Omega-3 fatty acids prevent nicotine withdrawal-induced exacerbation of anxiety and depression by affecting oxidative stress balance, inflammatory response, BDNF and serotonin metabolism in rats.

Adolescents are known to be more vulnerable than adults to the adverse effects of nicotine dependence. In the present study, we aimed to investigate whether adolescent nicotine exposure, followed by a period of abstinence, could affect the anxiety- and depressive-like behaviors in rats. For this purpose, behavioral assessments were carried out using open field test, elevated plus maze and forced swimming test in male rats received chronic nicotine intake during adolescence followed by a period of abstinence in adulthood, compared to their control counterparts. In addition, O3 pre-treatment was done at three different doses to reveal whether it could prevent nicotine withdrawal effects. Then, animals were euthanized and the cortical concentrations of oxidative stress markers, inflammatory indices, brain-derived neurotrophic factor, serotonin and the enzymatic activity of monoamine oxidase-A were measured. Results indicated that nicotine withdrawal exacerbates the behavioral signs of anxiety through alteration of the brain oxidative stress balance, inflammatory response and serotonin metabolism. Moreover, we found that omega 3 pre-treatment significantly prevents the nicotine withdrawal-induced complications by restoration of changes in the mentioned biochemical indices. Moreover, the improving effects of O3 fatty acids were found to be dose-dependent in all experiments. Taken together, we would like to suggest the O3 fatty acids supplementation as a safe, inexpensive and effective strategy for prevention or amelioration of detrimental effects induced by nicotine withdrawal at cellular and behavioral levels.

Effects of ketogenic diet and ketone monoester supplement on acute alcohol withdrawal symptoms in male mice.

RATIONALE: After alcohol ingestion, the brain partly switches from consumption of glucose to consumption of the alcohol metabolite acetate. In heavy drinkers, the switch persists after abrupt abstinence, leading to the hypothesis that the resting brain may be "starved" when acetate levels suddenly drop during abstinence, despite normal blood glucose, contributing to withdrawal symptoms. We hypothesized that ketone bodies, like acetate, could act as alternative fuels in the brain and alleviate withdrawal symptoms. OBJECTIVES: We previously reported that a ketogenic diet during alcohol exposure reduced acute withdrawal symptoms in rats. Here, our goals were to test whether (1) we could reproduce our findings, in mice and with longer alcohol exposure; (2) ketone bodies alone are sufficient to reduce withdrawal symptoms (clarifying mechanism); (3) introduction of ketogenic diets at abstinence (a clinically more practical implementation) would also be effective. METHODS: Male C57BL/6NTac mice had intermittent alcohol exposure for 3 weeks using liquid diet. Somatic alcohol withdrawal symptoms were measured as handling-induced convulsions; anxiety-like behavior was measured using the light-dark transition test. We tested a ketogenic diet, and a ketone monoester supplement with a regular carbohydrate-containing diet. RESULTS: The regular diet with ketone monoester was sufficient to reduce handling-induced convulsions and anxiety-like behaviors in early withdrawal. Only the ketone monoester reduced handling-induced convulsions when given during abstinence, consistent with faster elevation of blood ketones, relative to ketogenic diet. CONCLUSIONS: These findings support the potential utility of therapeutic ketosis as an adjunctive treatment in early detoxification in alcohol-dependent patients seeking to become abstinent. TRIAL REGISTRATION: clinicaltrials.gov NCT03878225, NCT03255031.

Kratom Alkaloids, Natural and Semi-Synthetic, Show Less Physical Dependence and Ameliorate Opioid Withdrawal.

