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Anxiety - a special report

Pathomechanism:
Lactate:
Elevated blood lactate and/or increased lactate to pyruvate ratio may be associated with clinical anxiety. The lactate to pyruvate ratio may be increased by alcohol, sugar, and caffeine
	Buist RA. Anxiety neurosis: The lactate connection. Int Clin Nutr Rev 1985, 5:1-4.
Diet:
Alcohol:
Alcohol inhibits gluconeogenesis from lactate by increasing the hepatic NAD+ to NADH ratio. The resulting increased ratio of lactate to pyruvate is associated with clinical anxiety.
	Alberti KG, Nattrass M. Lactic acidosis. Lancet 1977, 2:25-9.
Withdrawal from alcohol is associated with anxiety and hyperventilation. The connection may be less apparent when the withdrawal is partial or due to a change in the drinking activities.
	Roelofs SM. Hyperventilation, anxiety, craving for alcohol: a subacute alcohol withdrawal syndrome. Alcohol 1985, 2(3):501-505.
Experimental Placebo-controlled study. The Spielberger State Anxiety Inventory was administered to 90 healthy male volunteers after receiving separate administrations of placebo and ethanol. Significant reports of decreased feelings of tension were obtained after placebo administration. However, ethanol administration was followed by significant reports of increased anxiety.
	Monteiro MG, et al. Subjective feelings of anxiety in young men after ethanol and diazepam infusions. J Clin Psychiatry 1990, 51(1):12-16.
Some minor tranquilizers, e.g., valium, operate through benzodiazepine receptors in the brain. The concentration of these receptors may be reduced after chronic alcohol consumption.
	Freund G. Benzodiazepine receptor loss in brains of mice after chronic alcohol consumption. Life Sci 1980, 27(11):987-992.
Caffeine
Caffeine increases the ratio of lactate to pyruvate. Increased ratios of lactate to pyruvate are associated with clinical anxiety.
	Alberti KG, Nattrass M. Lactic acidosis. Lancet 1977, 2:25-9.
	Lee MA, et al. Anxiogenic effects of caffeine on panic and depressed patients. Am J Psychiatry 1988, 145(5):632-635.
Observational study: Patients with panic disorder, patients with affective disorder, and normal controls rated themselves with respect to anxiety, depression, and caffeine consumption. Only in the panic disorder patients was the level of anxiety and depression correlated with the amount of caffeine consumption.
	Boulenger JP, et al. Increased sensitivity to caffeine in patients with panic disorders: Preliminary evidence. Arch Gen Psychiat 1984, 41:1067-1071.
Experimental study: 6 patients with anxiety disorder or panic disorder who had obtained minimal benefit from drugs or psychotherapy complied with directions to abstain from caffeine. They had been consuming the equivalent of 1.5 - 3.5 cups of coffee daily. After 1 week all felt such improvement that they volunteered to continue abstainance. The patients were followed for 6-18 months and 5 of the 6 became relatively asymptomatic. The 6th patient required low-dose diazepam. Five of the 6 patients experienced anxiety whenever they were reexposed to caffeine.
	Bruce M, Lader M. Caffeine abstention in the management of anxiety disorders. Psychol Med 1989, 19:211-14.
Experimental controlled study: 17 normals and 21 patients with panic disorder with and without agorophobia were given 10 mg/kg of caffeine. Plasma caffeine levels were measured and the subjects rated themselves for anxiety, fear, nausea, nervousness, palpitations, restlessness, and tremors. After caffeine the symptoms were significantly greater in the patients than in the controls. In the patients, but not in the controls, the symptoms were significantly correlated with plasma caffeine levels. 71% of the patients reported that the caffeine caused effects very similar to those of the panic attacks.
	Charney DS, et al. Increased anxiogenic effects of caffeine in panic disorders. Arch Gen Psychiatry 1985, 42:233-243.
Review article: The author reviews observations that anxiety disorders are mimicked by high caffeine consumption and also by caffeine withdrawal.
	Greden JF. Anxiety or caffeinism: A diagnostic dilemma. Am J Psychiatry 1974, Oct.
Observational study: Compared to normal controls, anxious patients were observed to consume less caffeine. This may be due to the anxiogenic effects of caffeine.
	Lee MA, et al. Anxiety and caffeine consumption in people with anxiety disorders. Psychiatry Res 1985, 15:211-217.
Experimental double-blind study: Both panic disorder patients and normal subjects exhibited increased plasma cortisol levels and anxiety in response to caffeine challenge. Two of the normal subjects experienced panic attacks along with a 5X increase in plasma cortisol after receiving 720 mg of caffeine.
