At Home Drug Withdrawal

Sobriety Success

The dependence on sobriety is defined as the state of sobriety. When a person is sober, they can live on a daily basis without their thoughts and behaviors being controlled by substance dependence. They do not feel obliged to use it because they manage to live without it. They see and appreciate so much the benefits of living without substance that they do not feel they have to use drugs or alcohol. Therefore, they refrain from using it to continue enjoying this new, healthier lifestyle. The success product of sobriety is a step-by-step manual for everyone. The product has been said to be beneficial for many people around the world. The reason why the product is gaining so much popularity among individuals. They see and appreciate so much the benefits of life without substance that they do not feel they have to use drugs or alcohol. Therefore, they refrain from using it to continue enjoying this new, healthier lifestyle. This strategy encourages you to maintain the long-term vision of recovery. Recognize that this is not a one-off thing, something you try for a few weeks to several months, then return to your previous life. You will be in recovery if you decide it's the life you want to live for the rest of your life. As such, there is no immediate timeline to which you must adhere, nor should you strive to achieve goals that you are clearly not ready to face. Read more here...

Sobriety Success Summary


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All of the information that the author discovered has been compiled into a downloadable ebook so that purchasers of Sobriety Success can begin putting the methods it teaches to use as soon as possible.

As a whole, this ebook contains everything you need to know about this subject. I would recommend it as a guide for beginners as well as experts and everyone in between.

Are amphetamine and cocaine addictive

It is commonly observed that amphetamine and cocaine are non-addictive, or cause psychological but not physical dependence. Such observations rest on a distinction in which the condition of addiction, or physical dependence, requires visible bodily withdrawal symptoms, but critics claim that this is of limited meaning now that there is an understanding of the neurobiological basis of drug withdrawal states. The current classification systems do retain some distinctions between physical and psychological dependence, and the issue is largely one of definition and semantics. The credibility of the label 'non-addictive' is certainly tested when individuals are encountered who have injected amphetamine 10 or more times every day for many years, or who spend vast amounts of money using crack in a highly compulsive manner.

Interference Peptides A Novel Therapeutic Approach Targeting Synaptic Plasticity In Drug Addiction

Synaptic plasticity at excitatory synapses has been proposed as the cellular substrate of information processing and memory formation in the brain under both physiological and pathological conditions, including addiction. There is a growing body of evidence that implicates long-term depression (LTD), particularly in the nucleus accumbens (NAc), as a potential mediator of drug-induced neural plasticity. In animals, behavioral sensitization is used to model enduring changes in neuronal activity and behavior that result from repeated exposure to drugs of abuse. Given the links between behavioral sensitization and enduring drug-induced neuroplasticity, it is possible that compounds that can disrupt LTD may form the basis for a rational drug development strategy for repairing abnormal synaptic functions that are related to exposure to addictive substances. The data reviewed here provide evidence that facilitated AMPAR endocytosis and LTD in the NAc is critically involved in behavioral...

Potential Utility Of Interference Peptides In The Treatment Of Drug Addiction

Given the involvement of the NAc in the maintenance of behavioral sensitization and its association with enhanced LTD, LTD in the NAc may be a critical substrate for the expression of sensitization. LTD observed in the hippocampal CA1 region and LTD in the NAc in animals sensitized to repeated exposure to drugs such as amphetamine or cocaine seem to share a common mechanism, manifested as a consequence of specific reduction of AMPARs, possibly by facilitated endocytosis of AMPARs24. Peptides developed to specifically inhibit regulated AMPAR endocytosis, and hence LTD, when delivered into neurons in the NAc, should prevent sensitization-related LTD, thereby blocking the expression of sensitization behavior.

Eliminate drug toxicity and treat drug withdrawal

Intense agitation and visual hallucinations are often seen in states of drug withdrawal. Such symptoms should raise the clinician's suspicion of withdrawal syndromes. Fever, tremulousness, diaphoresis, and tachycardia are further corroborating signs. The successful treatment of withdrawal-induced agitation and confusion requires the replacement of the same substance or a cross-reacting compound with less adverse effects and a better pharmacokinetic profile.

Neurosteroids and Personality Aggressivity and Drug Dependence

Characteristic for type A personality is also a tendency for antisocial behaviors and substance abuse. We have recently demonstrated that the low plasma levels of DHEA(S) are highly predictive of propensity to relapse in detoxified cocaine addicts (79). Lower than normal plasma levels of DHEA were also found in children and adolescents with attention deficit hyperactivity disorder (ADHD) (80), and this disorder constitutes a major risk factor for stimulant dependence (81). One can predict therefore that supplementation of some cocaine addicts with DHEA may compensate for the existing deficits of this steroid and might aid their treatment. We have initiated testing this hypothesis in a clinical trial.

Clinical Interest in Enkephalin Degrading Enzyme Inhibitors in Opioid Addiction Treatment

Protracted Withdrawal Syndrome

Nevertheless, although early abstinence syndrome may be an important clinical problem, the most difficult aspect of the treatment of addiction is the protracted abstinence syndrome, one of the main factors contributing to relapse. Indeed, in the first days after cessation of prolonged drug use an acute withdrawal syndrome is observed, which consists of physiological changes (i.e., agitation, hyperalgesia, tachycardia, hypertension, diarrhea, and vomiting) and a variety of phenomena, i.e., cardiovascular, visceral, thermoregulatory, and subjective changes including a depressive state that may persist for months or more after the last dose of opiate. Thus, the main challenge in the management of opioid addiction is to develop a pharmacotherapy to minimize the short-term withdrawal syndrome and protracted opiate abstinence syndrome. Compounds used classically for clinical treatment of opiate withdrawal, such as clonidine and methadone, were investigated using a spontaneous abstinence,...


