tetrodotoxin and Heroin-Dependence

1. Tetrodotoxin (TTX) is a powerful sodium channel blocker extracted from the puffer fish. The efficacy and safety of TTX as monotherapy for the treatment of acute heroin withdrawal syndrome were evaluated in the present study. This 7-day, multicentre, randomized, double-blind, placebo-controlled study was carried out between December 2008 and October 2009. In total, 216 patients who met the Diagnostic and Statistical Manual of Mental Disorders IV diagnosis of heroin addiction were recruited. After providing written informed consent, subjects were randomly assigned to double-blind treatment in one of the following groups: 5 μg TTX group (group 1), 10 μg TTX group (group 2) or the placebo group (group 3). 2. Evidence suggests that both 5 and 10 μg TTX significantly reduced withdrawal symptoms by day 3 compared with placebo, and there was no significant difference in the incidence of adverse events in the three groups. 3. In conclusion, this clinical trial shows that TTX (5 and 10 μg given t.i.d.) is effective in alleviating opiate withdrawal symptoms with few side-effects.

Topics: Adult; Behavior, Addictive; Cues; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Heroin; Heroin Dependence; Humans; Male; Middle Aged; Placebos; Psychiatric Status Rating Scales; Sodium Channel Blockers; Substance Withdrawal Syndrome; Tetrodotoxin; Treatment Outcome; Young Adult

Tetrodotoxin (TTX) is a neurotoxin found in puffer fish and other marine animals. New clinical studies suggest that low-dose TTX can safely relieve severe, treatment-resistant cancer pain. The therapeutic potential of TTX in addiction is supported by studies in laboratory animals. The purpose of this double-blind, placebo-controlled study was to assess the effect of a single intramuscular dose of TTX on cue-induced craving and anxiety in abstinent heroin addicts.. Forty-five abstinent heroin addicts were randomly assigned to three treatment groups: placebo, 5 microg TTX, or 10 microg TTX. Participants were exposed to a neutral video or a heroin-related video. Craving, anxiety, blood pressure, and heart rate were measured pre- and post-exposure.. Heroin-related cues increased both craving and anxiety and had no effect on blood pressure and heart rate. A single dose of TTX dose-dependently attenuated the increases in craving and anxiety while having no effect on blood pressure or heart rate.. The results suggest that low-dose TTX is acutely effective in reducing cue-induced increases in heroin craving and associated anxiety.

Topics: Adolescent; Adult; Animals; Anxiety; Blood Pressure; Double-Blind Method; Female; Heart Rate; Heroin Dependence; Humans; Male; Middle Aged; Neurotoxins; Substance Withdrawal Syndrome; Tetrodotoxin; Young Adult

Intermittent footshock stress has been shown to reinstate extinguished drug-taking behaviour in rats, but the brain areas involved in this effect are to a large degree unknown. Here we studied the role of the septum in stress-induced reinstatement of heroin seeking. Rats were trained to self-administer heroin for 9-10 days (three 3-h sessions per day, 0.1 mg/kg per infusion). Following training, extinction sessions were given for 8-13 days by substituting saline for heroin, and then tests for reinstatement of heroin seeking were carried out. Reversible inactivation of the medial septum with tetrodotoxin (TTX; 1-5 ng, infused 25-40 min before the test sessions) reliably reinstated heroin seeking, mimicking the effect of 15 min of intermittent footshock. This effect of TTX was not observed after infusions made 1.5 mm dorsally into the lateral septum. In other experiments, it was found that infusions of a low, subthreshold dose of TTX (0.5 ng) into the medial septum, when combined with 2 min of footshock that in itself was ineffective, reinstated heroin seeking. Furthermore, electrical stimulation (400 microA pulses, 100 micros duration, 100 Hz frequency) of the medial septum during exposure to 10 min of intermittent footshock attenuated footshock-induced reinstatement of heroin seeking. These data suggest a role for the medial septum in stress-induced relapse to drug seeking. The septum is thought to be involved in neuronal processes underlying behavioural inhibition, thus we speculate that stressors provoke relapse by interfering with these processes.

Topics: Animals; Electroshock; Extinction, Psychological; Heroin; Heroin Dependence; Male; Neurons; Rats; Rats, Long-Evans; Recurrence; Self Administration; Septal Nuclei; Stress, Psychological; Tetrodotoxin