Clinical Studies | Addictive Disorders


CLINICAL STUDY 1 — Analgesic Effect, Tolerance Development and Dependence Potential of D-phenylalanine

—Dove B, Morgenstern E, Gores E.

In comparison to well-established non-narcotic analgesics, the amino acid d-phenylalanine produces similar, dose-dependent analgesic effects in animal experiments, but acts significantly longer. Neither a tolerance of mice to D-Phe after administration for 10 d nor a development of drug dependence in rats following treatment for 6 weeks could be regarded. PMID: 4070349

CLINICAL STUDY 2 — Reward Deficiency Syndrome: a Biogenetic Model for the Diagnosis and Treatment of Impulsive, Addictive, and Compulsive Behaviors

—Blum K, Braverman ER, Holder JM, Lubar JF, Monastra VJ, Miller D, Lubar JO, Chen TJ, Comings DE. – Department of Biological Sciences, University of North Texas, Denton, Texas, USA

The dopaminergic system, and in particular thed-phenylalanineD2 receptor, has been implicated in reward mechanisms. The net effect of neurotransmitter interaction at the mesolimbic brain region induces “reward” when dopamine(DA) is released from the neuron at the nucleus accumbens and interacts with a dopamine D2 receptor. “The reward cascade” involves the release of serotonin, which in turn at the hypothalmus stimulates enkephalin, which in turn inhibits GABA at the substania nigra, which in turn fine tunes the amount of DA released at the nucleus accumbens or “reward site.” It is well known that under normal conditions in the reward site DA works to maintain our normal drives. In fact, DA has become to be known as the “pleasure molecule” and/or the “antistress molecule.” When DA is released into the synapse, it stimulates a number a DA receptors (D1-D5) which results in increased feelings of well-being and stress reduction. A consensus of the literature suggests that when there is a dysfunction in the brain reward cascade, which could be caused by certain genetic variants (polygenic), especially in the DA system causing a hypodopaminergic trait, the brain of that person requires a DA fix to feel good. This trait leads to multiple drug-seeking behavior. This is so because alcohol, cocaine, heroin, marijuana, nicotine, and glucose all cause activation and neuronal release of brain DA, which could heal the abnormal cravings. Certainly after ten years of study we could say with confidence that carriers of the DAD2 receptor A1 allele have compromised D2 receptors. Therefore lack of D2 receptors causes individuals to have a high risk for multiple addictive, impulsive and compulsive behavioral propensities, such as severe alcoholism, cocaine, heroin, marijuana and nicotine use, glucose bingeing, pathological gambling, sex addiction, ADHD, Tourette’s Syndrome, autism, chronic violence, posttraumatic stress disorder, schizoid/avoidant cluster, conduct disorder and antisocial behavior. In order to explain the breakdown of the reward cascade due to both multiple genes and environmental stimuli (pleiotropism) and resultant aberrant behaviors, Blum united this hypodopaminergic trait under the rubric of a reward deficiency syndrome. PMID: 11280926

(l-glutamine is the precursor to gamma-aminobutyric acid GABA)

CLINICAL STUDY 3 — Alcoholism: Scientific Basis of a Neuropsychogenetic Disease

—Blum K, Trachtenberg MC. – Department of Pharmacology, University of Texas Health Sciences Center, San Antonio 78284

Until recently alcoholism was regarded as being an incurable psychological problem. During the last decade a chain of research has led to a new insight into the causes and potential alleviation of alcohol craving: Recent discoveries indicate that the brain has receptor sites for naturally occurring opiate-like substances (endorphins and enkephalins) which are produced by the nervous system. Opiates such as morphine or heroin, and some of the metabolic products of alcohol (tetrahydroisoquinolines), can also attach themselves to these receptors. It has been further discovered that the craving for alcohol is related to a deficiency of the naturally occurring opiate-like substances as well as other neurotransmitter substances. This deficiency can occur genetically or as a result of prolonged stress or long-term heavy drinking. The neurochemical imbalance may be treated chemically, leading to a possible alleviation of the craving for alcohol, especially in conjunction with psychotherapeutic and counseling regimens. PMID: 2906332

CLINICAL STUDY 4 — Reward Deficiency Syndrome: Genetic Aspects of Behavioral Disorders

—Comings DE, Blum K. – Department of Medical Genetics, City of Hope Medical Center, Duarte, CA, USA