Cocaine hydrochloride remains useful primarily because of the vasoconstriction it provides with topical use. Toxicity prohibits its use for other than topical anesthesia. Cocaine has a rapid onset of action (1 minute) and a duration of up to 2 hours, depending on the dose or concentration. Lower concentrations are used for the eye, while the higher ones are used on the nasal and pha- ryngeal mucosa. Epinephrine plus cocaine, although still used occasionally, is hazardous because the cate-cholamine potentiates the cardiovascular toxicity (e.g., arrhythmia, ventricular fibrillation) of cocaine. Cocaine is readily absorbed from mucous membranes, so the potential for systemic toxicity is great. The CNS is stimulated, and euphoria and cortical stimulation (e.g., restlessness, excitement) frequently result. Overdosage leads to convulsions followed by CNS depression. The cortical stimulation it produces is responsible for the drug's abuse (see Chapter 35).

Drug abusers

Therapeutic communities for drug abusers use the American concept-based model. They form one part of the range of treatments for drug abuse, which includes other residential models such as Christian communities and the Minnesota model, methadone maintenance programmes, and psychotherapy. A large number of concept-based therapeutic communities for drug abusers have been established in American prisons since the mid-1980s, accompanied by a growing number of after-care programmes providing employment and drug-free accommodation. Several national studies have evaluated the outcome of these programmes. Randomized controlled trials show that no-treatment groups have a higher level of recidivism than those who complete treatment in a prison therapeutic community, and that recidivism is further reduced by participation in a community aftercare therapeutic community. ( .8) The general conclusion is that residents who stay in the programmes for longer periods have lower rates of drug use and...

The burden of mental illness

Using the DALY as the basic statistic, the World Development Report(2) concludes that mental health problems make up 8.1 per cent of the total GBD. Of that 8.1 per cent, the largest contributors are depressive disorders, self-inflicted injuries. Alzheimer's disease and other dementia, and alcohol dependence, followed by epilepsy, psychoses, drug dependence, and post-traumatic stress disorder. Depressive and anxiety disorders account for between one-quarter and one-third of all primary-health-care visits worldwide.(3,,4) When appropriately diagnosed and treated, suffering is alleviated, disability prevented, and function restored when ignored, major losses persist.(5) By the year 2025, three-quarters of all elderly persons with dementia (about 80 million) will live in low-income societies. Mental retardation and epilepsy rates are three to five times higher in low-income societies compared with industrialized countries. In some Asian and African countries, up to 90 per cent of patients...

Epidemiological aspects

Causes of cardiac arrest that are unrelated to coronary heart disease include many disparate conditions, but drugs, trauma, infections, and cardiomyopathies are the principal causes. These conditions are relatively more common in younger patients and provoke cardiac arrest by producing increased susceptibility to malignant ventricular arrhythmias. Cocaine, a 'recreational' drug that increases myocardial sensitivity to catecholamines by blocking their presynaptic uptake, is one example.

Brigitte L Kieffer and Frdric Simonin 1 Introduction

Opium, extracted from the seed of the poppy Papaver somniferum, has been used and abused for several thousand years. This substance is highly efficient to relieve pain or treat dysentery, and also shows strong euphoric and addictive properties. Due to their exceptional therapeutic potential, the active ingredients of opium have been the subject of intense investigations. Morphine, named after Morpheus, the Greek god of dreams, was isolated in 1806 (1) and is considered the prototypic opioid compound. This compound retains both analgesic and addictive properties of opium. Despite numerous adverse effects (2), morphine remains the best painkiller in contemporary medicine, and its clinical use is under tight regulation. In 1898 heroin was chemically synthesized by morphine diacetylation, in an attempt to obtain a drug with lower abuse liability. In fact, this morphine derivative showed even higher addictive potential due to its distinct pharmacokinetic properties. Heroin is being...

Chronic Morphine in Knockout Models 61 Tolerance and Sensitization

Morphine tolerance was unchanged in CB1 knockout mice (33), while sensitization to hyperlocomotion was abolished (35). This result indicates that the two processes can be dissociated, at least at the level of the cannabinoid system. In addition, this effect seemed specific to morphine, because sensitization to cocaine was unchanged (Table 4). Tolerance was also unchanged in DCGRP and OFQ N-deficient mice.

Adipose tissuederived proteins

Leptin signals via a single-transmembrane-domain receptor. Alternative mRNA splicing and post-translational processing results in multiple iso-forms of the receptor (Ob-R), such as the long, short and secreted form of the Ob-R (Stanley et al. 2005). Many effects of leptin on food intake and energy expenditure are mediated primarily via hypothalamic pathways. It is therefore hardly surprising that the long form of the Ob-R is expressed widely within the hypothalamus, in particular in the arcuate nucleus (ARC), but also in areas of the brain stem that are involved in the control of food intake. Two major types of ARC neurons carry the long form of the Ob-R (1) neurons expressing the orexigenic neuropeptides neuropeptide Y (NPY) and agouti-related peptide (AgRP), and (2) neurons expressing proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART). Through the Ob-R, leptin inhibits the activity of orexigenic NPY AgRP neurons and activates anorectic POMC CART...