Chronic administration of opioids produces physical dependence and opioid-induced hyperalgesia. Users claim the Thai traditional tea "kratom" and component alkaloid mitragynine ameliorate opioid withdrawal without increased sensitivity to pain. Testing these claims, we assessed the combined kratom alkaloid extract (KAE) and two individual alkaloids, mitragynine (MG) and the analog mitragynine pseudoindoxyl (MP), evaluating their ability to produce physical dependence and induce hyperalgesia after chronic administration, and as treatments for withdrawal in morphine-dependent subjects. C57BL/6J mice (n = 10/drug) were administered repeated saline, or graded, escalating doses of morphine (intraperitoneal; i.p.), kratom alkaloid extract (orally, p.o.), mitragynine (p.o.), or MP (subcutaneously, s.c.) for 5 days. Mice treated chronically with morphine, KAE, or mitragynine demonstrated significant drug-induced hyperalgesia by day 5 in a 48 °C warm-water tail-withdrawal test. Mice were then administered naloxone (10 mg/kg, s.c.) and tested for opioid withdrawal signs. Kratom alkaloid extract and the two individual alkaloids demonstrated significantly fewer naloxone-precipitated withdrawal signs than morphine-treated mice. Additional C57BL/6J mice made physically dependent on morphine were then used to test the therapeutic potential of combined KAE, mitragynine, or MP given twice daily over the next 3 days at either a fixed dose or in graded, tapering descending doses. When administered naloxone, mice treated with KAE, mitragynine, or MP under either regimen demonstrated significantly fewer signs of precipitated withdrawal than control mice that continued to receive morphine. In conclusion, while retaining some liabilities, kratom, mitragynine, and mitragynine pseudoindoxyl produced significantly less physical dependence and ameliorated precipitated withdrawal in morphine-dependent animals, suggesting some clinical value.

Argan oil supplementation attenuates voluntary ethanol consumption and withdrawal syndrome promoted by adolescent intermittent ethanol in rat.

The present study investigates the potential neuroprotective effect of argan oil (AO), a natural vegetable oil, commonly used in folk Moroccan medicines, on adolescent intermittent ethanol intoxication (IEI), induced voluntary ethanol consumption, and withdrawal syndrome in rats. Animals were treated with ethanol (intraperitoneally [i.p.], 3 g/kg body weight [bw]) in intermittent doses (2 days on; 2 days off, from postnatal day 30-43), with/without oral AO pre-treatment (10 mL/kg/day bw, from postnatal day 21-121). A 2-bottle free access test was performed over 10 weeks to assess 10% ethanol consumption. Behavioral signs of withdrawal were observed after 2, 6, 24, 48, and 72 h after ethanol removal. Anxiety-like behaviors in the elevated plus maze and the light/dark box tests were also evaluated at 72 h of withdrawal. We found that AO pre-treatment significantly decreased the voluntary ethanol consumption induced by adolescent IEI. In addition, by establishing low ethanol consumption, AO pre-treatment counteracts negative effects of ethanol withdrawal and anxiety-like behaviors in ethanol-treated rats after 72 h of abstinence. Following behavioral assays, oxidative stress markers were evaluated and histologic analysis of neurodegeneration was also performed. The results showed that the low ethanol drinking in the AO-supplemented rats was associated with inhibition of oxidative stress and neurodegeneration in the rats' brains. These findings provide evidence for the promising neuroprotective effect of AO supplementation in voluntary ethanol consumption and withdrawal syndrome, at least in part through counteracting oxidative stress markers and neurodegeneration.

Electroacupuncture for tapering off long-term benzodiazepine use: A randomized controlled trial.