The dopaminergic and opioidergic reward pathways of the brain are critical for survival since they provide the pleasure drives for eating, love and reproduction; these are called ‘natural rewards’ and involve the release of dopamine in the nucleus accumbens and frontal lobes. However, the same release of dopamine and production of sensations of pleasure can be produced by ‘unnatural rewards’ such as alcohol, cocaine, methamphetamine, heroin, nicotine, marijuana, and other drugs, and by compulsive activities such as gambling, eating, and sex, and by risk taking behaviors. Since only a minority of individuals become addicted to these compounds or behaviors, it is reasonable to ask what factors distinguish those who do become addicted from those who do not. It has usually been assumed that these behaviors are entirely voluntary and that environmental factors play the major role; however, since all of these behaviors have a significant genetic component, the presence of one or more variant genes presumably act as risk factors for these behaviors. Since the primary neurotransmitter of the reward pathway is dopamine, genes for dopamine synthesis, degradation, receptors, and transporters are reasonable candidates. However, serotonin, norepinephrine, GABA, opioid, and cannabinoid neurons all modify dopamine metabolism and dopamine neurons. We have proposed that defects in various combinations of the genes for these neurotransmitters result in a Reward Deficiency Syndrome (RDS) and that such individuals are at risk for abuse of the unnatural rewards. Because of its importance, the gene for the dopamine D2 receptor was a major candidate gene. Studies in the past decade have shown that in various subject groups the Taq I A1 allele of the DRD2 gene is associated with alcoholism, drug abuse, smoking, obesity, compulsive gambling, and several personality traits. A range of other dopamine, opioid, cannabinoid, norepinephrine, and related genes have since been added to the list. Like other behavioral disorders, these are polygenically inherited and each gene accounts for only a small per cent of the variance. Techniques such as the Multivariate Analysis of Associations, which simultaneously examine the contribution of multiple genes, hold promise for understanding the genetic make up of polygenic disorders. PMID: 11105655

(l-glutamine is the precursor to gamma-aminobutyric acid GABA)

CLINICAL STUDY 5 — Decreased Glutathione in Patients with Anorexia Nervosa – Risk Factor for Toxic Liver Injury?

—Zenger F, Russmann S, Junker E, Wüthrich C, Bui MH, Lauterburg BH. – Department of Clinical Pharmacology, University of Bern, Switzerland

OBJECTIVE: To investigate glutathione and amino acids related to glutathione metabolism in patients with anorexia nervosa in order to test the hypothesis that these patients exhibit a deficiency of glutathione and therefore might be at an increased risk of developing toxic liver injury. DESIGN: Controlled observatory study and case report. SETTING: University Hospital. SUBJECTS: Subjects included 11 female patients with anorexia nervosa and 12 healthy female controls. INTERVENTIONS: Determination of fasting free and total glutathione, homocysteine, vitamins B (6) and B (12) and folic acid in plasma. RESULTS: A 14-y-old patient with a body mass index of 12.6 kg/m (2) presented with markedly elevated transaminases (ALAT >50 x upper limit of normal), and paracetamol was detected in her blood. Patients with anorexia nervosa exhibited lower circulating concentrations of free cysteine (8.9+/-1.5 vs 12.0+/-1.4 micromol/l) and free and total glutathione (5.0+/-1.3 vs 7.1+/-1.2 and 11.2+/-3.8 vs 16.2+/-5.0 micromol/l, respectively). The plasma concentrations of homocysteine (17.5+/-4.9 vs 12.0+/-3.8 micromol/l) and also of glycine (194+/-37 vs 143+/-41 micromol/l) and glutamine (422+/-51 vs 353+/-51 micromol/l) were significantly higher in patients with anorexia nervosa who were not deficient in folic acid, vitamin B (6) and B (12). CONCLUSIONS: Lower plasma concentrations of glutathione suggest lower intracellular concentrations of the tripeptide. Higher homocysteine, glycine and glutamine concentrations point to a decreased utilization of these amino acids for glutathione synthesis and an impairment of trans-sulfuration. Consequently, the capacity of patients with anorexia nervosa to detoxify electrophilic metabolites and reactive oxygen species via glutathione may be impaired. PMID: 14749742

CLINICAL STUDY 6 — Aromatic Amino Acids in Weight-Recovered Females with Anorexia Nervosa

