Work, tourism, and sport lead many people to practice their activities at medium and high altitudes.1,2 It is noteworthy that some of these subjects may experience significant distress related to adaptation to reduced oxygen content. Several studies have already investigated the brief and long-term neurological effects of exposure to high altitude and the related sequelae of hypoxia on memory and cognition.3–23 In contrast, few authors have discussed the psychic symptoms that are liable to appear during high-altitude activities, focusing mainly on patients with preexisting psychiatric symptoms or who are, in many ways, prone to develop them.24–30 These authors suspect that the reexacerbation or the worsening of psychiatric symptoms are the expressions of maladaptive behavior because of the change in environmental conditions.20,31–34 Moreover, in some subjects with anxiety traits, a reduction in atmospheric pressure causes maladaptive reactions, including signs of respiratory dysregulation and an increase in anxiety levels.35,36
There are several theoretical links between the physiology and psychology of altitude adaptation and anxiety disorders. At least 3 explanatory models—“The hyperventilation model,”37 “The suffocation false alarm model,”38 and “The cognitive misinterpretation model”39—suggest close links between adaptation to high altitude and anxiety levels.40
“The hyperventilation model” explains how hypocapnia is related to hyperventilation (tachypnea), which is an adaptive consequence of hypoxia. Hypoxia leads to hyperventilation, which in its turn results in hypocapnia. Hypocapnia causes vasoconstriction and the most sensitive district is the brain (the initial symptom is the headache, which may be followed by other neurological manifestations, even severe ones), followed by gastrointestinal (nausea, vomit), cutaneous (pallor, dry skin), and muscular system (hyposthenia, muscle pain with lactic acid accumulation) symptoms.
“The suffocation false alarm model,” on the other hand, highlights how panic attacks could be triggered by the hypersensitivity of the central chemoreceptors located on the ventrolateral surface of the bulb, which can be activated by minimal increases in CO2 or spontaneously, giving a sensation of suffocation and, consequently, an increase in respiratory frequency.
“The cognitive misinterpretation model” proposes that the panic attacks are because of the erroneous interpretation by the subject of situations that seem to him/her to pose a potential danger, so causing a hyperarousal of the autonomic system.
Thus, theoretical models and clinical data jointly support the possibility that reduced oxygen tension and early maladaptive altitude symptoms may act as a conditional stimulus causing anxious reactions in those who experienced similar symptoms earlier or are predisposed to develop them.
We describe a case report of a patient with a history of alcohol nonmedical use because of panic attacks with elements of the panic-agoraphobic spectrum who, after a long-lasting period of alcohol abstinence, became exposed to high altitudes at work, and developed a severe alcohol use disorder (AUD) with progressive worsening affecting functionality in the social and workplace dimensions.
Mr A is a 53-year-old white male patient suffering from sporadic panic attacks and presenting social elements on the panic-agoraphobic spectrum. He had been married for 30 years until separation from his wife in 2016 and has 2 children; he received an elementary school diploma and currently works as a bricklayer.
The family anamnesis regarding mental disorders was positive: his father suffered from AUD with elements of impulse disruption disorder; 1 of his 6 brothers presented a bipolar disorder type II, and his only sister had a bipolar disorder type II with symptoms of the anxious spectrum. The patient has never used any psychotropic or psychostimulant agents (cannabinoids, heroin, cocaine, or nicotine) during his entire life; he is only a moderate user of caffeine (40 mL/d). The patient suffers from arterial hypertension with recurrent episodes of epistaxis, mild venous insufficiency in the lower limbs, and a mild metabolic syndrome for which he takes the following therapy: valsartan, 160 mg/d; hydrochlorothiazide 12, 5 mg/d; and nifedipine, 60 mg/d.
Since childhood, he has been shy and introverted, with features of the personality C cluster (dependent, avoidant) and elements of the panic-agoraphobic spectrum. Psychomotor development and early physiological acts are reported as having been acquired regularly. He suffered from the common exanthematic diseases of childhood.