OBJECTIVE: To evaluate the efficacy of using electroacupuncture as an adjunct treatment in enhancing the benzodiazepine cessation rate in long-term benzodiazepine users. METHODS: This was a randomized, assessor- and subject-blinded, controlled trial. One hundred and forty-four long-term benzodiazepine users were randomly assigned to receive either electroacupuncture or placebo acupuncture (a sham itervention using non-invasive placebo needles) combined with a gradual benzodiazepine tapering schedule for 4 weeks. The primary outcome was the cessation rate of benzodiazepine use. Subjects were assessed on their benzodiazepine usage, benzodiazepine withdrawal symptoms, insomnia severity, and anxiety and depressive symptoms at baseline, week 6 and week 16. RESULTS: The cessation rates of the electroacupuncture and placebo acupuncture groups at 12 weeks post-treatment were 9.17% and 10.83%, respectively. Both groups showed a reduction in benzodiazepine usage by a self-completed drug record at week 16 (compared to baseline: electroacupuncture group -40.23% versus placebo acupuncture group -48.76%). However, no significant between-group differences were found in the benzodiazepine cessation rate, reduction in benzodiazepine usage, and other secondary measures across all the study time points. CONCLUSIONS: Electroacupuncture showed a similar cessation rate in benzodiazepine use to that of non-invasive placebo acupuncture in long-term users during a 4-week gradual tapering schedule. The evidence did not support advantages of electroacupuncture over non-invasive placebo acupuncture on reducing insomnia, anxiety, depression, or other withdrawal symptoms during the gradual tapering schedule. Despite a 40% decrease in the benzodiazepine usage in both groups, the effects may be attributed to the non-specific effects of acupuncture. TRIAL REGISTRATION: ClinicalTrials.gov # NCT02475538.

Dispositional Mindful Attention in Relation to Negative Affect, Tobacco Withdrawal, and Expired Carbon Monoxide On and After Quit Day.

BACKGROUND: Mindfulness (or "Mindful Attention") has been described as the presence or absence of attention to, and awareness of, what is occurring in the present moment. Among smokers, greater mindfulness is associated with greater effect stability and reduced cue-induced craving. While studies have shown that mindfulness is associated with other smoking-related factors such as reduced withdrawal symptoms using cross-sectional data, relatively little is known about the associations between baseline mindful attention and future abstinence-related effect/withdrawal. The current study sought to examine whether levels of mindful attention before cessation predicts negative affect, withdrawal, and level of expired carbon monoxide (CO) on quit day, and also 3 and 7 days after quitting, during a self-quit attempt. METHODS: Data from 58 adults (mean age = 34.9; 65.5% male) participating in a self-quit study were available for analysis. Self-report measures of mindful attention, negative affect, and withdrawal symptoms were collected. Biochemical measurement of expired CO was also collected. Dependent variables were assessed on quit day, and also 3 and 7 days after quitting. Covariates included age, race, sex, self-reported level of cigarette dependence, and smoking status through 7 days. Multivariate regression was used to evaluate the association of baseline mindful attention in relation to the studied outcomes. RESULTS: Greater mindful attention predicted lower negative affect and reduced withdrawal at all 3 time-points. Mindful attention did not predict levels of expired CO. CONCLUSIONS: The findings suggest that mindful attention before or during smoking-cessation treatment may help to reduce negative affect and withdrawal, which serve as barriers to cessation for many smokers.

Interventions for treatment and/or prevention of alcohol hangover: Systematic review.

OBJECTIVE: To evaluate new research conducted over the past few years (2009-2016) assessing the effectiveness of potentially curative and/or preventive methods of alcohol hangover. METHODS: Data were retrieved by a 4-stage systematic search process. A search of the online Pubmed and Scopus databases were performed, using a combination of keywords: "Alcohol," "Ethanol," and "C2 H5 OH," in combination with the terms "Hangover," "Treatment," and "Prevention." The search comprised studies listed between January 1, 2009 and June 30, 2016. Findings were synthesized using a systematic approach. Quantitative analysis was not done because of the heterogeneity of the included studies. RESULTS: Six controlled human studies were identified (placebo controlled-3, controlled studies with a comparator intervention-3). Of the interventions, the use of polysaccharide rich extract of Acanthopanax senticosus, red ginseng antihangover drink, Korean pear juice, KSS formula, and the After-Effect© were associated with a significant improvement of hangover symptoms (p < .05). The highest improvement was observed for the following symptoms: tiredness, nausea/vomiting, and stomachache. None of the methods were effective for all the symptoms. CONCLUSION: The available evidence suggests that several products are capable of significantly improving some, but not all, of the symptoms related to alcohol hangover. Therefore, further research is necessary to develop clinically effective hangover treatments.