	Uhde TW, et al. Caffeine and behavior: Relation to psychopathology and underlying mechanisms. Psychopharm Bull 1984, 20(3):426-430.
Sugar
Infusion of glucose in susceptible individuals can produce model panic attacks.
	Rainey JM, et al. Specificity of lactate infusion as a model of anxiety. Psychopharm Bull 1984, 20(1):45-9.
Experimental controlled study: Psychoneurotics (15), schizophrenics (28) and healthy controls (6) were given 100mg glucose as a cola drink. 7 of the psychoneurotics and 8 of the schizophrenics also experienced anxiety. Only in the anxiety-prone patients was the blood lactate concentration markedly elevated post-glucose ( in the third, fourth, and fifth hours ). In all the patients blood pyruvate was significantly depressed starting at about the second hour post-glucose, especially in the schizophrenics. For all anxiety-prone patients the lactate to pyruvate ratio increased to a maximum of +29.1. In the non-anxiety group the ratio increased a maximum of +4.0.
	Wendel OW, Beebe WE. Glycolytic activity in schizophrenia. In Hawkins D, Pauling L, Eds. Orthomolecular Psychiatry: Treatment of Schizophrenia. San Francisco, W. H. Freeman, 1973.
	Uhde TW, et al. Glucose tolerance testing in panic disorder. Am J Psychiatry 1984, 141(11):1461-3.
Vitamins:
B-Complex
Observational study: Twelve agoraphobic patients were studied for selected nutritional deficiencies. 7 were deficient in thiamine, 6 in pyridoxine, 3 in niacin, 3 in B12, 2 in folic acid, and 1 in riboflvin.
	Abbey LC. Agoraphobia. J Orthomol Psychiatry 1982, 11:243-259.
Experimental study: 23 agoraphobic patients were given nutritional counseling, high-potency broad spectrum nutritional supplementation, and were treated for any B vitamin deficiencies detected by laboratory tests. At 3 months 19/23 were significantly improved and 11/23 were free of panic attacks.
	Abbey LC. Agoraphobia. J Orthomol Psychiatry 1982, 11:243-259.
Niacin
Niacin is a precurser of NAD+ (nicotinamide-adenine dinucleotide) which increases the conversion of lactate to pyruvate and thus reduces the lactate to pyruvate ratio. Higher ratios are associated with clinical anxiety.
	Wendel OW, Beebe WE. Glycolytic activity in schizophrenia. In Hawkins D, Pauling L, Eds. Orthomolecular Psychiatry: Treatment of Schizophrenia. San Francisco, W. H. Freeman, 1973.
Animal experimental study: Supplementation of the diets of animals with nicotinamide was found to produce anti-aggressive, anti-confict, muscle relaxant and hypnotic actions similar to that produced by benzodiazepines.
	Mhler H, et al. Nicotinamide is a brain constituent with benzodiazepine-like actions. Nature 1979, 278:563-565.
Pyridoxine
13 patients with hyperventilation syndrome were given L-tryptophan (2 g/day) and pyridoxine (125mg 3X/day). These patients had experienced at least 2 attacks per week for 0.5 to 3 years. After 3 weeks 9 patients (70%) were free from attacks. Xanthurenic acid excretion, an index of tryptophan metabolism, had been abnormal in 8/9 of the improved patients and normal in the remaining patients. After 4 weeks of supplementation xanthurenic acid excretion became normalized. The responders then remained symptom free without any further supplementation for 3 months of follow-up. Pyridoxine deficiency may diminish the conversion of tryptophan to serotonin. Serotonin depletion may then produce anxiety.
	Hoes MJ, et al. Hyperventilation syndrome, treatment with L-tryptophan and pyridoxine; Predictive value of xanthurenic acid excretion. J Orthomol Psych 1981, 100(1):7-15.
Increased lactate and/or increased lactate to pyruvate ratio is associated with clinical anxiety. Supplementation with pyridoxine may reduce the conversion of pyruvate to lactate by enhancing transamination and thereby produce more substrate for the Krebs Cycle.
	Buist RA. Anxiety neurosis: the lactate connection. Int Clin Nutr Rev 1985, 5:1-4.
Thiamine
Prolonged moderate thiamine restriction may produce emotional instability, psychosomatic complaints, fearfulness and agitation.
	Williams RD, et al. Induced thiamine (Vitamin B1) deficiency in man; relation of depletion of thiamine to development of biochemical defect and polyneuropathy. Arch Intern Med 1943, 71:38-53.