The onset of the psychopathologic picture seems to date back to the time when the patient presented sporadic behaviors of alcohol nonmedical use in binge mode for recreational purposes in social situations that were progressively abandoned during the following years.
He reported that since reaching the age of 20, and despite the absence of stressful life events, he became subject to sporadic panic attacks with neurovegetative expressiveness (sweating, tremor, pallor, headache), cardiorespiratory tract (dyspnea), symptoms of derealization, and depersonalization for which, however, the patient decided not to go to a psychiatric specialist; in that period the symptomatology did not damage his social or work functionality.
At the age of 45, the patient found a job in a construction company that occasionally carried out work in high-altitude locations. The patient reported, in close synchrony with the job change, a spontaneous return to sporadic episodes of alcohol abuse in binge mode during the time spent at high altitude.
The patient reports having experienced fluctuations in mood and anxiety levels on a reactive basis over the following years, which, however, never reached a clinical level of intensity and did not, as he expressed it, justify contact with a psychiatric specialist.
The patient reported a worsening of the clinical picture over the last 2 years, with an increase in anxiety levels and subcritical/critical episodes, and an increase in the episodes of alcohol abuse in binge mode. The patient had asked for help on numerous occasions from the local emergency department and faced a gradual decline in social and work functionality (economic difficulties, work problems, separation from his wife in 2016); he decided to contact the local addiction services for the treatment of AUD, but there was no clinical benefit.
Given the persistence of abuse and the further deterioration of global functionality, this patient decided to contact our clinic, where, after the first clinical evaluation, we proposed hospitalization in our psychiatric ward.
On clinical examination at the entrance, the patient seemed lucid, alert, and mnesic. He was oriented in the classic spatiotemporal parameters and toward things and people. Eye contact was discontinuous. Fairly good personal hygiene and self-care. Available at the interview but not readily accessible to intrapsychic experiences. Mimicking and body language expressed anguish, tension, and a state of alarm. His mood was oriented to the negative pole, with experiences of sadness, ideas of worthlessness and guilt. Fairly good levels of energy reported. No alterations of the content and form of thought appeared. Levels of anxiety were rather high, and he referred to daily fluctuations. He denied craving for alcohol and reported that the last intake occurred about a month ago when he was working at a high altitude. He denied the presence of withdrawal symptoms since the last alcohol intake, and there were no clinical signs of alcohol withdrawal at the entrance examination. His insomnia was subtotal.
During hospitalization, we performed blood counts, electrolytes, liver and renal function enzymes, thyroid function tests, vitamin profile, serological hepatitis markers viral, urine toxicology, and standard analysis of urine samples. The battery of tests named above did not show any remarkable results.
During hospitalization, we decided to contact a cardiologist for a consultation about the hemodynamic and cardiovascular situation. Electrocardiogram, echocardiogram, and eco-color Doppler of the epiaortic vessels did not show any rhythmic or morphostructural alterations. There was a slight calcification of the carotid syphons.
An abdominal ultrasound was performed too, but it did not highlight any specific abnormalities. Magnetic resonance showed ischemic-hemorrhagic areas on a vascular base suggestive of a mild vascular encephalopathy.
A psychopharmacological therapy on the basis of gabapentin, 900 mg/d; paroxetine, 30 mg/d; quetiapine, 75 mg/d; and clonazepam, 1.5 mg/d was prescribed.
At the time of discharge, which took place after 20 days, the patient showed an improvement in mood, a reduction in anxiety levels, and regularization of the sleeping pattern; he did not present panic attacks at any time during the entire hospitalization. The use of Disulfiram, 200 mg/d, was suggested as an add-on treatment.
The patient was reevaluated 3 times in the following 6 months; whenever the patient denied the presence of mood swings, an improvement in the management of anxiety levels became very evident, with sporadic oscillations, and the absence of critical episodes. However, the patient continued to have an irregular sleeping profile, alternating fragmented sleep with terminal insomnia, after which it was first decided to increase quetiapine to 100 mg/d and then add zolpidem at a dose of 10 mg/d, with fairly good clinical improvement. The patient resumed working after about 10 days from discharge with good results and had not experienced any other episode of alcoholic intoxication after almost 8 months from the time of discharge.