Gender differences among treatment-seeking adults with cannabis use disorder: Clinical profiles of women and men enrolled in the achieving cannabis cessation-evaluating N-acetylcysteine treatment (ACCENT) study.

BACKGROUND AND OBJECTIVES: Recent evidence suggests that women may fare worse than men in cannabis trials with pharmacologic interventions. Identifying baseline clinical profiles of treatment-seeking cannabis-dependent adults could inform gender-specific treatment planning and development. METHODS: The current study compared baseline demographic, cannabis use, and psychiatric factors between women (n = 86) and men (n = 216) entering the Achieving Cannabis Cessation-Evaluating N-acetylcysteine Treatment (ACCENT) study, a multi-site, randomized controlled trial conducted within the National Drug Abuse Treatment Clinical Trials Network. RESULTS: Women reported greater withdrawal intensity (p = .001) and negative impact of withdrawal (p = .001), predominantly due to physiological and mood symptoms. Women were more likely to have lifetime panic disorder (p = .038) and current agoraphobia (p = .022), and reported more days of poor physical health (p = .006) and cannabis-related medical problems (p = .023). Women reporting chronic pain had greater mean pain scores than men with chronic pain (p = .006). Men and women did not differ on any measures of baseline cannabis use. DISCUSSION AND CONCLUSIONS: Cannabis-dependent women may present for treatment with more severe and impairing withdrawal symptoms and psychiatric conditions compared to cannabis-dependent men. This might help explain recent evidence suggesting that women fare worse than men in cannabis treatment trials of pharmacologic interventions. Baseline clinical profiles of treatment-seeking adults can inform gender-specific treatment planning and development. SCIENTIFIC SIGNIFICANCE: Cannabis-dependent women may benefit from integrated treatment focusing on co-occurring psychiatric disorders and targeted treatment of cannabis withdrawal syndrome.(Am J Addict 2017;26:136-144).

Hyperbaric oxygen treatment suppresses withdrawal signs in morphine-dependent mice.

Hyperbaric oxygen (HBO2) therapy reportedly reduces opiate withdrawal in human subjects. The purpose of this research was to determine whether HBO2 treatment could suppress physical signs of withdrawal in opiate-dependent mice. Male NIH Swiss mice were injected s.c. with morphine sulfate twice a day for 4 days, the daily dose gradually increasing from 50mg/kg on day 1 to 125mg/kg on day 4. On day 5, withdrawal was precipitated by i.p. injection of 5.0mg/kg naloxone. Mice were observed for physical withdrawal signs, including jumping, forepaw tremor, wet-dog shakes, rearing and defecation for 30min. Sixty min prior to the naloxone injection, different groups of mice received either a 30-min or 60-min HBO2 treatment at 3.5atm absolute. HBO2 treatment significantly reduced naloxone-precipitated jumping, forepaw tremor, wet-dog shakes, rearing and defecation. Based on these experimental findings, we concluded that treatment with HBO2 can suppress physical signs of withdrawal syndrome in morphine-dependent mice.

Salvia officinalis L. attenuates morphine analgesic tolerance and dependence in rats: possible analgesic and sedative mechanisms.

