Natural Product-Derived Treatments for Attention-Deficit/Hyperactivity Disorder: Safety, Efficacy, and Therapeutic Potential of Combination Therapy.

Typical treatment plans for attention-deficit/hyperactivity disorder (ADHD) utilize nonpharmacological (behavioral/psychosocial) and/or pharmacological interventions. Limited accessibility to behavioral therapies and concerns over adverse effects of pharmacological treatments prompted research for alternative ADHD therapies such as natural product-derived treatments and nutritional supplements. In this study, we reviewed the herbal preparations and nutritional supplements evaluated in clinical studies as potential ADHD treatments and discussed their performance with regard to safety and efficacy in clinical trials. We also discussed some evidence suggesting that adjunct treatment of these agents (with another botanical agent or pharmacological ADHD treatments) may be a promising approach to treat ADHD. The analysis indicated mixed findings with regard to efficacy of natural product-derived ADHD interventions. Nevertheless, these treatments were considered as a "safer" approach than conventional ADHD medications. More comprehensive and appropriately controlled clinical studies are required to fully ascertain efficacy and safety of natural product-derived ADHD treatments. Studies that replicate encouraging findings on the efficacy of combining botanical agents and nutritional supplements with other natural product-derived therapies and widely used ADHD medications are also warranted. In conclusion, the risk-benefit balance of natural product-derived ADHD treatments should be carefully monitored when used as standalone treatment or when combined with other conventional ADHD treatments.

Conditioned place preference studies with atomoxetine in an animal model of ADHD: effects of previous atomoxetine treatment.

To investigate the putative rewarding effects of atomoxetine, a non-stimulant medication for Attention-deficit/hyperactivity disorder (ADHD), we conducted conditioned place preference (CPP) tests in an animal model of ADHD, the spontaneously hypertensive rat (SHR). The effects of drug pre-exposure were also evaluated, thus, parallel experiments were done in rats which have undergone 14 days of atomoxetine treatment. The responses of SHR were compared with the rat strain representing the "normal" heterogeneous population, the Wistar rats. Neither rat strain showed significant CPP to atomoxetine. However, previous atomoxetine treatment produced place preference responses in rats, more profoundly in Wistar rats conditioned with the low and moderate atomoxetine doses. In conclusion, acute exposure to atomoxetine does not have any rewarding effect, however, drug pretreatment produces responses characteristic of reward or psychological dependence, more specifically in the "normal" vs. the ADHD animal model. The present findings call for more studies with atomoxetine, especially those that investigate the effects of long-term or chronic drug treatment.

4-Chloro-7-trifluoromethyl-10H- benzo[4,5]furo[3,2-b]indole-1-carboxylic acid (TBIC), a putative BK(Ca) channel opener with uterine relaxant activities.

In the present study, we examined the uterine relaxant activity of 4-chloro-7-trifluoromethyl-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid (TBIC), a putative opener of the large conductance Ca(2+)-activated K(+) (BK(Ca)) channel. TBIC concentration-dependently inhibited spontaneous uterine contractions (EC(50) = 4.63 µmol/l; E(max) = 94.85 ± 1.85%; 100 µmol/l, n = 6). It also reduced contractions induced by oxytocin (EC(50) = 4.10 µmol/l; E(max) = 84.3 ± 3.83%; 100 µmol/l, n = 6), prostaglandin F(2)(α) (EC(50) = 2.14 µmol/l; E(max) = 73.70 ± 5.21%; 100 µmol/l, n = 6) and acetylcholine (EC(50) = 4.37 µmol/l; E(max) = 83.67 ± 4.82; 100 µmol/l, n = 6). TBIC decreased KCl (20 mmol/l) -induced contractions (EC(50) = 3.04 µmol/l; E(max) = 94.0 ± 3.12%; 100 µmol/l, n = 6) indicating its K(+) channel opening activity. BK(Ca) channel blockers penitrem A (100 nmol/l) and tetraethylammonium chloride (1 mmol/l) attenuated the inhibitory activities of TBIC (p < 0.001) but not other K(+) channel blockers such as barium chloride and glibenclamide (K(IR) and K(ATP) channel blockers, respectively). These results demonstrate the uterine relaxant effects of TBIC in a mechanism of action largely referable to the potentiation of the BK(Ca) channels. We have provided evidence for the potential use of TBIC as a tocolytic agent and support for the utility of BK(Ca) channel openers in pathophysiologic conditions involving smooth muscle hyperactivity.

