schizophrenic process. For example, on one occasion the patient saw a funnel-shaped whirlwind in front of him. It is also significant that they were always visual. Not only was he suffering from paranoid delusions, but also delusions of guilt. He began to assess his practice in an overly scrupulous fashion, blaming himself for shortcomings, and feeling that he deserved to be punished. It is important to note that tangential thinking existed at this time. Psychological testing, which included the Wechsler Adult Intelligence Scale, the Minnesota Multiphasic Personality inventory, the Tactual Performance Test of the Holstead battery, the Reitan-Indiana Aphasia Screening Test, the Purdue Pegboard, the Reitan Trailmaking Test, and the Rorschach, was conducted following the commencement of therapy in the hospital. Testing revealed a very mild disruption of mental abilities. There appeared to be a mild bilateral disturbance of temporal-lobe functions. Immediate memory was impaired, probably as a result of cerebra1 dysfunction. There was questionable dysgraphia of the right hand. Evidence of a mild bilateral motor uncoordination, maxima1 in the right hand (hence involvement of the left motor cortex) was documented. Visual motor speed, though normal, was not as good as expected for his intellectual level. Perseverate response elicited on the Rorschach provided further evidence of a toxic state at the time of the examination. The impression following psychological testing was that there was a mild residual of toxic cerebral dysfunction. It was also felt, as a result of the testing, that the patient was experiencing much more in the way of somatic symptomatology than he was willing to admit. Within 1 week of hospitalization the secondary psychotic symptoms had disappeared. Treatment modalities employed included milieu therapy, psychotherapy, and chemotherapy. The antipsychotic agent utilized was trifluoperazine (IO mg q 12 hr). This was selected because of the value of an alerting, nonsedative antipsychotic agent in the presence of organic involvement.3 By the end of 112 weeks this dose was decreased (5 mg q I2 hr). At the time of discharge all of the toxic symptoms found on mental-status examination had disappeared. The patient was maintained on a small dose of trifluoperazine (2 mg q 12 hr) until I week posthospitalization. At this point all medications were discontinued. During the first week posthospitalization, the patient endured one night in which he experienced recurrence of some of his paranoid thinking. An l8-month follow-up had shown the patient to be free of any delusional thinking, or psychotic symptomatology in general. DISCUSSION
We have ruled out the possibility of the patient having been psychotic prior to his use of nitrous oxide. There is no question that at the very least a decompensation was precipitated by the nitrous oxide inhalation. In the absence of psychological testing it would be more difficult for us to distinguish between what may be termed a paranoid schizophrenic decompensation, merely precipitated by nitrous oxide, and a toxic psychosis. However, we are fortunate in being able to document specific areas of cerebral dysfunction that cannot be accounted for on a “functional” basis. In addition, we see no evidence premorbidly of a pre-
NITROUS
OXIDE
187
schizophrenic matrix. We are also able to appease those who would subscribe to a genetic hypothesis of schizophrenia by pointing to the absence of anything remotely resembling schizophrenia in the patient’s immediate family over the last two generations. We have the additional benefit of the results of psychological testing conducted on this patient as a university undergraduate, approximately 6 years prior to this episode. At that time there was no evidence of any cerebral dysfunction or of a paranoid matrix. Now it becomes incumbent upon us to postulate a mechanism by which the chronic use of nitrous oxide produced a disruption in cerebral function and a clinical picture of a toxic psychosis. We are aware of the fact that nitrous oxide inhalation in high concentrations does produce a state of cerebral anoxia; as a consequence methemoglobinemia, low arterial PO*, and acidosis (which produces a shift in the oxyhemoglobin dissociation curve) develop.4 We believe that the potential for a nitrous oxide psychosis is universal. We can draw an analogy to the other psychotomimetic agents. For our purposes we will make the comparison with amphetamines: Although chronic use would appear to have the better potential for inducing a psychosis, potential exists also with acute use. In effect we would then have to consider the influence of nitrous oxide (its effective dosage) coupled with constitutional factors. The possibility may exist that nitrous oxide favors the metabolism of biogenic amines along aberrant pathways, ultimately producing psychotomimetic transmethylated derivatives. This could take place either through enhancement of these pathways directly or indirectly through blocking the enzyme [email protected]* In vitro and in vivo studies of the action of nitrous oxide on neuronal metabolism, e.g., tryptophan transport ratio, biogenic amine levels, dopamine$hydroxylase, etc., should be emphasized in order to formulate an accurate mechanism. The need for more careful evaluation of nitrous oxide from both physiologic and psychologic vantage points is apparent in view of current clinical and psychedelic use.
SUMMARY
1. In the presence of increased abuse of nitrous oxide for its psychedelic effects, the absence of studies dealing with its psychological sequelae was noted. 2. A case was presented of a patient who developed psychotic and “toxic organic” features following 6 months of almost daily inhalation of nitrous oxide. 3. The mental-status examination and psychological testing pointed strongly toward an organic substrate. 4. A mechanism for the psychotogenic effect of nitrous oxide was postulated. 5. The need for more intensive follow-up studies involving the psychological effects of nitrous oxide was emphasized.
*This is a current hypothesis elucidating
a biochemical
etiology of schizophrenia.
188
BRODSKY
AND ZUNIGA
REFERENCES 1. Bergstrom H, Bernstein K: Psychic reactions after analgesia with nitrous oxide for caesarean section. Lancet 7567:541-542, 1968 2. Brodsky L: Biochemical survey of schizophrenia. Can Psychiatr Assoc J 15:375388, 1970 3. Detre TP, Jarecki HJ: Modern Psychiatric Treatment. Philadelphia, JB Lippincott, 1971, pp 413-422
4. Dillon JB: Nitrous oxide inhalation as a fad. Calif Med 106444-446, 1967 5. Goth A: Textbook of Pharmacology (ed 7). St. Louis, CV Mosby, 1974 6. Meyler L, Herxheimer ML: Side effects of drugs, vol 7. Amsterdam, Excerpta Medica 1972, p 189 7. Stein L: Neurochemistry of reward and punishment. J Psychiatr Res8:345-361, 1971