—Ehrlich S, Franke L, Schneider N, Salbach-Andrae H, Schott R, Craciun EM, Pfeiffer E, Uebelhack R, Lehmkuhl U. – Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Charité-Universitätsmedizin Berlin, Berlin, Germany

OBJECTIVE: Most previous studies investigating amino acid levels in anorexia nervosa (AN) have focused on acutely underweight patients. The present study assessed the availability of aromatic amino acids in the plasma of weight-recovered outpatients with AN (recAN) in comparison to acutely underweight AN patients (acAN) and healthy control woman (HCW). METHOD: Plasma tryptophan (TRP), tyrosine (TYR), and phenylalanine (PHEN) as well as leptin concentration were determined in 32 recAN, 32 acAN, and 32 HCW. RESULTS: Both recAN and acAN patients showed significantly lower levels of TRP and PHEN when compared to HCW. TYR was reduced in acAN patients only. DISCUSSION: Normal weight and normal leptin levels but lower availability of TRP and PHEN in recAN patients might indicate that outside a tightly controlled setting these patients still engage in abnormal eating patterns. Reduced peripheral availability of these precursor amino acids could impact on 5-HT and catecholamine functioning in the brain. PMID: 18803171

(phenylalanine is the precursor to tyrosine)

CLINICAL STUDY 7 — Use of micronutrients attenuates cannabis and nicotine abuse as evidenced from a reversal design: a case study

—Harrison R, Rucklidge JJ, Blampied N. Journal of Psychoactive Drugs.

Prior research shows that micronutrients, particularly amino acids, can assist individuals with substance dependence to quit various drugs of abuse, including cannabis, alcohol, and cocaine. As part of a wider investigation of the impact of micronutrients (mostly vitamins and minerals) on psychiatric symptoms, such as Attention-Deficit/Hyperactivity Disorder (ADHD), depression, and anxiety, we observed that many participants reduced or eliminated use of alcohol, cigarettes, and cannabis. One case using a single-case reversal (off-on-off-on-off) design is presented and shows not only on-off control of psychiatric symptoms as micronutrients are consumed or withdrawn, but also simultaneous on-off use of cannabis and cigarettes, despite not directly targeting this substance use as part of the treatment protocol. This case adds to a growing body of research supporting the use of micronutrients in the treatment of psychiatric symptoms and suggests it may extend to substance dependence. Micronutrients, by assisting with mood regulation and reductions in anxiety, may assist with successful cessation of drug use. Alternatively, they may directly impact on the brain reward circuitry believed to be involved in the expression of addictions, thereby providing the appropriate precursors and cofactors necessary for adequate neurotransmitter synthesis. This case should continue to stimulate researchers to consider the role of nutrients, in particular vitamins and minerals, in drug treatment programs and encourage more rigorous trials. PMID: 23909004

CLINICAL STUDY 8 — Shaken but unstirred? Effects of micronutrients on stress and trauma after an earthquake: RCT evidence comparing formulas and doses

—Rucklidge, J. J., Andridge, R., Gorman, B., Blampied, N., Gordon, H. 8 Bogg., A. (2012). Hum Psychopharmacol Clin Exp. DOI: 10.1002/hup.2246.

OBJECTIVE: To compare two micronutrient (vitamins and minerals) formulas (Berocca™ and CNE™) and assess their impact on emotions and stress related to the 6.3 earthquake on February 22(nd) 2011 in Christchurch, New Zealand. METHODS: 91 adults experiencing heightened anxiety or stress 2-3 months following the earthquake were randomized to Berocca™, CNE™ low dose (CNE4), or CNE™ high dose (CNE8), for 28 days and monitored weekly via on-line questionnaires and followed 1 month post-trial. A nonrandomized control group (n = 25) completed questionnaires at baseline and 4 weeks. RESULTS: All treatment groups experienced significant declines in psychological symptoms (p < .001). CNE™ groups experienced greater reduction in intrusive thoughts as compared with Berocca™ (p = .05), with no group differences on other measures of psychological symptoms. However, CNE8 group reported greater improvement in mood, anxiety, and energy (p < .05) with twice as many reporting being "much" to "very much" improved and five times more likely to continue taking CNE™ post-trial than Berocca™ group. Treated participants had better outcomes on most measures over 4 weeks as compared to controls. CONCLUSIONS: This study supports micronutrients as an inexpensive and practical treatment for acute stress following a natural disaster with a slight advantage to higher doses ACTRN 12611000460909. PMID: 22782571

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