Individuals with congenital lacticacidaemia are deficient in pyruvate dehydrogenase, the enzyme for the conversion of pyruvate to acetyl-CoA. The coenzyme for pyruvate dehydrogenase is thiamine. The enzyme may be induced to higher activity through administration of the coenzyme thiamine, and thus such individuals are said to be thiamine dependent. Administration of high doses of thiamine is required in order to prevent lactate elevation.
	Wick H, et al. Thiamine dependency in a patient with congenital lacticacidaemia. Agents Actions 1977, 7(3):405-410.
Minerals
Calcium
Case reports: Two females, one 49 and the other 58, each with at least 30 years of generalized anxiety with fear, worry, trembling, sweating, insomnia and mild depression. Both experienced sudden increase in symptoms without obvious increased stress. The 49 year old, a post-menopausal vegetarian, developed spontaneous rib fractures 5 weeks later. She was found to have marked osteoporosis and serum calcium of 7.2 mg/dL (normal: 8.5-10.5). Her anxiety returned to its former level upon correction of the hypocalcemia and administration of estrogen. The 58 year old patient, an insulin-dependent diabetic, proceeded to develop spasms, stuttering, tetany and displayed a positive Chvostek's sign. She was found to have idiopathic hypoparathyroidism and serum calcium of 6.1 mg/dL. Her anxiety returned to its previous level following treatment.
	Carlson RJ. Longitudinal observations of two cases of organic anxiety syndrome. Psychosomatics 1986, 27(7):529-31.
See also:
	Cramer JL. Calcium metabolism and mental disorder. Psychol Med 1977, 7(4):557-560.
	Houssain M. Neurological and psychiatric manifestations in idiopathic hypoparathyroidism: Response to treatment. J Neurol Neurosurg Psychiatry 1970, 33:153-156.
Magnesium:
Magnesium depletion increases the ratio of lactate to pyruvate, which has been associated with development of clinical anxiety.
	Buist RA. Anxiety neurosis: The lactate connection. Int Clin Nutr Rev 1985, 5:1-4.
Magnesium depletion is frequently associated with anxiety.
	Seelig MS, et al. Latent tetany and anxiety, marginal Mg deficit, and normocalcemia. Dis Nerv Syst 1975, 36:461-465.
Phosphorus:
The development of hypophosphatemia is associated with apprehension, irritability, numbness, paresthesiae, and weakness.
	Webb WL, Gehi M. Electrolyte and fluid imbalance: Neuropsychiatric manifestations. Psychosomatics 1981, 22(3):199-203.
Experimental controlled study: Inorganic phosphorus levels were significantly (p<0.016) lower in 57 patients with panic disorder than in 29 controls. When patients and controls were provoked with lactate infusion there were no significant differences in phosphorus levels between those who subsequently experienced panic and those who did not.
	Balon R, et al. Relative hypophosphatemia in patients with panic disorder. Letter. Arch Gen Psychiatry 1988, 45:294-295.
Experimental study: Patients who panicked following infusion of lactate were more often those with low baseline inorganic phosphate levels.
	Gorman JM, et al. Blood gas changes and hypophosphatemia in lactate-induced panic. Arch Gen Psychiatry 1986, 43:1067-71.
Other Nutritional Factors:
Inosital
Supplementation with inosital was found to effect the EEG in a manner similar to chlordiazepoxide and meprobomate.
	Pfeiffer C. Mental and Elemental Nutrients. Keats Publishing Comp, New Canaan, Conn., 1975.
Omega-3 Fatty Acids:
Case reports: Four patients with history of agoraphobia for 10+ years were observed to have signs and symptoms suggesting omega-3 fatty acid deficiency, namely, autonomic neuropathies, dry dermatoses, fatigue, and tinnitus. These omega-3 fatty acids provide substrate upon which niacin and other B vitamin enzymes act to produce prostaglandin 3 series hormones. The patients were given linseed oil 2-6 tbsp/day and 3/4 patients showed significant improvement in 2-3 months.
	Rudin DO. The major psychoses and neuroses as omega-3 essential fatty acid deficiency syndrome: Substrate pellagra. Biol Psychiatry 1981, 16(9):837-850.
L-Tryptophan:
13 patients with hyperventilation syndrome were given L-tryptophan (2 g/day) and pyridoxine (125mg 3X/day). These patients had experienced at least 2 attacks per week for 0.5 to 3 years. After 3 weeks 9 patients (70%) were free from attacks. Xanthurenic acid excretion, an index of tryptophan metabolism, had been abnormal in 8/9 of the improved patients and normal in the remaining patients. After 4 weeks of supplementation xanthurenic acid excretion became normalized. The responders then remained symptom free without any further supplementation for 3 months of follow-up. Pyridoxine deficiency may diminish the conversion of tryptophan to serotonin. Serotonin depletion may then produce anxiety.