After analyzing the psychopathologic history of the patient, one striking feature to be noted is his previous misuse of alcohol in adolescence in specific social contexts. Mr A, as already reported in the anamnesis, presents traits of the panic-agoraphobic and social-phobic spectrum, with a tendency to introversion and to avoiding social contexts. In general, both spectra have, showing a maximum symptomatic expression, several anxiety disorders such as panic attack disorder, social phobia, separation anxiety disorder, a generalized anxiety disorder.41–45 The link between anxiety disorders (especially social phobia and panic attack disorder) and substance use disorder has been widely reported in the literature.46–48 Among substances of abuse, alcohol is certainly the most closely associated with psychiatric disorders and, particularly, with anxiety disorders; alcohol, because of its intrinsic myorelaxant, disinhibitory, anxiolytic effects and being, among all substances of abuse, the most socially accepted and available, is absolutely the most commonly consumed substance of abuse.49–57
Nowadays, alcohol clinics rarely treat “pure” alcoholics, as patients with comorbid psychiatric disorders constitute most of the alcoholic population.58 Schneider et al59 observed an overall comorbidity rate in treatment-seeking alcohol-dependent patients of 42.3% for any anxiety disorder, 13.7% for social phobia, 13.1% for agoraphobia, and 5.2% for panic disorder. The NEMESIS study60,61 reported that 8.3% of the population with alcohol dependence had a panic disorder with or without agoraphobia, 4.5% agoraphobia, and 7.4% a social phobia. The National Comorbidity Study estimated an even higher prevalence for alcohol dependence and social phobia [19.3%, odds ratio (OR)=2.41] and for agoraphobia (6.5%, OR=1.82).62,63 One possible explanation for the high comorbidity rates found is the “self-medication hypothesis”.64–68 Initially, the use of alcohol may decrease anxiety symptoms, but later it promotes the persistent and excessive use of alcohol through negative reinforcement. Kushner et al’s69 study focuses on comorbid social phobia and agoraphobia because these anxiety disorders tend to precede alcohol dependence.
In the case of Mr A, he had, while still an adolescent, started to use alcohol in binge drinking mode for recreational and disinhibitory purposes to get over his relational problems in the social sphere. Alcohol misuse was progressively suspended, thanks to the changes for the better in the social and personal context of the patient: engagement and subsequent marriage, with the formation of a family unit and less exposure to potential social stress. Mr A described the sporadic presence of panic attacks with neurovegetative expression during the following years, including symptoms of derealization, which were apparently unrelated to specific events and situations.
The patient had enjoyed a psychoaffective equilibrium up to the age of 45, when he was forced to apply for a job in a different environmental context. As previously mentioned, Mr A works as a bricklayer, and his new company worked on contracts in places that were sometimes at average altitudes, but at others at high altitudes (>1500 m), usually alternating 3 months in new locations with 1 month at home with his family. In this context, the patient reported the reappearance of his long-abandoned alcohol abuse behavior in response to a subjective state of general discomfort. His use of alcohol, as recalled by the patient, in a first phase alleviated this malaise. Progressively, however, the patient has increased his alcohol consumption, so impairing both his work and social functioning (running the risks of dismissal and of separation from his wife, respectively). This clinical worsening led to several episodes of recourse to the emergency room for acute alcohol intoxication, obliging the patient to make the first contact with the local services for the treatment of addictions, but without positive results. Only when we arranged for comprehensive psychopharmacological therapy with the aim of treating the underlying panic-agoraphobic symptoms, did the alcohol misuse decrease, leading to a progressive improvement in global functioning. According to our hypothesis, a fundamental change had taken place once the subject, because of becoming exposed to a more demanding (high altitude) environmental condition aggravated by the distance from his family (so sparking separation anxiety), had presented an increase in anxiety levels. So, unconsciously and automatically, according to a mode of copying previously experienced in adolescence (social phobia and disinhibitory use of alcohol), he implemented binge drinking behaviors for self-medication and antianxiety purposes, which gradually triggered a mechanism of AUD.