Red ginseng supplementation more effectively alleviates psychological than physical fatigue.

Red ginseng (RG, the extract of Panax ginseng Meyer) has various biological and psychological activities and may also alleviate fatigue-related disorders. The present study was undertaken to evaluate what kind of fatigue red ginseng alleviate. Animals were orally administered with 50, 100, 200, 400 mg/kg of RG for 7 days. Before experiments were performed. Physiological stress (swimming, rotarod, and wire test) are behavioral parameters used to represent physical fatigue. Restraint stress and electric field test to a certain degree, induce psychological fatigue in animals. Plasma concentration of lactate and corticosterone (CORT) were also measured after these behavioral assays. RG supplementation (100 mg/kg) increased movement duration and rearing frequency of restrainted mice in comparison with control. 100 and 200 mg/kg of RG increased swimming time in cold water (8±4℃) while at 100 mg/kg, RG increased electric field crossing over frequencies. 50, 100 and 200 mg/kg RG prolonged running time on the rotarod and at 100 mg/kg, it increased balancing time on the wire. RG at those doses also reduced falling frequencies. RG supplementation decreased plasma CORT levels, which was increased by stress. Lactate levels were not significantly altered. These results suggest that RG supplementation can alleviate more the damages induced by psychological than physical fatigue.

Methylphenidate self-administration and conditioned place preference in an animal model of attention-deficit hyperactivity disorder: the spontaneously hypertensive rat.

The abuse potential of methylphenidate, the most commonly used drug for attention-deficit hyperactivity disorder (ADHD), has been shown in many studies. However, it is not yet known whether methylphenidate has reinforcing or rewarding effects in any animal model of ADHD. In this study, we investigated whether methylphenidate facilitates self-administration and induces conditioned place preference in the spontaneously hypertensive rat (SHR), the most validated animal model of ADHD. We also explored whether the behavioral responses of SHR differ from those of Wistar rats, the strain representing the 'normal' heterogeneous population. ADHD is highly prevalent among adolescents, such that behavioral assays should be conducted in adolescent SHR. In line with this, we carried out conditioned place preference tests in adolescent SHR and Wistar rats and observed strain and age-related differences in behavioral responses to the motivational effects of methylphenidate. Self-administration tests confirmed the reinforcing effect of methylphenidate in SHR, and showed that, in FR2 and FR3 schedules, SHR responded more to methylphenidate infusions than the Wistar rats. In conditioned place preference tests, both strains responded similarly to the rewarding effects of methylphenidate. However, it was found that adolescence also alters the euphorigenic effects of methylphenidate, most especially in SHR. The implications of these findings are discussed.

Reinforcing effects of methamphetamine in an animal model of attention-deficit/hyperactivity disorder--the spontaneously hypertensive rat.

Substrains of the Spontaneously Hypertensive rat (SHR), a putative animal model of Attention-Deficit/Hyperactivity Disorder (ADHD), have demonstrated increased sensitivity to many drugs of abuse, including psychostimulants. Therefore, it was suggested that studies in SHR may help elucidate ADHD and comorbidity with substance use disorder (SUD). However, the drug intake profile of the SHR in the most relevant animal model of drug addiction, the self-administration (SA) test, and its response on the conditioned place preference (CPP) paradigm are not yet determined. In the present study, we employed SA and CPP tests to investigate the reinforcing effects of the psychostimulant methamphetamine in an SHR substrain obtained from Charles River, Japan (SHR/NCrlCrlj). Concurrent tests were also performed in Wistar rats, the strain representing "normal" heterogeneous population. To address if the presence of ADHD behaviors further increases sensitivity to the rewarding effect of methamphetamine during adolescence, a critical period for the onset of drug abuse, CPP tests were especially conducted in adolescent Wistar and SHR/NCrlCrlj. We found that the SHR/NCrlCrlj also acquired methamphetamine SA and CPP, indicating reinforcing effects of methamphetamine in this ADHD animal model. However, we did not observe increased responsiveness of the SHR/NCrlCrlj to methamphetamine in both SA and CPP assays. This indicates that the reinforcing effects of methamphetamine may be similar in strains and that the SHR/NCrlCrlj may not adequately model ADHD and increased sensitivity to methamphetamine.