BACKGROUND: Salvia officinalis L. (SO) has effects on the central nervous system, including anti-addiction properties that may involve an opioid mechanism. OBJECTIVE: Effects of a hydroalcoholic extract of SO on nociception and on morphine-induced tolerance and dependence were evaluated in rats. METHODS: Tolerance and dependence were induced by injection of morphine (10 mg/kg, s.c.) or escalating doses of morphine (2.5, 2.5, 5, 10, 20, 40 and 50 mg/kg, s.c.) twice daily for 7 days. SO (400, 600 and 800 mg/kg, i.g.) was administered before morphine. The tail-flick and naloxone precipitation withdrawal tests were used to evaluate tolerance and dependence. Sedative effects as well as total polyphenolic and flavonoid were also measured. RESULTS: The morphine-treated group showed significant decrements in the percentage maximum possible effect (%MPE) on days 5 and 7 compared to the first day, illustrating morphine tolerance. Higher doses decreased morphine tolerance. Furthermore, SO (600 and 800 mg/kg) attenuated almost all of the withdrawal signs including weight loss, jumping, penis licking, teeth chattering, wet dog shakes, rearing, standing, sniffing, face grooming and paw tremor and increased sleep duration (64.5 ± 9.7, 100.3 ± 4.7, respectively). Total polyphenolic and flavonoid content of SO was 138 and 69 mg per g of dried extract, respectively. CONCLUSION: SO has antinociceptive effects and may decrease tolerance and dependence induced by repeated morphine administration. However, to determine whether treatment with SO blocks tolerance by interfering with neurobiological mechanisms that mediate the development of morphine tolerance will require further studies.

Marijuana for Glaucoma: A Recipe for Disaster or Treatment?

Marijuana has been shown to lower intraocular pressure (IOP) but with limited duration of action and numerous adverse effects. Use of marijuana to lower IOP as a means of glaucoma treatment would require frequent use throughout the day, leading to significant adverse effects, possible progression toward Cannabis Use Disorder (CUD), and/or withdrawal symptoms. The treatment of glaucoma based on the cannabis plant or drugs based on the cannabinoid molecule should be considered carefully before being prescribed. Considerations should include the adverse physical and psychological adverse effects, including substance abuse. Currently, the deleterious effects of marijuana outweigh the benefits of its IOP-lowering capacity in most glaucoma patients. Under extremely rare circumstances, a few categories of glaucoma patients may be potential candidates for treatment with medical marijuana. Further studies on alternate routes and more focused means of cannabinoid molecule delivery to the eye for glaucoma treatment are needed.

Preliminary effects of progressive muscle relaxation on cigarette craving and withdrawal symptoms in experienced smokers in acute cigarette abstinence: a randomized controlled trial.

BACKGROUND: Cigarette craving usually occurs in conjunction with unpleasant feelings, including stress, as part of a withdrawal syndrome. Progressive muscle relaxation (PMR), a behavioral technique used to reduce stress by concentrating on achieving muscle relaxation, may reduce levels of cigarette craving and other substance-related negative feelings and withdrawal symptoms. METHODS: Demographic and cigarette use data were collected from 32 experienced smokers at the King Chulalongkorn Memorial Hospital, Bangkok, Thailand using the Semi-Structured Assessment for Drug Dependence and Alcoholism. Participants were asked to refrain from smoking for at least 3 hours before the visit (acute abstinence) and were randomly allocated to a 1-session PMR group (n =16) or a control activity group (e.g., reading newspaper, n =16). The intervention group was instructed to practice PMR individually in a quiet, private, air-conditioned room for about 20minutes. Craving, other substance-related feelings, and autonomic nervous responses (e.g., blood pressure and pulse rate) were assessed immediately before and after the 1-session intervention. RESULTS: There were no differences in demographics, cigarette use/dependence, and baseline craving characteristics between the PMR and control groups. However, the control group had higher levels of high and paranoia feeling, and pulse rate than the PMR group at baseline. After practicing PMR, but not after a control activity, smokers undergoing acute abstinence had significantly lower levels of cigarette craving, withdrawal symptoms, and systolic blood pressure than at baseline. After controlling for baseline differences, abstaining smokers using PMR had lower levels of cigarette craving, withdrawal symptoms, and systolic blood pressure than smokers who undertook a control activity. CONCLUSIONS: PMR significantly reduces cigarette craving, withdrawal symptoms, and blood pressure in smokers undergoing acute abstinence. PMR may be used as an adjunct to cigarette dependency treatments.