The anxiety management made possible by our psychopharmacological therapy may have lowered the need to “self-medicate” with alcohol. The magnitude or duration of anxiety difficulties, may, in any case, influence the development of alcohol problems. Patients who manifested an anxiety disorder at an early age, as indicated by a childhood history of anxiety disorders, were more likely to have an alcohol-dependent history according to unadjusted critical values. Patients were more likely to have a history of alcohol dependence if they had a diagnosis of social phobia in addition to their panic disorder diagnosis. Social phobia is itself an identified risk factor for alcohol abuse, and in studies assessing both panic disorder and social phobia, the social phobia has been associated with higher rates of alcohol abuse than those found in panic disorder patients.70,71 Kushner et al54 suggested that for social phobias, anxiety may be cued more often in situations where it is socially appropriate to drink, so leading to higher rates of alcohol abuse for this population. Alcohol use may be especially reinforcing for patients with social phobia; the fear of negative social evaluation is a cardinal component of social anxiety,72 and alcohol intoxication seems to weaken the ability to encode social feedback, and the harmful self-evaluative components of anxiety.73,74 Identification of the characteristics of panic disorder patients with comorbid alcohol dependence allows the development of additional strategies for clinical management. Moreover, as the majority of panic patients believe that alcohol is useful in helping them manage their anxiety,75 patient education that targets particularly vulnerable groups, including those with a history of social phobia, may help to reduce rates of alcohol abuse.
1. Hoffman MD. Performance trends in 161-km ultramarathons. Int J Sports Med. 2010;31:31–37.
2. Rust CA, Knechtle B, Rosemann T, et al. Analysis of performance and age of the fastest 100-mile ultra-marathoners worldwide. Clinics (Sao Paulo). 2013;68:605–611.
3. Saugy J, Place N, Millet GY, et al. Alterations of neuromuscular function after the world’s most challenging mountain ultra-marathon. PLoS One. 2013;8:e65596.
4. Millet GP, Millet GY. Ultramarathon is an outstanding model for the study of adaptive responses to extreme load and stress. BMC Med. 2012;10:77.
5. Millet GY, Tomazin K, Verges S, et al. Neuromuscular consequences of an extreme mountain ultra-marathon. PLoS One. 2011;6:e17059.
6. Millet GY, Lepers R. Alterations of neuromuscular function after prolonged running, cycling and skiing exercises. Sports Med. 2004;34:105–116.
7. Millet GY, Lepers R, Maffiuletti NA, et al. Alterations of neuromuscular function after an ultramarathon. J Appl Physiol (1985). 2002;92:486–492.
8. Belenky G, Wesensten NJ, Thorne DR, et al. Patterns of performance degradation and restoration during sleep restriction and subsequent recovery: a sleep dose-response study. J Sleep Res. 2003;12:1–12.
9. Hornbein TF, Townes BD, Schoene RB, et al. The cost to the central nervous system of climbing to extremely high altitude
. N Engl J Med. 1989;321:1714–1719.
10. Goel N, Basner M, Rao H, et al. Circadian rhythms, sleep deprivation, and human performance. Prog Mol Biol Transl Sci. 2013;119:155–190.
11. Dinges DF, Kribbs NB, Schwartz AR, et al. Objective measurement of nasal continuous positive airway pressure use: ethical considerations. Am J Respir Crit Care Med. 1994;149:291–292.
12. Dinges DF, Kribbs NB. Performing while sleepy: effects of experimentally-induced sleepiness. In: Monk TH, ed. Sleep, Sleepiness and Performance
. New York, NY: John Wiley & Sons; 1991:97–128.