Conclusion and Perspectives

Finally, a number of knockout models have been tested for cocaine or nicotine (for example D1, D3, D4, nAChR-D2 knockout mice, reviewed in ref. 110), but not morphine. It is likely that the genes inactivated in those mice are also implicated in responses to chronic opioid exposure, and this should be tested in future studies. More generally, a systematic screen of mice genetically modified in the central nervous system could be considered, because many genes involved in opioid addiction remain to be discovered.

CREB Function in Brain

From Molecular Biology of Drug Addiction Edited by R. Maldonado Humana Press Inc., Totowa, NJ Several molecular changes have been described during exposure to opioids (19-22). Acute opioid administration inhibits adenylyl cyclase activity, whereas chronic opioid treatment leads to a dramatic upregulation of the cAMP pathway at every major step of the cascade between receptor activation and physiological response (23) (Fig. 1). This upregulation occurs in discrete brain areas including the locus coeruleus (LC) and the nucleus accumbens (NAc), providing a neuroanatomical link for opioid physical dependence and rewarding effects, respectively (24-26) Upregulation of the cAMP pathway also seems to be involved in the addictive mechanisms of other drugs of abuse, such as cocaine (23,27). The phosphorylation state of CREB was shown to be decreased in the LC after acute morphine administration, whereas chronic morphine produces an increase in the phosphorylation and expression of CREB in this...

Genetically Altered CREB Mutant Mice

To investigate the role of CREB in drug dependence and motivational responses, we made use of two independent genetically modified CREB mutant mice. On the one hand, we have used CREB mice that lack the two major and CREB isoforms (8) These mice were generated by targeting the second CREB exon, which harbors the first translated ATG codon (Fig. 2) (29). Although the major CREB and isoforms were ablated, this mutation allowed for the translation of a novel and previously unidentified CREB isoform, at levels higher than in wild-type mice (30). In essence, these mice carry a hypomorphic CREB allele and are termed CREBm mice.

Dependence versus Tolerance

There is an important difference between drug dependence and drug tolerance although sometimes these terms are used interchangeably. Drug dependence occurs when the patient has a psychological and or physical dependence on the drug that results in withdrawal symptoms that can become unbearable for the patient to endure. Relief comes only when the patient is administered a dose of the drug.

Commonly Abused Substances

There are five groups of drugs that are commonly abused in the United States and in other developed countries. These are heroin, cocaine, cannabis, hallucinogens, and inhalants. Heroin is a Schedule I drug (see Chapter 1) that has no accepted medical use in the United States. Cocaine stimulates the central nervous system (see Chapter on CNS). Cannabis includes drugs such as marijuana and hashish. Hallucinogens are drugs that alter perception and feeling. These include LSD, mescaline, psilocybin, and PCP. Inhalants are aerosols and volatile hydrocarbons such as airplane glue and paint thinner that give the drug abuser a buzz or feeling of euphoria.

Physician as Catalyst

Given this environment, how the physician sees himself or herself in the doctor-patient relationship is important. Primary care physicians shift between various doctor-patient roles throughout the day. For instance, a patient who presents to the office having just experienced the death of a spouse needs a physician who will empathetically listen more than talk. In this situation, the physician is a counselor. For the patient presenting with an anaphylactic reaction, the physician must quickly take action. It is not time to be a counselor but instead to take control and make rapid decisions. In either case, the physician's role is based on the presenting needs of the patient. Treating patients with tobacco dependency, alcoholism, or drug addiction requires a triage approach that is different from treating hypertension or diabetes. My responsibility is to identify how willing a patient is to fight an addiction and then be a catalyst in providing the right intervention at the right...

Classification Of Adverse Drug Reactions

There are many different classifications for adverse drug reactions. For the purpose of this chapter, we will use the original classification proposed by (Rawlins and Thompson, 1991), which divided adverse drugs reactions into two types type A (pharmacological) and type B (idiosyncratic) (Table 6.2). The type A reactions represent an augmentation of the known pharmacological actions of a drug, are dose-dependent and, perhaps more importantly from the viewpoint of safety, are readily reversible on drug withdrawal, or even simply after dose-reduction

Contributions Of Many Cultures

At the turn of the nineteenth century, methods became available for the isolation of active principles from crude drugs. The development of chemistry made it possible to isolate and synthesize chemically pure compounds that would give reproducible biological results. In 1806, Serturner (1783-1841) isolated the first pure active principle when he purified morphine from the opium poppy. Many other chemically pure active compounds were soon obtained from crude drug preparations, including emetine by Pelletier (1788-1844) from ipecacuanha root quinine by Carentou (1795-1877) from cinchona bark strychnine by Magendie (17831855) from nux vomica and, in 1856, cocaine by Wohler (1800-1882) from coca.

Release Reuptake and Degradation

The dopamine transporters are not located at the active zone of the presynaptic site but are restricted to perisynaptic areas. This implies that dopamine diffuses away from the intersynaptic cleft. Besides its physiological role, dopamine transporters provide pharmacological targets for cocaine and amphetamines.

Pharmacological and psychological aspects of drugs of abuse

Drug abuse, misuse, and addiction are major issues in society because of their enormous personal, social, and economic costs. They also have important psychiatric components. Many drug treatment programmes are run by psychiatrists, and the evidence strongly supports the notion that a significant proportion of severe drug abusers are psychiatrically ill. Moreover, drug misuse is becoming more frequent in patients with other psychiatric disorders, where it can lead to problems in treatment and a poor outcome. It is therefore essential for all psychiatrists and related health professionals to have a good understanding of the basis of drug misuse.

