Nonmedical use of prescription drugs in adolescents and young adults: not just a Western phenomenon

Abstract

onists have been tested in ASD associated with fragile X syndrome, and showed promise in a subgroup of patients. GABAergic agents, such as the GABA-B receptor agonist arbaclofen (STX209), have shown some effect on irritability and social withdrawal in ASD children. The peptide hormone oxytocin is important in social cognition and behavior. In ASD adults, acute intravenous administration of oxytocin reduced repetitive behaviors and improved accuracy of recognizing emotions in speech over time. Intranasal administration improved social cognition in children, adolescents and adults with ASD. A vasopressin 1a receptor antagonist had some effect on speech recognition of emotions such as fear and lust in high-functioning ASD adults. Insulin-like growth factor 1 (IGF-1) is important in central nervous system maturation, development and connectivity, that are perturbed in ASD. Studies in Shank-3 deficient mice that model Phelan-McDermid syndrome (PMS), which may be associated with some cases of ASD, indicated that IGF-1 may reverse structural changes in ionotropic glutamate receptors, functional synaptic plasticity changes, and excitation/inhibition imbalance. A clinical trial with recombinant human IGF-1 in PMS children showed improvement in social impairment and restricted behaviors. Agents modulating the immune system have been tested in ASD. The immune response induced by the whipworm Trichuris suis ova has shown benefit on the repetitive behavior domain in adult ASD. Immunosuppressive and protein synthesis inhibiting drugs such as the mTOR inhibitor rapamycin have been shown to improve social deficits in some forms of ASD. The alpha-7 nicotinic acetylcholine receptor (nACR) gene is associated with autism and ADHD. nACR drugs tested in clinical trials include mecamylamine, transdermally administered nicotine, and donepezil. Some alpha-7 nACR antagonists such as galantamine have shown promise in animal models and clinical trials. Drugs modulating the cannabinoid system, such as cannabidiol, have been found effective in childhood epilepsy, and may be worth studying in ASD due to their anti-anxiety, antiepileptic, immunomodulating and cognitive-enhancing effects and good safety. Interestingly, social reward and oxytocin induce release of endocannabinoids in nucleus accumbens. In ASD animal models, cannabidiol has some impact on social deficits, repetitive behaviors and irritability. Complementary and alternative medicine (CAM) treatments have been tested in ASD. However, they are not strictly regulated and have not been studied in large-scale clinical trials. Therefore, their safety and efficacy is not well determined. CAM treatments may complement rather than replace proven therapies for ASD. Melatonin may be used for sleep disorders, omega-3 fatty acids for reducing repetitive behaviors and improving sociability. Vitamin B12 supplements are believed to protect against the oxidative damage in ASD. Curcumin, an active ingredient of turmeric, may be beneficial in ASD, perhaps owing to its anti-oxidant and anti-inflammatory properties. Probiotics such as yogurt may have effects on the gut microbiome and on pro-inflammatory cytokines that may play a role in the pathogenesis of ASD. In summary, the enormous heterogeneity in ASD complicates development of new pharmacotherapies. Personalized treatments are desirable, and studies of syndromal orphan populations may accelerate drug development. Design of future clinical trials needs to address patient stratification on the basis of biomarkers or etiology (for example, immune-inflammatory) and target populations stratified by clinical symptoms. New pharmacotherapies such as oxytocin/vasopressin antagonists, anti-inflammatory agents, IGF-1, drugs regulating excitation/inhibition balance, protein synthesis inhibitors, and microbiome-targeting drugs may be of particular promise. Existing drugs such as anticonvulsants, SSRIs and atypical antipsychotics may be beneficial in some patients. It is important to test the effectiveness of drugs in younger children who may benefit most from early intervention. The ultimate goal of ASD pharmacotherapy will be to match the treatment to the underlying molecular mechanisms in individual patients.