13. van Dongen VC, Vanelderen PJ, Koopmans-Klein G, et al. Patient preference with respect to QoL and reduction in opioid-induced constipation (OIC) after treatment with prolonged-release (PR) oxycodone/naloxone compared with previous analgesic therapy [PREFER study]. Int J Clin Pract. 2014;68:1364–1375.
14. Van Dongen HPA, Hursh SRKryger MH, Roth T, Dement WC. Fatigue, performance, errors, and accidents. Principles and Practice of Sleep Medicine. St. Louis, MO: Elsevier Saunders; 2010:753–759.
15. Van Dongen HP, Maislin G, Mullington JM, et al. The cumulative cost of additional wakefulness: dose-response effects on neurobehavioral functions and sleep physiology from chronic sleep restriction and total sleep deprivation. Sleep. 2003;26:117–129.
16. Lucas SJ, Anson JG, Palmer CD, et al. The impact of 100 hours of exercise and sleep deprivation on cognitive function and physical capacities. J Sports Sci. 2009;27:719–728.
17. Hurdiel R, Peze T, Daugherty J, et al. Combined effects of sleep deprivation and strenuous exercise on cognitive performances during The North Face® Ultra Trail Du Mont Blanc® (UTMB®). J Sports Sci. 2015;33:670–674.
18. Hufner K, Brugger H, Kuster E, et al. Isolated psychosis during exposure to very high and extreme altitude - characterisation of a new medical entity. Psychol Med. 2018;48:1872–1879.
19. Brugger P, Regard M, Landis T. Illusory reduplication of one’s own body: phenomenology and classification of autoscopic phenomena. Cogn Neuropsychiatry. 1997;2:19–38.
20. Fagenholz PJ, Murray AF, Gutman JA, et al. New-onset anxiety disorders at high altitude
. Wilderness Environ Med. 2007;18:312–316.
21. Kety SS, Schmidt CF. The effects of altered arterial tensions of carbon dioxide and oxygen on cerebral blood flow and cerebral oxygen consumption of normal young men. J Clin Invest. 1948;27:484–492.
22. Mayr E. Toward a New Philosophy of Biology. Cambridge, MA: Harvard University Press; 1988.
23. Cohen ME, White PD. Life situations, emotions, and neurocirculatory asthenia (anxiety neurosis, neurasthenia, effort syndrome). Psychosom Med. 1951;13:335–357.
24. Maremmani I, Dell’Osso L, Rovai L, et al. Temperamental traits of women applying for a type of job that has been characterized historically by male identity: the military career as case study. J Affect Disord. 2011;130:275–279.
25. Maremmani I, Dell’Osso L, Rovai L, et al. Discriminant and convergent validity of TEMPS-A[P] correlation with MMPI and the emotional-affective state following a stressful situation. J Affect Disord. 2011;129:27–33.
26. Montserrat Gomà-i-Freixanet M. Personality profile of subjects engaged in high physical risk sports. Pers Individ Dif. 1991;12:1087–1093.
27. Karam EG, Salamoun MM, Yeretzian JS, et al. The role of anxious and hyperthymic temperaments in mental disorders: a national epidemiologic study. World Psychiatry. 2010;9:103–110.
28. Robinson DW. Stress seeking: selected behavioral characteristics of elite rock climbers. J Sport Psychol. 1985;7:400–404.
29. Siwek MDD, Drozdowicz K, Jaeschke R, et al. Temperamental dimensions of the TEMPS-A in male and female subjects engaging in extreme or/and high risk sports. J Affect Disord. 2015;170:66–70.
30. Siesjo BK, Johannsson H, Ljunggren B, et al. Brain dysfunction in cerebral hypoxia and ischemia. Res Publ Assoc Res Nerv Ment Dis. 1974;53:75–112.
31. Sracic MK, Thomas D, Pate A, et al. Syndrome of acute anxiety among marines after recent arrival at high altitude
. Mil Med. 2014;179:559–564.
32. Roth WT, Gomolla A, Meuret AE, et al. High altitudes, anxiety, and panic attacks
: is there a relationship? Depress Anxiety. 2002;16:51–58.