	Hoes MJ, et al. Hyperventilation syndrome, treatment with L-tryptophan and pyridoxine; Predictive value of xanthurenic acid excretion. J Orthomol Psych 1981, 100(1):7-15.
	Hoyse SE. Experiences with L-tryptophan in a child and family psychiatric department. J Int Med Res 1982, 10(3):157-9.
Food Sensitivities:
Experimental double-blind study: 20 female and 10 male patients, ages 17-56, with complaints of anxiety and/or other psychological symptoms were tested with sublingual antigens or placebo. Cognitive-emotional symptoms were significantly increased (p=0.001) following antigen exposure but not placebo. Heart rate was also found to vary more for allergens than placebo (p=0.008). The sublingual antigens were alternaria, auto exhaust, chlorine, and common foods.
	King DS. Can allergic exposure provoke psychological symptoms? A double-blind test. Biol Psychiatry 1981, 16(1):3-19.
Multiple Supplementation
Alcohol withdrawal
Experimental placebo-controlled study: 38 male alchoholics participated in a 30-day residential treatment program. None were allowed to take antianxiety or antidepression medications. The experimental group took supplements 3 times per day consisting of vitamin C 1g, niacin 1g, vitamin B6 200mg, and vitamin E 200 IU. At 21 days the experimental group demonstrated significantly less anxiety than the placebo group as determined by the State and Trait Anxiety Scales of the Spielberger State-Anxiety Inventory and by the psychastenia ("Pt") scale of the MMPI.
	Replogle WLH, Eicke FJ. Megavitamin therapy in the reduction of anxiety and depression among alcoholics. J Orthomol Med 1989 4(4):221-224.
Phytomedicine (Herbal Therapy)
Eschscholzia (California Poppy)
	Rolland A, Fleurentin J, Lanhers MC, Younos C, Misslin R, Mortier F, Pelt JM. Behavioural effects of the American traditional plant Eschscholzia californica: sedative and anxiolytic properties. Planta Med 1991, 57(3):212-6.
Panax ginseng
Panax ginseng root extract was found to be comparable to diazepam in its effects reducing the physiological parameters of anxiety in stressed rats.
	Bhattacharya SK, Mitra SK. Anxiolytic activity of Panax ginseng roots: An experimental study. J Ethnopharmacol 1991, 34:87-92.
Panax ginseng root extract standardized for 15% ginsenoside content was shown to have an anti-stress effect in mice.
	Della Loggia R, et al. Anti-stress activity of a ginseng extract: A subchronic study in mice. Planta Med 1991, 57(Sup 2):6.
A group of nurses who had recently switched from day shift to night shift were given either panax ginseng root extract or placebo. The group receiving ginseng rated higher in scores for mood, competance, performance and reported greater sense of well-being.
	Hallstrom C, et al. Effect of ginseng on the performance of nurses on night duty. Comp Med East West 1982, 6:277-82.
	Fulder SJ. Ginseng and the hypothalamic-pituitary control of stress. Am J Chin Med 1981, 9:112-8.
Piper mythysticum, Kava
58 patients were given either kava extract (100mg 3 times/day) or placebo over a 4 week period. Measures of anxiety, e.g., the Hamilton-Anxiety scale, showed significant reduction in anxiety in the group receiving the kava extract.
	Kinzler E, Kromer J, Lehmann E. Effect of a special kava extract in patients with anxiety, tension, and excitation states of non-psychotic genesis. Arzneim Forsch 1991, 41(6):584-8.
	Backhauss, Kriegstein J. Extract of kava (Piper methysticum) and its methysticum constituents protect brain tissue against ischemic damage in rodents. Eur J Pharmacol 1992, 215:265-9.
	Davies LP, et al. Kava pyrones and resin: Studies on GABAa, GABAb and benzodiazepine binding sites in rodent brain. Pharm Toxicol 1992, 71:120-126.
	Holm E, et al. Studies on the profile of the neurophysiological effects of D,L-kavain: Cerebral sites of action and sleep-wakefulness-rhythm in animals. Arzneim Forsch 1991, 41:673-83.
	Jamieson DD, Duffield PH. The antinociceptive action of kava components in mice. Clin Exp Pharmacol Physiol 1990, 17:495-508.
	Keledjian J, et al. Uptake into mouse brain of four compounds present in the psychoactive beverage kava. J Pharm Sci 1988, 77:1003-6.
