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Background:Kratom orMitragyna speciosaKorth has been widely used to relieve the severity of opioid withdrawal in natural settings. However, several studies have reported that kratom may by itself cause dependence following chronic consumption. Yet, there is currently no formal treatment for kratom dependence. Mitragynine, is the major psychoactive alkaloid in kratom. Chronic mitragynine treatment can cause addiction-like symptoms in rodent models including withdrawal behaviour. In this study we assessed whether the prescription drugs, methadone, buprenorphine and clonidine, could mitigate mitragynine withdrawal effects. In order to assess treatment safety, we also evaluated hematological, biochemical and histopathological treatment effects.Methods:We induced mitragynine withdrawal behaviour in a chronic treatment paradigm in rats. Methadone (1.0 mg/kg), buprenorphine (0.8 mg/kg) and clonidine (0.1 mg/kg) were i.p. administered over four days during mitragynine withdrawal. These treatments were stopped and withdrawal sign assessment continued. Thereafter, toxicological profiles of the treatments were evaluated in the blood and in organs.Results:Chronic mitragynine treatment caused significant withdrawal behaviour lasting at least 5 days. Methadone, buprenorphine, as well as clonidine treatments significantly attenuated these withdrawal signs. No major effects on blood or organ toxicity were observed.Conclusion:These data suggest that the already available prescription medications methadone, buprenorphine, and clonidine are capable to alleviate mitragynine withdrawal signs rats. This may suggest them as treatment options also for problematic mitragynine/kratom use in humans.

Objectives : The aim of this study is to review the acupoints used in cocaine studies and interpret the effectiveness in an aspect of meridian theory of Korean medicine. Methods : Authors searched 50 articles in PubMed, 16 in KISS, 9 in OASIS, 40 in NDSL, and 19 in DBPIA, with the keyword of ‘cocaine’ or ‘acupuncture’. The articles written in English only were included. The articles related with cocaine(abuse, dependence, sensitization, intake, withdrawal sign, withdrawal syndrome, reinstatement, seeking) only were subjected. The articles which used manual- or electro-acupuncture were included, and auricular was excluded. Results : The most frequently used acupoint was HT7, while LI4, LU9, ST36, and SP6 were used once respectively. HT7 could be understood to be used from the meaning of the name as well as the theory that Heart Meridian is deeply related with the brain function. LU9 seems to be used to enhance the effect of HT7. LI4 is thought to control reverting yin that flows toward the top of head following the theory of Jang Bu Sang Tong. ST36 appears to be used because it could regulate stress reaction that reverting yin is associated with. SP6 seems to have effect on brain function due to its ability to control spiritual disorder. Conclusions : The acupoints used in the cocaine studies are thought to influence the brain function through diverse mechanism, and Jang Bu Sang Tong theory seems to be involved in the mechanism, at least in part.

The present study was designed to ascertain the influence of repeated exposure to stress on the development of ethanol dependence in mice. Mice were chronically treated with 3% ethanol for 7 days, with or without exposure to restraint stress for 1 h/day. A significant loss of body weight was observed in the ethanol plus stress group compared with the other groups. In the ethanol plus stress group, mice exhibited persistent piloerection, which is considered to be a withdrawal sign that reflects emotion, after the discontinuation of ethanol treatment. The ethanol plus stress group also showed a marked increase in the intake of liquid diet, which is considered to be trying to avoid an unpleasant ethanol-withdrawal symptom, during ethanol withdrawal. In the hole-board test, a significant decrease in head-dipping behavior was observed in both the ethanol alone and ethanol plus stress groups at 6 h after the discontinuation of ethanol treatment. This abnormal emotion was recovered in the ethanol alone group, but not in the ethanol plus stress group, at 48 h after the discontinuation of ethanol treatment. These results suggest that repeated exposure to stress may affect the development of ethanol dependence and prolong the expression of withdrawal-induced emotional abnormality.