33. van den Hout MA, De Jong P, Zandbergen J, et al. Waning of panic sensations during prolonged hyperventilation. Behav Res Ther. 1990;28:445–448.
34. Cowley DS, Roy-Byrne PP. Hyperventilation and panic disorder. Am J Med. 1987;83:929–937.
35. Papp LA, Martinez JM, Klein DF, et al. Respiratory psychophysiology of panic disorder: three respiratory challenges in 98 subjects. Am J Psychiatry. 1997;154:1557–1565.
36. Wilhelm FH, Roth WT. The somatic symptom paradox in DSM-IV anxiety disorders: suggestions for a clinical focus in psychophysiology. Biol Psychol. 2001;57:105–140.
37. Kerr WJ, Gliebe PA, Dalton JW. Physical phenomena associated with anxiety states: the hyperventilation syndrome. Cal West Med. 1938;48:12–16.
38. Klein DF. False suffocation alarms, spontaneous panics, and related conditions. An integrative hypothesis. Arch Gen Psychiatry. 1993;50:306–317.
39. Clark DM. A cognitive approach to panic. Behav Res Ther. 1986;24:461–470.
40. Smoller JW, Pollack MH, Otto MW, et al. Panic anxiety, dyspnea, and respiratory disease. Theoretical and clinical considerations. Am J Respir Crit Care Med. 1996;154:6–17.
41. Benvenuti A, Rucci P, Calugi S, et al. Relationship of residual mood and panic-agoraphobic spectrum phenomenology to quality of life and functional impairment in patients with major depression. Int Clin Psychopharmacol. 2010;25:68–74.
42. Berrocal C, Ruiz Moreno MA, Gil Villa M, et al. Multidimensional assessment of the panic-agoraphobic spectrum: reliability and validity of the Spanish version of the PAS-SR. J Anxiety Disord. 2006;20:562–579.
43. Rucci P, Miniati M, Oppo A, et al. The structure of lifetime panic-agoraphobic spectrum. J Psychiatr Res. 2009;43:366–379.
44. Shear MK, Cassano GB, Frank E, et al. The panic-agoraphobic spectrum: development, description, and clinical significance. Psychiatr Clin North Am. 2002;25:739–756.
45. Shear MK, Frank E, Rucci P, et al. Panic-agoraphobic spectrum: reliability and validity of assessment instruments. J Psychiatr Res. 2001;35:59–66.
46. Bizzarri JV, Sbrana A, Rucci P, et al. The spectrum of substance abuse in bipolar disorder: reasons for use, sensation seeking and substance sensitivity. Bipolar Disord. 2007;9:213–220.
47. Kushner MG, Sher KJ, Erickson DJ. Prospective analysis of the relation between DSM-III anxiety disorders and alcohol use disorders. Am J Psychiatry. 1999;156:723–732.
48. Grant BF, Stinson FS, Dawson DA, et al. Prevalence and co-occurrence of substance use disorders and independent mood and anxiety disorders: results from the National Epidemiologic Survey on alcohol and related conditions. Arch Gen Psychiatry. 2004;61:807–816.
49. Kushner MG, Maurer E, Menary K, et al. Vulnerability to the rapid (“telescoped”) development of alcohol dependence in individuals with anxiety disorder. J Stud Alcohol Drugs. 2011;72:1019–1027.
50. Menary KR, Kushner MG, Maurer E, et al. The prevalence and clinical implications of self-medication among individuals with anxiety disorders. J Anxiety Disord. 2011;25:335–339.
51. Kushner MG. Relationship between alcohol problems and anxiety disorders. Am J Psychiatry. 1996;153:139–140.
52. Thomas SE, Randall PK, Book SW, et al. A complex relationship between co-occurring social anxiety and alcohol use disorders: what effect does treating social anxiety have on drinking? Alcohol Clin Exp Res. 2008;32:77–84.
53. Thomasson P, Psouni E. Social anxiety and related social impairment are linked to self-efficacy and dysfunctional coping. Scand J Psychol. 2010;51:171–178.