Personality variables and the genetics of addiction

The role of personality in addiction is a major issue, with some believing in an 'addictive personality' and others suggesting different personality types might predispose to different aspects or forms of drug misuse. (26,27 In this highly controversial field a few facts are generally agreed. Predisposition to experiment with both licit and illicit drugs is more likely in those with sensation-seeking or impulsive behaviour traits, and in extroverts rather than introverts. However, once drug dependence is established, those with obsessional, dependent, or anxious characteristics find it hardest to stop. (2B) The genetics of drug abuse are beginning to be unravelled and already these studies have thrown up some important insights in relation to personality. The best studied dependence is that on alcohol, where the Scandinavian adoption studies have found the risk of alcoholism in male children of male alcoholics is the same regardless of whether the child is reared with the alcoholic...

The routes and risks of addiction

In addition to the impact of drug misuse on the social aspects of life, it can lead to significant medical problems. The dangers of drug abuse relate to two main factors the route of use of the drug and the effects it has in the brain outside of the reinforcement circuit. For most drugs of abuse the faster the drugs reach their target site in the brain the better they are liked and the more psychologically reinforcing they are. Indeed, the 'pharmaceutical' history of most abused drugs illustrates the progressive refinement of their preparation, in order to accelerate their rate of entry into the brain. A good example is cocaine. The Andean Indians originally used it by chewing coca leaves which produced low levels of cocaine over a period of time. An increase in vigour and a resistance to fatigue is produced, but little pleasure. Over the centuries cocaine has become more refined, first to paste and then to cocaine hydrochloride powder (snow) which when taken nasally produces high...

Chapter References

Field review of the basis of drug dependence. Medical Research Council, London. 7. Goudie, J.G. and Demellweek, C. (1986). Conditioning factors in drug tolerance. In Behavioral analysis of drug dependence (ed. S.R. Goldberg and I.P. Stolerman), pp. 225-85. Academic Press, New York. 9. Tiffany, S.T., Singleton, E., Haertzen, C.A., and Henningfield, J.E. (1993). The development of a cocaine craving questionnaire. Drug and Alcohol Dependence, 34, 19-28. 26. Altman, S.J., Everitt, B.J., Glautier. S., et al. (1996). The biological, social and clinical bases of drug addiction commentary and debate. Psychopharmacology, 125, 285-345. 30. Nutt, D.J. (1997). Neuropharmacological basis for tolerance and dependence. In Drug addiction and its treatment nexus of neuroscience and behavior (ed. B.A. Johnson and J.D. Roache), pp. 171-86. Raven Press, New York. 34. Di Chiara, G. (1995). The role of dopamine in drug abuse viewed from the perspective of its role in...

What caused this stroke

The history and examination may provide important aetiological clues (for example, the use of oral anticoagulants, the presence of an irregular pulse or heart murmur). Unusual causes are considerably more likely in younger patients (for example, evidence of drug abuse or recent cervical trauma precipitating arterial dissection). Our approach to investigation aims to be reasonably cost effective. We perform some simple investigations (full blood count, ESR, plasma glucose, urea and electrolytes, random plasma cholesterol, urinalysis, 12-lead EGG, and CT brain scan) in all patients in whom we are considering active management, even if our clinical assessment strongly suggests a common cause. These

Drug Pharmacokinetics Dose Response and Time Duration

Conditioning paradigms such as CPP are dependent on matching time of maximal pharmacological effect with establishing the conditional association with an environment. As with humans, the rewarding qualities are indirectly related to time of onset of the pharmacological effects. For example, a drug with a slow onset and a long duration of action (phenobarbital) is not a good reinforcer. The onset of the drug is to make an association between the drug effect and a specific behavioral state. Cocaine, on the other hand, has a rapid onset, especially when inhaled or injected intravenously, and thus is very readily used because of its rewarding stimulus effects.

Number and Duration of Conditioning Trials

Drugs with powerful reinforcing properties (amphetamine, cocaine, and morphine) require fewer and shorter conditioning trials then a weaker reinforcing drug (nicotine). Drugs with a very short half-life may allow a researcher to run a drug session in the morning and a vehicle session in the afternoon.

Specific neurotransmitter antagonists

Acamprosate enhances g-aminobutyric acid (GABA) transmission and antagonizes glutamate transmission, probably by antagonizing M-methyl-D-aspartate receptors (see Chapter.6.2.8). It reduces drinking in alcohol-dependent animals, and reduces the reinstatement of drinking behaviour in animals re-exposed to alcohol after a period of abstinence. Animals do not seek out acamprosate as they do addictive substances, and it does not have mood-altering or drug-abuse potential in humans.(46) It has no deterrent or disulfiram-like effect.

Who uses drugs and why

Polydrug use is the norm on the club scene. Among a sample of Scottish clubbers,(6) individuals had consumed a lifetime average of 11 different drugs. Drug use within the past year included alcohol (96 per cent), cannabis (96 per cent), ecstasy (87 per cent), tobacco (86 per cent), LSD (79 per cent), amphetamine (77 per cent), cocaine (59 per cent), 'poppers' (51 per cent), psylocybin mushrooms (47 per cent), temazepam (39 per cent), diazepam (26 per cent), codeine (19 per cent), heroin (11 per cent), ketamine (7 per cent), solvents (6 per cent), and buprenorphine (6 per cent). Other studies confirm that use of LSD, amphetamine, ecstasy, magic mushrooms, and poppers cluster together among young people. A quarter of all 18-year-olds have tried two or more illegal drugs. In a consecutive sample of 100 patients attending an Oxford drug dependency unit, 22 per cent were regularly using three or more street drugs apart from heroin at presentation (unpublished data). Risk-taking is an...