Spironolactone decreases the somatic signs of opiate withdrawal by blocking the mineralocorticoid receptors (MR).

Pharmacological evidence has accumulated showing that glucocorticoids and glucocorticoid receptor (GR) facilitate several responses to different drugs of abuse. Recent findings have attributed a prominent role to the mineralocorticoid receptor (MR) in modulating behavior during the addictive process. The purpose of this study was to investigate the effects of MR blockade on: brain stress system responses to naloxone-induced morphine withdrawal, the somatic signs of abstinence; the effects of morphine withdrawal on noradrenaline (NA) turnover in the paraventricular nucleus (PVN), c-Fos expression and tyrosine hydroxylase (TH) phosphorylated at Ser31 levels in the nucleus tractus solitarius noradrenergic cell group (NTS-A2); and finally, hypothalamus-pituitary-adrenocortical (HPA) axis activity. The role of MR signaling was assessed with i.p. pretreatment with the MR antagonist, spironolactone. Rats were implanted with two morphine (or placebo) pellets. Six days later rats were pretreated with spironolactone or vehicle 30min before naloxone. The physical signs of abstinence, NA turnover, TH activation, c-Fos expression and the HPA axis activity were measured using HPLC, immunoblotting and RIA. Spironolactone attenuated the somatic signs of withdrawal that were seen after naloxone administration to chronic morphine treated animals. On the other hand, pretreatment with spironolactone resulted in no significant modification of the increased NA turnover, TH activation, c-Fos expression or HPA axis activity that occurred during morphine withdrawal. These results suggest that somatic signs of opiate withdrawal are modulated by MR signaling. However, blockade of MR did not significantly alter the brain stress system response to morphine withdrawal.

Chronic sazetidine-A maintains anxiolytic effects and slower weight gain following chronic nicotine without maintaining increased density of nicotinic receptors in rodent brain.

Chronic nicotine administration increases the density of brain α4ß2* nicotinic acetylcholine receptors (nAChRs), which may contribute to nicotine addiction by exacerbating withdrawal symptoms associated with smoking cessation. Varenicline, a smoking cessation drug, also increases these receptors in rodent brain. The maintenance of this increase by varenicline as well as nicotine replacement may contribute to the high rate of relapse during the first year after smoking cessation. Recently, we found that sazetidine-A (saz-A), a potent partial agonist that desensitizes α4ß2* nAChRs, does not increase the density of these receptors in brain at doses that decrease nicotine self-administration, increase attention in rats, and produce anxiolytic effects in mice. Here, we investigated whether chronic saz-A and varenicline maintain the density of nAChRs after their up-regulation by nicotine. In addition, we examined the effects of these drugs on a measure of anxiety in mice and weight gain in rats. After increasing nAChRs in the rodent brain with chronic nicotine, replacing nicotine with chronic varenicline maintained the increased nAChR binding, as well as the α4ß2 subunit proteins measured by western blots. In contrast, replacing nicotine treatments with chronic saz-A resulted in the return of the density of nAChRs to the levels seen in saline controls. Nicotine, saz-A and varenicline each demonstrated anxiolytic effects in mice, but only saz-A and nicotine attenuated the gain of weight over a 6-week period in rats. These findings suggest that apart from its modest anxiolytic and weight control effects, saz-A, or drugs like it, may be useful in achieving long-term abstinence from smoking.

Potential role of N-acetylcysteine in the management of substance use disorders.