Substance abuse and dependence pose several risks in the perioperative setting. For example, excessive alcohol use increases the risk of morbidity during surgery—including cardiopulmonary, infections, wound, bleeding, and neurologic complications. Surgical patients who drink over four alcoholic drinks daily have a two- to threefold increased risk for postoperative complications when compared to patients who drink less than two drinks a day. However, other than for alcohol, there are limited data for interventions to improve perioperative outcomes.

Using various administration schedules, the physical dependence produced by dihydroetorphine (DHE) was compared with that of morphine in mice. Physical dependence, evaluated by naloxone-precipitated withdrawal signs, did not develop following daily treatment with DHE (10, 20, 100 and 1000μg/kg, i. p. or 30, 100 and 1000 ng/mouse, i. c. v.) for 6d. However, 5 repeated injections of DHE (10μg/kg, i. p.) at 1 or 2 h intervals did produce physical dependence and the dependent state disappeared after 2h. Accordingly, it was demonstrated that a sufficient degree of antinociceptive activity needed to be maintained, longer than several hours, for the development of physical dependence on DHE and that the duration of the dependent state was very short. In the single dose suppression test, a single dose of DHE completely suppressed the natural withdrawal signs that appeared following abstinence in morphine-dependent animals without reappearance of significant withdrawal signs, indicating the suitability of DHE as a substitute for morphine. The characteristic properties of DHE, the extremely potent antinociceptive effect and minimal dependence, indicate the separation of the antinociceptive effect from dependence, and suggest that it may be possible to develop a novel drug which may be safely used in clinical situations., Biological & Pharmaceutical Bulletin, 17(8), pp.1056-1059; 1994

The aim of study was determine the effect of ultra-rapid opiate detoxification (UROD) on the presence or absence of withdrawal syndrome in a group of patients with opiate dependency. In this study, withdrawal syndrome of 173 patients with opiate addiction was evaluated before and after UROD using the Objective Opioid Withdrawal Scale. Hence, each patient was observed for 5 minutes before UROD and at different hours afterward to observe any withdrawal sign. The most prevalent withdrawal sign before UROD was anxiety. Restlessness was the most prevalent finding at 1, 3, and 6 hours. After 12 hours, yawning was reported as the most prevalent finding in 39 participants. Anxiety was reported as the most prevalent finding in 61 participants after 24 hours. Patients with opioid dependency who underwent UROD showed the highest rate of withdrawal symptoms at one hour after anesthesia. Most of these symptoms subsided after 24 hours. UROD can be applied for detoxification of patients with opioid dependency w...

Prostaglandines and other eicosanoids are involved in a multitude of normal and pathological processes at CNS level.

We are celebrating Prof. Egon Diczfalusy’s 80th birthday. In his lifetime he has seen a dramatic change in the way we think about disease and how to control it. One needs to consider the knowledge of our field in the first half of the twentieth century to appreciate this: it was a world devoid of antibiotics and pure pharmaceutical compounds, a world which did not have immunoassays, and certainly knew virtually nothing about DNA and everything we now understand by the terms molecular biology or biotechnology. What we should, therefore, consider in this discussion are not just ideas which could become realistic in the next 5 years or so, but also visions of a future world with changes and revolutions as dramatic as Professor Diczfalusy has seen in his lifetime. We should also think about whether we want the changes that are possible. In this way scientists need the “utopian standpoint” referred to by Prof. Mittelstrass, with a vision of the future, but also with a notion of how to get there in small steps. Partly, as Prof. Benagiano pointed out, much of what we need to do is simply to spread what we already know to the rest of the world, to apply the skills and information we already have. But we are still presented with many knowledge barriers which need first to be surpassed.