Consequences of drug use for young people

However, most legal and illegal drug users escape such acute disasters, and there is an enormous discrepancy between the large numbers revealed through population surveys to have experimented with various drugs and those who go on to develop problems with them later in life. Prospective studies (1.1 l31,4 and1.5) also suggest that modest controlled consumption rarely produces measurable long-term damage. Some people are able to use 'hard' drugs such as heroin, cocaine, and amphetamine in a controlled way, and differ significantly in their personal characteristics and patterns of use from those who surface in clinics or police cells as a result of legal, medical, or social problems. (16

The range of service providers and the impact of treatment

Those who experience problems with opiates may present to wide range of professionals within the health-care, social, and legal systems. The range of treatment options available within statutory and non-statutory agencies will vary, as will the provision of either maintenance or detoxification for opiate dependents depending upon differing treatment philosophies and treatment settings. Partly in response to this diversity of resource provision, an ongoing multicentre prospective outcome study (National Treatment Outcome Research Study) was set up in 1995 to compare the impact of different treatment approaches on subsequent drug use as well as upon psychosocial and physical outcomes. Preliminary results2** suggested that all four types of intervention (residential rehabilitation, inpatient drug dependency units, methadone maintenance, and reduction) led to reductions in illicit drug use and criminal activity as well as reductions in injecting and sharing behaviours. Least impact was...

Clinical features

The effects and withdrawal effects of amphetamine and cocaine can be considered together, as the main features are equivalent. However, amphetamine has a slower onset of action than cocaine and a longer elimination half-life, while crack is the most quickly absorbed of the cocaine preparations. This is reflected not only in the generally more intense effects of cocaine than amphetamine, but in the timescales involved. Thus an amphetamine user may experience desired effects, unwanted mental effects, and withdrawal features over the course of a few days, while a crack user can report the same sequence occurring in a matter of hours or even less. The main effects and withdrawal effects of these two stimulant drugs are shown in Table 1. Table 1 Effects and withdrawal effects of amphetamine and cocaine Such withdrawal features have been delineated most closely in relation to cocaine. A three-stage process has been described (2) initially agitation, anorexia, and acute craving second,...

Course and prognosis Course

A far greater proportion of amphetamine and cocaine misuse than opiate misuse is recreational in nature, with few significant complications occurring. It is assumed that the vast majority of those who are identified in school and teenage surveys as having used stimulants simply give them up in due course, although little systematic data is available. Complications and involvement with treatment services are more likely where there is dependent usage, and there may be psychiatric contact in episodes of psychosis. A very small proportion of amphetamine injectors progress to high-dose daily usage, while the heavy use of cocaine appears to be

Etiology and risk factors

The third important factor is the precipitating condition, which determines when seizures occur. Common precipitating factors include fever for children with febrile seizures, alcohol and sedative drug withdrawal, sleep deprivation, stimulant drugs and in some patients stress. Reflex seizures are precipitated by specific sensory stimuli. The most common are photosensitive seizures induced by flickering light, but some patients have very specific reflex epilepsy with seizures precipitated by such stimuli as being startled, particular types of music, certain visual patterns, reading, eating and hot-water baths. Identification of precipitating factors is helpful if they can be avoided, but in most patients specific precipitating factors are not apparent, and may not exist at all.

Phencyclidine abuse dependence and organic mental disorder

Many of the treatments applicable to patients addicted to the opiates, alcohol, and cocaine apply to this population. Several aspects of treating the phencyclidine patient depart from the more conventional addiction treatments. A triad of confusion, decreased cognitive function, and assaultiveness mark an organic mental disorder associated with phencyclidine use. Reduced cognition is a barrier to recovery that must be recognized and addressed in any prospective treatment plan. Neuropsychological assessment is helpful in this regard. Secondly, there is good evidence that phencyclidine is sequestered in fat for extended periods of time. (1,3) Conditions associated with weight loss are likely to release long-held phencyclidine into the blood and brain.

Dopamine Transporter Null Mice

Interestingly, cocaine and amphetamine are unable to induce an increase in horizontal or vertical motor activity in DAT-deficient mice administered with the drugs after 2 h of habituation to the testing chamber (7). Paradoxically, when the psychostimulants are administered just before, or 30 min after, introduction of the mice in the chamber, the animals exhibit a dramatic hypolocomotor behavior (22,23). This hypolocomotion can also be induced by agents acting on different levels of the serotonin (5-HT) neurotransmission to increase the extracellular concentration of 5-HT (22,23), unmasking a negative counterbalanced participation of the 5-HT system in the hyperlocomotor property of psychostimulants in normal mice. This contribution of the 5-HT neurotransmission Even more puzzling than the hypolocomotor effect of psychostimulant in DAT-deficient mice, is the observation that these mutant mice are still responsive to the reinforcing effects of cocaine to an extent similar to that of...

Physical complications from MDMA

Concurrent administration of cocaine and amphetamine will potentiate the stimulant effects of MDMA and may increase the likelihood of hyperthermic and cardiac problems. Some users take benzodiazepines and other depressant drugs to treat insomnia and restlessness. Stimulant drugs reduce the individual's awareness of intoxication by alcohol and may lead to higher alcohol consumption and hence increase the risk of accidents.

