We review evidence that structural brain abnormalities are associated with abuse of amphetamines. A brief history of amphetamine use/abuse and evidence for toxicity is followed by a summary of findings from structural magnetic resonance imaging (MRI) studies of human subjects who had abused amphetamines and children who were exposed to amphetamines in utero. Evidence comes from studies that used a variety of techniques including manual tracing, pattern matching, voxel-based, tensor-based, or cortical thickness mapping, quantification of white matter signal hyperintensities, and diffusion tensor imaging. Ten studies compared controls to individuals who were exposed to methamphetamine. Three studies assessed individuals exposed to 3-4-methylenedioxymethamphetamine (MDMA). Brain structural abnormalities were consistently reported in amphetamine abusers, as compared to control subjects. These included lower cortical gray matter volume and higher striatal volume than control subjects. These differences might reflect brain features that could predispose to substance dependence. High striatal volumes might also reflect compensation for toxicity in the dopamine-rich basal ganglia. Prenatal exposure was associated with striatal volume that was below control values, suggesting that such compensation might not occur in utero. Several forms of white matter abnormality are also common and may involve gliosis. Many of the limitations and inconsistencies in the literature relate to techniques and cross-sectional designs, which cannot infer causality. Potential confounding influences include effects of pre existing risk/protective factors, development, gender, severity of amphetamine abuse, abuse of other drugs, abstinence, and differences in lifestyle. Longitudinal designs in which multimodal datasets are acquired and are subjected to multivariate analyses would enhance our ability to provide general conclusions regarding the associations between amphetamine abuse and brain structure.

/pdf/abuse-of-amphetamines-and-structural-abnormalities-in-the-1mk9rnb285.pdf

Abuse of amphetamines and structural abnormalities in the brain.

Amphetamine stimulants have been used medically since early in the twentieth century, but they have a high abuse potential and can be neurotoxic. Although they have long been used effectively to treat attention deficit hyperactivity disorder (ADHD) in children and adolescents, amphetamines are now being prescribed increasingly as maintenance therapy for ADHD and narcolepsy in adults, considerably extending the period of potential exposure. Effects of prolonged stimulant treatment have not been fully explored, and understanding such effects is a research priority. Because the pharmacokinetics of amphetamines differ between children and adults, reevaluation of the potential for adverse effects of chronic treatment of adults is essential. Despite information on the effects of stimulants in laboratory animals, profound species differences in susceptibility to stimulant-induced neurotoxicity underscore the need for systematic studies of prolonged human exposure. Early amphetamine treatment has been linked to slowing in height and weight growth in some children. Because the number of prescriptions for amphetamines has increased several fold over the past decade, an amphetamine-containing formulation is the most commonly prescribed stimulant in North America, and it is noteworthy that amphetamines are also the most abused prescription medications. Although early treatment does not increase risk for substance abuse, few studies have tracked the compliance and usage profiles of individuals who began amphetamine treatment as adults. Overall, there is concern about risk for slowed growth in young patients who are dosed continuously, and for substance abuse in patients first medicated in late adolescence or adulthood. Although most adult patients also use amphetamines effectively and safely, occasional case reports indicate that prescription use can produce marked psychological adverse events, including stimulant-induced psychosis. Assessments of central toxicity and adverse psychological effects during late adulthood and senescence of adults who receive prolonged courses of amphetamine treatment are warranted. Finally, identification of the biological factors that confer risk and those that offer protection is also needed to better specify the parameters of safe, long-term, therapeutic administration of amphetamines to adults.

Potential adverse effects of amphetamine treatment on brain and behavior: a review

Diethylstilbestrol Usage: Its Interesting Past, Important Present, and Questionable Future

Parents of 44 hyperactive children were assigned to either a behavior modification group (PAT), a communications group (PET), or a delayed-treatment control group. Parents in the treatment groups participated in 9-week training workshops. Parents and their children were assessed before and after the workshops on measures that included ratings of hyperactivity and severity of problems, a daily checklist of problem occurrence, parental attitudes, and direct observations in a laboratory situation. Both treatment methods were more effective than a no-treatment control condition in reducing hyperactivity ratings, problem severity ratings, and daily problem occurrence. Additionally, parents receiving behavior modification training rated their children as more improved than did PET parents, were more willing to recommend the program to a friend, felt the program was more applicable to them, and were less likely to drop out of the program. Nine-month follow-up assessments indicated that treatment parents continued to view their children's behavior more positively than did control group parents. Results are discussed with respect to the implications that an educational approach to teaching child management can be an effective means of reducing behavioral problems in children, that methods differing in theoretical background and actual skills taught may result in similar outcomes, and that a "psychological," as opposed to a medical, approach to the treatment of hyperactive children can have considerable merit.

Training parents of hyperactive children in child management: a comparative outcome study

The differential effectiveness of oral and silent reading on comprehension was evaluated for two third-grade children who were hyperactive and who displayed comprehension deficits. Oral reading res...