Prolonged exposure of neuronal cells to an addictive drug causes adaptations which may manifest themselves in tolerance to and dependence on the drug concerned. With respect to opioids, several theories have been advanced to explain these compensatory mechanisms; these theories have centered on changes at the opioid receptor level or related to other components of the neurotransmitter systems (Shuster 1961; Collier 1968; Goldstein and Goldstein 1968; Jaffe and Sharpless 1968; Smith et al. 1988). Further interest has focused on the issue of whether adaptations are confined to opioid-responsive nerves (“cellular dependence”; Collier 1980) or involve cells adjacent to the opioid receptor-carrying neurons (Wuster et al. 1985).

Abecarnil (isopropyl 6-benzyloxy-4-methoxymethyl-β-carboline-3-carboxylate; ZK 112,119), which is a (β-carboline, exerts pharmacological effects at the benzodiazepine binding site on the gamma-aminobutyric acid type A (GABAA)-receptor complex. Its distinct profile of biochemical and behavioral effects has been suggested to indicate partial and/or selective benzodiazepine-receptor activity (Stephens et al. 1990). A series of experiments in baboons further characterized the behavioral pharmacological profile of abecarnil and provides information about its relative abuse liability (Sannerud et al. 1992). Specifically, tolerance, withdrawal, self-injection, and drug discrimination were evaluated with abecarnil using methods for which data have been previously reported for benzodiazepines and related novel compounds

Experiments on opiate sensitive peripheral tissue preparations such as the mouse vas deferens and the guinea-pig ileum have demonstrated the ability to induce very high degrees of selective tolerance towards particular opiate agonists. Interestingly, the highly tolerant mouse vas deferens failed to display any sign of dependence as judged by the inability of naloxone to precipitate a withdrawal sign. In analogy, the present studies on the guinea-pig ileum revealed a striking dissociation in the degree of tolerance and dependence developed. Opiate receptor binding studies on both tissues point to distinct differences in the opiate-induced effector mechanisms. It is concluded that adaptational changes upon chronic opiate receptor activation may occur at multiple sites within the effector system of the opiate receptor.

The topic of this article is the experimental psychology and experimental pharmacology of benzodiazepines as applied to their abuse liability assessment.1 The issues of physiological and psychological dependence on benzodiazepines are considered to be separate topics and will be examined as such.

Evidence has been accumulating to indicate that the spinal cord plays an important role in the expression of several narcotic abstinence signs in the intact animal. One characteristic and reproducible withdrawal sign which can be elicited in both intact and spinal-transected dependent rats is the naloxone-induced increase in arterial blood pressure. Employing this model, this autonomic component of narcotic withdrawal was quantitated in dependent spinal (C1)-transected rats with intact dorsal roots and in those with surgical lesions of the dorsal roots from T3 to L4. The withdrawal-associated hypertension observed in animals with intact dorsal roots was abolished in the rats having the lesioned roots. The central spinal location of the opiate receptors mediating the naloxone response was confirmed by experiments demonstrating the failure of a selective peripherally acting narcotic antagonist to elicit a comparable withdrawal response. It was concluded that continuous afferent input and spinal opiate receptors are requirements for the expression of spinal narcotic withdrawal.

An elderly female alcohol and benzodiazepine addict presented with an atypical amnestic episode. Five days later she showed several complex partial seizures as main signs of a withdrawal state. The value of the EEG in the differential diagnosis of amnestic syndromes is emphasized. Temporolimbic involvement in withdrawal states is discussed and our ignorance regarding drug dependence and withdrawal in the elderly is stressed. It is suggested that late-onset partial seizures with unknown etiology in the elderly might be more often related to drug dependence than generally accepted.

In 1964, the WHO Expert Committee on Addiction-Producing Drugs recommended substitution of the term “drug dependence” for the terms “drug addiction” and “drug habituation.” The WHO Scientific Group (1964) endorsed this recommendation.

The identification of the neurobiological concomitants of ethanol dependence and withdrawal would not only provide a better understanding of the basic nature of such phenomena, but would also facilitate the development of techniques of detection, prevention, and treatment of alcoholic disease and its psychobiological consequences.