Prevalence of volatile substance use

Volatile substances are used throughout the world. A World Health Organization report gives an overview of the issue, (6) and a National Institute on Drug Abuse (NIDA) report presents prevalence studies worldwide.(7) A Pompidou Group report(8) indicated that VSA was a pan-European problem. In the United Kingdom, up to 20 per cent of young people have tried sniffing volatile substances. (9) In continental Europe, while prevalence is lower, experimental volatile substance use among teenagers comes second only to cannabis, and in Greece and Sweden it is higher than cannabis use. (10)

Norepinephrine Transporter Null Mice

Administration of cocaine induces a significantly higher dose-dependent increase in locomotion in NET-deficient mice compared to wild-type controls (29). A similar enhanced response is observed with a single dose of amphetamine. However, when treated for 5 d with cocaine according to a sensitization protocol, the mutant mice do not show a further augmentation in locomotion, which is the case for the wild-type mice (29). This result suggests that the NET-deficient mice are already sensitized to the action of cocaine and that a repeated treatment with the higher dose of cocaine used (20 mg kg) is not able to surpass a ceiling effect on locomotion already reached acutely with this dose of the drug. However, by using a conditioned place preference paradigm, the authors were able to further demonstrate the supersensitivity of these mutant mice to cocaine, since the NET-deficient mice presented a greater preference for the chamber previously associated with the injection of 20 mg kg of...

Size and nature of the problem

There is considerable concern about illicit drugs and an international commitment to reducing demand for these products. (23) This policy is hampered by considerable imprecision about the number of people using illicit drugs and the number of people who experience problems. Estimates suggest a global annual population prevalence rate for illicit drug use of between 3 and 4 percent, with a modest decline over recent years. In particular, the global population totals for the use of heroin and cocaine are estimated at approximately 8 million and 13.3 million adults respectively. (4) In the United Kingdom there have been no representative national population surveys focusing exclusively on drug use. However, the latest British Crime Survey of almost 11 000 participants aged 16 to 59 in England and Wales has provided valuable data on the prevalence of illicit drug use. (5) Lifetime prevalence estimates from the British Crime Survey are as follows cannabis, 22 per cent amphetamines, 9 per...

The user in withdrawal

If the regular supply of a psychoactive drug (especially sedative drugs such as opiates, barbiturates, benzodiazepines, and alcohol) is interrupted to the dependent user, a classic withdrawal syndrome is likely to develop (e.g. opiate withdrawal syndrome). The nature of the withdrawal syndrome will be determined by the substance group (e.g. opiates, cocaine, benzodiazepines, etc.) whilst the time course of the syndrome will be determined more by the specific drug used (e.g. methadone, heroin). The user in withdrawal from opiates, hypnotics sedatives, and in some circumstances cocaine may require special short-term detoxification. Detoxification describes a process of supportive medical care and usually pharmacotherapy for neuroadaptation reversal to facilitate a return to abstinence and physiologically normal levels of functioning. (41 Medically supervised detoxification can be delivered in inpatient, residential, or outpatient settings. Detoxification should not be considered in...

The recovering dependent drug user

Dependent drug users who attain abstinence may require continuing specialist treatment delivered in a residential setting. Maintaining the commitment to altering a drug-oriented lifestyle is a major and enduring task for many individuals and there are relatively few contemporary services to support this. The treatment philosophy and operation of residential rehabilitation programmes varies quite widely. In the United States, the majority are therapeutic communities and are based on the 12-step or Minnesota Model. The programme length of therapeutic communities varies from short term (e.g. 6 weeks) with aftercare to long-term programmes with a duration of over 1 year. Common to all therapeutic communities is an emphasis on peers and staff as role models for recovery. For some individuals, detoxification can be a gateway into drug-free counselling. Achieving a drug-free state is necessary for entry into many residential rehabilitation programmes or (for opiate users) to receive relapse...

Dopamine Receptors see Table

Therefore, pharmacological studies investigating the contribution of dopamine receptors in the action of psychostimulant drugs have focused on D1 and D2 receptors. Blockage of these receptors induces an inhibition of well-characterized properties of cocaine and amphetamine, including locomotor hyperactivity and stereotyped behaviors (47), rewarding and reinforcing properties assessed by self-administration and place-preference paradigms (48-50), and the development of psychostimulant-induced behavioral sensitization (51). Moreover, there is some evidence that D1 and D2 receptors contribute in opposite ways to mediate the action of psychostimulant drugs on downstream targets, such as the expression of the immediate early genes c-fos and zif268 (52,53) and that of neuropeptide genes coexpressed with these receptors, including substance P, dynorphin, enkephalin, and neurotensin (54). Recently, development of more selective ligands for the D3 receptor provides the opportunity to...

Leptin And Central Nervous System

Another set of neurons located in the lateral ARC and exhibiting a similar projection pattern expresses pro-opiomelanocortin (POMC) and cocaine- and amphetamine-related transcript (CART).23 26 These neurons are generally inhibited by starvation and activated by leptin. Multiple lines of evidence support the possibility that second order neurons expressing corticotrophin releasing hormone (CRH), thyrotropin releasing hormone (TRH), melanin-concentrating hormone (MCH), and hypocretin orexin may ultimately produce many of the physiological effects of leptin. The reader is directed to recent reviews for more information on these pathways.23 2629 The putative roles of some of these neurotransmitters in the sympathetic and cardiovascular actions of leptin are discussed later.