54. Kushner MG, Sher KJ, Beitman BD. The relation between alcohol problems and the anxiety disorders. Am J Psychiatry. 1990;147:685–695.
55. Kushner MG, Abrams K, Thuras P, et al. Individual differences predictive of drinking to manage anxiety among non-problem drinkers with panic disorder. Alcohol Clin Exp Res. 2000;24:448–458.
56. Lisansky ES. Alcoholism in women: social and psychological concomitants. I. Social history data. Q J Stud Alcohol. 1957;18:588–623.
57. Hobbs JD, Kushner MG, Lee SS, et al. Meta-analysis of supplemental treatment for depressive and anxiety disorders in patients being treated for alcohol dependence. Am J Addict. 2011;20:319–329.
58. Ross HE, Glaser FB, Germanson T. The prevalence of psychiatric disorders in patients with alcohol and other drug problems. Arch Gen Psychiatry. 1988;45:1023–1031.
59. Schneider U, Altmann A, Baumann M, et al. Comorbid anxiety and affective disorder in alcohol-dependent patients seeking treatment: the first multicentre study in Germany. Alcohol Alcohol. 2001;36:219–223.
60. Bijl RV, Ravelli A, van Zessen G. Prevalence of psychiatric disorder in the general population: results of the Netherlands mental health survey and incidence study (nemesis). Soc Psychiatry Psychiatr Epidemiol. 1998;33:587–595.
61. Bijl RV, van Zessen G, Ravelli A, et al. The Netherlands Mental Health Survey and Incidence Study (NEMESIS): objectives and design. Soc Psychiatry Psychiatr Epidemiol. 1998;33:581–586.
62. Kessler RC, McGonagle KA, Zhao S, et al. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey. Arch Gen Psychiatry. 1994;51:8–19.
63. Kessler RC, Berglund P, Demler O, et al. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey replication. Arch Gen Psychiatry. 2005;62:593–602.
64. Achalu E. A review of the two major theories and the research evidence. The self-medication hypothesis; 2002. Available at: http://self-med-hypothesis.tripod.com/id1.html
. Accessed January 12, 2019.
65. Khantzian EJ. The self-medication hypothesis of substance use disorders: a reconsideration and recent applications. Harv Rev Psychiatry. 1997;4:231–244.
66. Khantzian EJ. The self-medication hypothesis of addictive disorders: focus on heroin and cocaine dependence. Am J Psychiatry. 1985;142:1259–1264.
67. Khantzian EJ. The injured self, addiction, and our call to medicine. Understanding and managing addicted physicians. JAMA. 1985;254:249–252.
68. Awad AG, Voruganti LL. Revisiting the “self-medication” hypothesis in light of the new data linking low striatal dopamine to comorbid addictive behavior. Ther Adv Psychopharmacol. 2015;5:172–178.
69. Kushner MG, Abrams K, Borchardt C. The relationship between anxiety disorders and alcohol use disorders: a review of major perspectives and findings. Clin Psychol Rev. 2000;20:149–171.
70. Amies PL, Gelder MG, Shaw PM. Social phobia
: a comparative clinical study. Br J Psychiatry. 1983;142:174–179.
71. Thyer BA, Parrish RT, Himle J, et al. Alcohol abuse among clinically anxious patients. Behav Res Ther. 1986;24:357–359.
72. Fyer AJ, Mannuzza S, Gallops MS, et al. Familial transmission of simple phobias and fears. A preliminary report. Arch Gen Psychiatry. 1990;47:252–256.
73. Steele CM, Josephs RA. Alcohol myopia. Its prized and dangerous effects. Am Psychol. 1990;45:921–933.
74. Yankofsky L, Wilson GT, Adler JL, et al. The effect of alcohol on self-evaluation and perception of negative interpersonal feedback. J Stud Alcohol. 1986;47:26–33.
75. Bibb JL, Chambless DL. Alcohol use and abuse among diagnosed agoraphobics. Behav Res Ther. 1986;24:49–58.