	Kinzler E, Kromer J, Lehmann E. Effect of a special kava extract in patients with anxiety, tension, and excitation states of non-psychotic genesis. Arzneim Forsch 1991, 41(6):584-8.
	Lindenberg D, Pitule-Schodel H. D,L-kavain in comparison with oxazepam in anxiety disorders: A double-blind study of clinical effectiveness. Forschr Med 1990, 108:49-54.
	Meyer HJ. Pharmacology of kava. In: Holmstedt B, Kline NS (Eds.). Ethnopharmacological Search for Psychoactive Drugs. Raven Press, New York, NY, 1979.
	Warnecke G. Neurovegetative dystonia in the femal climacteric. Studies on the clinical efficacy and tolerance of kava extract WS 1490. Porschr Med 1991, 109:120-22.
Suan Zao Ren Tang Pian (Chinese herb formula)
A group of patients complaining of anxiety, irritability and insomnia were treated with suan zao ren tang (250 mg 3x/day) or diazepam (valium 2 mg 3x/day). The herb formula was shown to have approximately the same anti-anxiety effect as the diazepam, but unlike the diazepam, it improved daytime psychomotor performance and was free from side effects.
	Unknown. Suanzaorentang versus diazepam: A controlled double-blind study in anxiety. Int J Clin Pharmacol Ther Toxicol 1986, 24(12):646-50.
60 patients with cardiac anxiety and symptoms such as palpitations, chest pain, and shortness of breath, were treated with suan zao ren tang. The herbal formula exhibited significant anti-anxiety effects and also reduced elevated plasma norepinephrine and lactic acid levels.
	Hsieh MT, Chen HC. Suanzaorentang in cardiac patients with anxiety. Eur J Clin Pharmacol 1986, 30:481-4.
Chinese Patent Medicines
Chinese patent medicines known to have anti-anxiety effects include 1) An Mien Pien; 2) Ding Xin Wan; 3) Tian Wang Bu Xin Wan; 4) Pai Tzu Yang Hsin Wan, 5) Suan Zao Ren Tang Pian, all available in Chinese herb stores. They should be individually studied and compared because each is suitable for a certain 'conformation' or type of person with anxiety.
	Fratkin J. Chinese Herbal Patent Formulas - A Practical Guide. Institute for Traditional Medicine, Portland Oregon, 1986.
Valeriana officinalis Root
Valerian root's traditional use has been as a sedative for the relief of insomnia, anxiety, and as an adjunct in the treatment of pain. It has also been used successfully in the treatment of migraine, insomnia, hysteria, fatigue, intestinal cramps, and other nervous conditions.
	Murray MT. The Healing Power of Herbs. Prima Publishing, Rocklin CA, 1995.
	Mennini T, et al. In vitro study on the interaction of extracts and pure compounds from Valeriana officinalis roots with GABA, benzodiazepine and barbiturate receptors in rat brain. Fitoterapia 1993, 54:291-300.
	Houghton PJ. The biological activity of valerian and related plants. J Ethnopharmacol 1988, 22(2):121-42.
	Dressing H, et al. Insomnia: Are Valeriana/Melissa combinations of equal value to benzodiazepine? Therapiewoche 1992, 42:726-36.
Withania somnifera, Ashwagandha
Methanol extract of Withania somnifera root was found to contain a substance with GABA-like activity, as evidenced by in vivo and in vitro inhibition of GABA binding and enhanced binding of flunitrazepam to their respective receptor sites.
	Mehta AK, et al. Pharmacological effects of Withania somnifera root extract on GABA receptor complex. Ind J Med Res 1991, 94(B):312-5.
Thirty four individuals with anxiety neurosis were treated with an herb formula containing primarily Withania somnifera. After 12 weeks there were significant reductions in frequency, duration and intensity of symptoms. Laboratory analysis confirmed a significant reduction in 5-hydroxytryptophan and glutamate levels, and an increase in monamine oxidase and GABA.
	Upadhaya L, et al. Role of an indigenous drug Geriforte on blood levels of biogenic amines and its significance in the treatment of anxiety neurosis. Acta Nerv Super 1990, 32(1):1-5.
	Ghosal S, et al. Immunomodulatory and CNS effects of sitoindosides IX and X, two new glycowithanolides from Withania somnifera. Phytother Res 1989, 3(5):201-6.
	Bhattacharya SK, et al. Anti-stress activity of sitoindosides VII and VIII, new acylsterylglycosides from Withania somnifera. Phytother Res 1987, 1(1):32-7.

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