There is a clear and pressing need to expand pharmacotherapy options for substance use disorders (SUDs) in order to improve sustained abstinence outcomes. Preclinical literature has demonstrated the role of glutamate in addiction, suggesting that new targets for pharmacotherapy should focus on the restoration of glutamatergic function. Glutamatergic agents for SUDs may span multiple addictive behaviors and help demonstrate potentially overlapping mechanisms in addiction. The current review will focus specifically on N-acetylcysteine (NAC), a safe and well-tolerated glutamatergic agent, as a promising potential pharmacotherapy for the treatment of SUDs across several substances of abuse. Building on recently published reviews of the clinical efficacy of NAC across a broad range of conditions, this review will more specifically discuss NAC as a pharmacotherapy for SUDs, devoting particular attention to the safety and tolerability profile of NAC, the wealth of preclinical evidence that has demonstrated the role of glutamate dysregulation in addiction, and the limited but growing clinical literature that has assessed the efficacy of NAC across multiple substances of abuse. Preliminary clinical studies show the promise of NAC in terms of safety, tolerability, and potential efficacy for promoting abstinence from cocaine, nicotine, and cannabis. Results from randomized clinical trials have been mixed, but several mechanistic and methodological factors are discussed to refine the use of NAC in promoting abstinence and relapse prevention across several substances of abuse. Further preclinical and clinical investigation into the use of NAC for SUDs will be vital in addressing current deficits in the treatment of SUDs.

Treatment of cannabis dependence using escitalopram in combination with cognitive-behavior therapy: a double-blind placebo-controlled study.

BACKGROUND: Cannabis is the most frequently used illegal substance in the United States and Europe. There is a dramatic increase in the demand for treatment for cannabis dependence. Cannabis users frequently have co-morbid mood symptoms, especially depression and anxiety, and regular cannabis users may self-medicate for such symptoms. OBJECTIVES: We report a double-blind, placebo-controlled treatment study, for the prevention of cannabis use in cannabis-dependent individuals. METHOD: Regular cannabis-dependent users (n = 52) were treated for 9 weeks with weekly cognitive-behavior and motivation-enhancement therapy sessions together with escitalopram 10 mg/day. Urine samples were collected to monitor delta-9 tetrahydrocannabinol (THC) during treatment and questionnaires were administered to assess anxiety and depression. RESULTS: We observed a high rate of dropout (50%) during the 9-week treatment program. Fifty-two patients were included in the intention-to-treat analysis. Of these, ten (19%) remained abstinent after 9 weeks of treatment as indicated by negative urine samples for THC. Escitalopram provided no advantage over placebo in either abstinence rates from cannabis or anxiety and depression scores during the withdrawal and abstinent periods. CONCLUSIONS: Escitalopram treatment does not provide an additional benefit either for achieving abstinence, or for the treatment of the cannabis withdrawal syndrome. Due to limitations of our study, namely, a high dropout rate and effects of low abstinence rates on measures of anxiety, depression and withdrawal, it is premature to conclude that selective serotonin reuptake inhibitors are not effective for treatment of the cannabis withdrawal syndrome.

Nature cures nature: Hypericum perforatum attenuates physical withdrawal signs in opium dependent rats.

CONTEXT: Hypericum perforatum Linn. (Hypericaceae) (St. John's wort) attenuates opium withdrawal signs. AIM: To explore the therapeutic potential of Hypericum perforatum in the management of opium-induced withdrawal syndrome. MATERIALS AND METHODS: The effect of the Hypericum perforatum hydro-ethanol extract was investigated for potential to reverse naloxone (0.25 mg/kg)-induced opium withdrawal physical signs. Rats received opium extract (80-650 mg/kg) twice daily for 8 days along with Hypericum perforatum (20 mg/kg, orally) twice daily in chronic treatment and the same single dose 1 h before induction of withdrawal syndrome in the acute treated group. RESULTS: Hypericum perforatum reduced stereotype jumps and wet dog shake number in the chronic treatment compared to the saline control group (F(2, 24) = 3.968, p < 0. 05) and (F(2, 24) = 3.689, p < 0.05), respectively. The plant extract in the acutely treated group reduced diarrhea (F(2, 24) = 4.850, p < 0. 05 vs. saline). It decreased rectal temperature by chronic treatment at 30 min (F(2, 24) = 4.88, p < 0.05), 60 min (F(2, 240 = 5.364, p < 0.01) and 120 min (F(2, 24) = 4.907, p < 0.05). DISCUSSION AND CONCLUSION: This study reveals that the extract of Hypericum perforatum attenuates some physical signs of opium withdrawal syndrome possibly through direct or indirect interaction with opioid receptors. Further study is needed to clarify its mechanism.