Factors Which Influence Drug Dosage Effects

The therapeutic effects of some drugs are lessened in individuals after the drugs have been used for long periods. Thus, an individual who has used such a drug for a long time needs larger doses of the drug than he did when he first began to take it in order to obtain the same effect. This effect is called tolerance. Persons who use opium, heroin, cocaine, amphetamines, and barbiturates develop a tolerance to these substances. Cross-tolerance occurs when the use of one drug

Improving the Prescription of Licensed Drugs

Pharmacogenetics could also be incorporated into improved postmarketing surveillance of medicines. Patients who have suffered an ADR could be genotyped to see whether there was a genetic basis for their response (16). This might lead to the creation of a test to identify people at high risk of rare ADRs. Rather than leading to drug withdrawal, the introduction of this form of pharmacogenetic testing might also enable some products to remain on the market (18) or to be rescued after withdrawal (17). However, regulators have indicated that this latter option is unlikely to win much support.

Risk factors age of onset and outcome

If a factor operates to increase the risk of schizophrenia and to bring on its onset, then it is logical to think that if it is still present then it will be associated with a poor outcome. Thus, a family history of schizophrenia, a history of obstetric complication, childhood low IQ, and continued drug abuse are all associated with a poor outcome. On the other hand, those patients who develop psychosis following stressful life-events tend to have a better outcome than those with no such precipitant. (9)

Goifj Protein Null Mice

Cocaine no induction of locomotion and stereotypes Cocaine Lowered locomotor function (unpublished data) Cocaine and amphetamine supersensitivity to locomotor and stereotyped effects Cocaine heightened c-fos and dynorphin levels Cocaine and amphetamine Cocaine no locomotor sensitization and no conditioned place preferences Amphetamine no locomotor sensitization (68) or moderate locomotor sensitization (29) Cocaine elevation of substance P levels No cAMP pathway stimulation Cocaine and amphetamine facilitated place preference Cocaine heightened expression of way. This is illustrated by a decrease affinity of D1 receptor for DA in the striatum and an abolition of the locomotor effect of D1 receptor agonist in the mutant mice. Furthermore, it is demonstrated that the locomotor stimulant action of cocaine and its induction of the immediate early gene c-fos in the STR is absent in Golfa null mice, supporting the view of an action of cocaine through G-protein stimulation. These authors also...

Neurotrophic Factor Null Mice

Lately, a lot of interest has been devoted for the implication of different members of the nerve growth factor (NGF)-related family of neurotrophins in the mediation of psychostimulant drug actions. So, BDNF (brain-derived neurotrophic factor) and GDNF (glial cell line-derived neurotrophic factor) have been shown to support the survival and function of DA midbrain neurons in vivo and in vitro (111,112) and protect them against neurotoxic injuries induced by 6-OHDA or MPTP (113,114). These factors utilize respectively the TrkB receptor-protein tyrosine kinase and the GFR-1 and its associated protein tyrosine kinase Ret as the primary targets of their signal transduction, which are both highly expressed in DA midbrain neurons (115,116). The involvement of BDNF and GDNF in functions associated with DA, and specifically the long-term adaptations induced by repeated exposures to psychostimulants, is supported by the ability of these factors to block some biochemical and morphological...

Toni S Shippenberg and Vladimir I Chefer 1 Introduction

The acute administration of psychomotor stimulants, such as cocaine and amphetamine, produce behavioral activation in humans and increased locomotor activity in laboratory animals. These agents are also self-administered by various species by virtue of their reinforcing effects. It is generally accepted that these actions results, at least in part, from an increase in dopaminergic (DAergic) neurotransmission in the nucleus accumbens (NAc), a terminal projection region of dopamine (DA) neurons comprising the mesocorticolimbic system (1). Cocaine increases extracellular DA concentrations by binding to the DA transporter and inhibiting the uptake of DA from the synaptic cleft, whereas amphetamine causes a reversal of the DA transporter and increases DA release (2,3). Repeated exposure to psychostimulants and other drugs of abuse results in a progressive and enduring enhancement of their locomotor stimulatory effects, a phenomenon referred to as sensitization. A prior history of...

Hypercatecholamine states

These conditions usually constitute hypertensive urgencies or non-urgencies and are not associated with specific organ system damage. They are usually treated with oral medications, or simply observed. However, if the hypertension is particularly severe (e.g. diastolic blood pressure of 140 mmHg), unresponsive to oral medications, or associated with specific complications, parenteral medications are required. Intravenous labetalol, given by intermittent pulse therapy or constant infusion, has been successful in this setting. Second-line choices are the combined use of b-blockade with a vasodilator. Diazepam alone can be very effective for the hyperadrenergic state of cocaine or amphetamine toxicity (.Panac.ekJ.994).

Anatomy of the Mesocorticolimbic System

DA neurons project to various brain regions, including the dorsal and ventral striatum, medial prefrontal cortex, amygdala, and hippocampus (24). The mesocorticolimbic DA system, originating in the ventral tegmental area, consists of numerous topographically organized positive and negative feedback circuits (Fig. 1). As our understanding of the organization of these projections has advanced, new insights have emerged as to the neuronal circuitry mediating the acute actions of psychostimulants as well as the sensitized behavioral responses that occur following their repeated administration. The vast majority of the ventral tegmental area (VTA) projections to the NAc are DAergic (24), whereas about 60 of mesoprefrontal projections contain GABA (25). However, prefrontal cortex (PFC) glutamatergic terminals selectively synapse onto GABA cells that project to the NAc and DA cells that project to the PFC (26). These PFC projections exert an excitatory influence on target cells (27-29)....