Increasing reading comprehension of two hyperactive children: preliminary investigation.

The abuse of amphetamines has become a problem of international significance. Japan was the first country to recognize this problem, and by 1954 there were an estimated 500,000 to 600,000 abusers in Japan. More than ten years ago Japan banned the use of amphetamines. The United Kingdom restricted distribution of amphetamines to hospital pharmacies in 1968. Sweden categorized amphetamine as a narcotic in 1944 because of abuse; and in 1965 phenmetrazine (Preludin) and in 1968 methylphenidate (Ritalin) were removed from the market. Patients now requiring amphetamines are registered with the government. Sweden has about 10,000 drug addicts (almost all between 15 and 30 years of age) using central stimulants intravenously; this is about the same percentage of their population as the estimated percentage of heroin addicts in New York City.1 In contrast, the number of heroin and opiate addicts in Sweden is estimated to be less than 500. In 1970, the Food and Drug Administration (FDA) responded to the problem of amphetamine abuse in the United States by limiting the package insert labeling for amphetamines to three indications: narcolepsy, hyperkinesis in children, and the short-term treatment of obesity. Currently, the latter indication is being reviewed and may no longer be valid. Among the related agents there is some specificity in labeling, e.g., methylphenidate is approved for use in adults with mild depression, narcolepsy at any age, and children with minimal brain dysfunction but not obesity; phenmetrazine for use only in obesity, etc. However, in the broad view there is a similarity in the pharmacologic properties, side effects, and abuse liability of dextro-amphetamine, methamphetamine, methylphenidate, and phenmetrazine.

https://pediatrics.aappublications.org/content/pediatrics/51/2/302.full.pdf

USE OF d-AMPHETAMINE AND RELATED CENTRAL NERVOUS SYSTEM STIMULANTS IN CHILDREN

One of the most important concepts in pediatric pharmacology is that exposure to drugs or chemicals may have latent, unforeseen effects on the child later in life. Some of the most dramatic occurrences, other than teratogenesis, are those in which hormonal exposure during the fetal or newborn period alters adult sexual development. However, none of these episodes is more impressive and ominous than that reported by Herbst et al . 1 Herbst, an obstetrician at the Massachusetts General Hospital, was intrigued by the presentation of seven patients with adenocarcinoma of the vagina, an extremely rare tumor not previously seen at the hospital. The patients ranged in age from 14 to 22 years and sought medical advice because of vaginal bleeding. Several had benign adenosis, suggesting that the malignant change seen in all was based on a fundamental alteration in the biology of the vaginal epithelium. Six of the patients were treated with radical surgery, and one was treated with wide, local excision. One of the patients died after surgery. In what could serve as a model of a scientifically conducted, epidemiologic study, each of the seven patients, plus an additional patient from another hospital, was matched with four controls born in the same hospital within four days. Thus, the "control" group was chosen in a manner to eliminate many biases of artificially contrived control populations. A wide variety of possible influences in both mothers and offspring were considered, e.g., maternal age, smoking habits, exposure to X-rays, breast-feeding, birth weight, age at menarche, medications during pregnancy, and so forth.

https://pediatrics.aappublications.org/content/pediatrics/51/2/297.full.pdf

Stilbestrol and adenocarcinoma of the vagina

Neonatal screening for congenital hypothyroidism (CH) is based on the measurement of thyroid-stimulating hormone (TSH) in whole dried blood samples on filter paper in all newborns. The objective of screening for CH is to prevent mental retardation, which is irreversible in the event of a late diagnosis, by setting up prompt treatment (before day 15) with levothyroxine. The threshold value of TSH on filter paper on day 3 is 17 mIU/L in France in the GSP method (GSP, Genetic Screening Processor, Perkin Elmer): It is one of the highest thresholds used in the world. In many countries, the TSH threshold is between 6 and 12 mIU/L. Studies have found that a threshold of > 17 mIU/L may miss as much as 30% of cases of CH, with 30-80% of these being permanent CH. Recent studies suggest that mild CH (currently missed by the French TSH threshold) is associated with cognitive consequences if left untreated. An inverse relationship between TSH at screening (below the current threshold) and cognitive development at preschool or school age has been shown. These studies advocate for the evaluation of a lowering of the threshold of TSH on filter paper in France: (a) to determine the number of CH diagnoses with the new threshold and whether these "new cases" would be transitory or permanent; and (b) to analyze the cost-effectiveness of the strategy. 

Neonatal screening for congenital hypothyroidism: Time to lower the TSH threshold in France.

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USE OF d-AMPHETAMINE AND RELATED CENTRAL NERVOUS SYSTEM STIMULANTS IN CHILDREN

Stilbestrol and adenocarcinoma of the vagina

Neonatal screening for congenital hypothyroidism: Time to lower the TSH threshold in France.