Effect of Iboga alkaloids on µ-opioid receptor-coupled G protein activation.

OBJECTIVE: The iboga alkaloids are a class of small molecules defined structurally on the basis of a common ibogamine skeleton, some of which modify opioid withdrawal and drug self-administration in humans and preclinical models. These compounds may represent an innovative approach to neurobiological investigation and development of addiction pharmacotherapy. In particular, the use of the prototypic iboga alkaloid ibogaine for opioid detoxification in humans raises the question of whether its effect is mediated by an opioid agonist action, or if it represents alternative and possibly novel mechanism of action. The aim of this study was to independently replicate and extend evidence regarding the activation of µ-opioid receptor (MOR)-related G proteins by iboga alkaloids. METHODS: Ibogaine, its major metabolite noribogaine, and 18-methoxycoronaridine (18-MC), a synthetic congener, were evaluated by agonist-stimulated guanosine-5´-O-(γ-thio)-triphosphate ([(35)S]GTPγS) binding in cells overexpressing the recombinant MOR, in rat thalamic membranes, and autoradiography in rat brain slices. RESULTS AND SIGNIFICANCE: In rat thalamic membranes ibogaine, noribogaine and 18-MC were MOR antagonists with functional Ke values ranging from 3 uM (ibogaine) to 13 uM (noribogaine and 18MC). Noribogaine and 18-MC did not stimulate [(35)S]GTPγS binding in Chinese hamster ovary cells expressing human or rat MORs, and had only limited partial agonist effects in human embryonic kidney cells expressing mouse MORs. Ibogaine did not did not stimulate [(35)S]GTPγS binding in any MOR expressing cells. Noribogaine did not stimulate [(35)S]GTPγS binding in brain slices using autoradiography. An MOR agonist action does not appear to account for the effect of these iboga alkaloids on opioid withdrawal. Taken together with existing evidence that their mechanism of action also differs from that of other non-opioids with clinical effects on opioid tolerance and withdrawal, these findings suggest a novel mechanism of action, and further justify the search for alternative targets of iboga alkaloids.

Sustained reduction of nicotine craving with real-time neurofeedback: exploring the role of severity of dependence.

BACKGROUND: Neurofeedback delivered via real-time functional magnetic resonance imaging (rtfMRI) is a promising therapeutic technique being explored to facilitate self-regulation of craving in nicotine-dependent cigarette smokers. The current study examined the role of nicotine-dependence severity and the efficacy of multiple visits of neurofeedback from a single region of interest (ROI) in the anterior cingulate cortex (ACC) on craving reduction. METHODS: Nine nicotine-dependent cigarette smokers participated in three rtfMRI visits that examined cue-induced craving and brain activation. Severity of nicotine dependence was assessed with the Fagerström Test for Nicotine Dependence. When viewing smoking-related images with instructions to "crave," patient-tailored ROIs were generated in the vicinity of the ACC. Activity levels from the ROI were fed back while participants viewed smoking cues with the instruction to reduce craving. RESULTS: Neurofeedback from a single ROI in the ACC led to consistent decreases in self-reported craving and activation in the ACC across the three visits. Dependence severity predicted response to neurofeedback at Visit 3. CONCLUSIONS: This study builds upon previous rtfMRI studies on the regulation of nicotine craving in demonstrating that feedback from the ACC can reduce activation to smoking cues across three separate visits. Individuals with lower nicotine-dependence severity were more successful in reducing ACC activation over time. These data highlight the need to consider dependence severity in developing more individualized neurofeedback methods.