Modulation of Endogenous Opioid Systems by Psychostimulants

In addition to the modulatory effects of opioids on DA neurotransmission, it is also apparent that psychostimulants and other drugs that increase DA neurotransmission, affect the activity of endogenous opioid systems. The acute administration of cocaine, amphetamine, methamphetamine, or the DA uptake inhibitor GBR 12909 increase PDYN expression in the rodent NAc and dorsal striatum (94,95). This increase is delayed relative to the increase in DA levels, produced by these drugs and, in view, of the inhibitory effects of KOR agonists on extracellular DA levels, is consistent with it representing a compensatory mechanism that opposes stimulant-induced increase in DA neurotransmission. Increases in PDYN gene expression are also observed in the NAc and dorsal stria-tum immediately following the cessation of repeated cocaine self-administration or a binge pattern of cocaine or amphetamine administration (96,97). Although specific subterritories of the NAc have not been examined, the...

Modulation of Psychostimulant Induced Sensitization by OFQN

The intracerebroventricular application of OFQ N dose-dependently attenuates both basal and cocaine-induced locomotor activity as well as basal and cocaine-induced DA levels in the NAc (141). In accordance with the notion that changes in mesolimbic DA neurotransmission are involved in mechanisms of behavioral sensitization and the finding that OFQ N can modulate this neurotransmission (90,91), OFQ N does not prevent the development of behavioral sensitization when administered into the VTA prior to cocaine injection, but induces behavioral sensitization to a cocaine challenge when administered alone (142). As one of the possible explanations for this effect, the authors hypothesize that OFQ N, directly or indirectly, increases somatodendritic DA release, thereby reducing DA levels in the NAc (90,91). This increase would, presumably, result in subsensitivity of somatodendritic D2 autoreceptors in the VTA and a sensitized response to a subsequent cocaine challenge, when the peptide is...

Comorbidity of PTSD with other disorders and symptoms

Most of the comorbidity research has concentrated on the nature of the relationship between PTSD and alcohol or drug abuse. A recent longitudinal study (49) of 1007 adults showed that PTSD led to an increased risk of drug abuse or dependence, whereas exposure to traumatic events in the absence of PTSD did not increase the risk. Consistent with the interpretation that drug-use disorders are usually secondary to PTSD, there was no evidence that pre-existing drug abuse or dependence influenced the risk of PTSD after traumatic exposure. Similarly, the majority of studies have found that PTSD precedes the development of alcohol-abuse problems. There are probably several mechanisms for this relationship. In the short term, alcohol is used to self-medicate the symptoms of PTSD, but paradoxically intoxication and withdrawal symptoms may intensify the symptoms in the long term.(50)

Modulation of Psychostimulant Sensitization by MOR and DOR Ligands

Studies examining the influence of repeated administration of MOR and DOR agonists on the locomotor activating effects of amphetamine demonstrate an important role of these opioid receptor types in the modulation of sensitization. The repeated intra-VTA infusion of enkephalin, which results in sensitization to its locomotor-acti-vating effects, also results an enhancement of amphetamine- and cocaine-evoked activity (143). Exposure of animals to an environment previously paired with repeated systemic injections of low, but not high, doses of morphine also results in sensitization to the activating effects of amphetamine (144). Using the conditioned place preference and conditioned reinforcement paradigms, morphine-induced cross-sensitization to the rewarding effects of cocaine and amphetamine has also been demonstrated (5,145,146). Although anatomical mapping studies are limited, the findings that intra-VTA or intra-NAc infusions of MOR and DOR agonists facilitate the development of...

Summary and Conclusions

As is apparent from this review, interactions of opioid peptide and DA systems have been reported at the cellular, system, and behavioral level. Endogenous opioid peptide systems modulate DA neurotransmission in the NAc and its projections areas, and repeated psychostimulant administration can profoundly affect the activity of these same opioid systems. The repeated administration of cocaine and other drugs that increase DA neurotransmission in the NAc increase PDYN gene expression via D1 DA receptors, and it has been suggested that this increase is a compensatory response that opposes increases in DA that occur in response to these agents. Consistent with this hypothesis, the co-administration of KOR agonists with cocaine attenuates psychostimulant-induced sensi-tization, whereas KOR blockade results in an enhanced response to cocaine. Data regarding psychostimulant-induced changes in DOR and MOR systems are more limited. However, behavioral studies suggest that an increase in the...

Was the substance truly blood Was it the patients blood

Causes in children are multifactorial and not completely understood. Can occur in a stressed preterm or a healthy term infant. May be related to maternal medications (eg, tolazoline, a-adrenergic agonists, or NSAIDs). Maternal cocaine use also can be a risk factor. Ingesting certain medications, including aspirin, NSAIDs, and steroids, is a risk factor. Hemodynamically significant GI bleeding can result from standard dosing of NSAIDs. Parents may not consider these as medications, so ask specifically about their use. Stresses, including surgery, burns, increased intracranial pressure, or sepsis, can cause gastritis or ulceration. Other causes include mucosal irritation from milk-protein allergy, a lodged foreign body, gastrostomy tubes, or infection (Haemophilus pylor).

Types And Causes Of Hypertension

The sympathetic nervous system or insulin resistance can also cause hypertension.19 Abnormal renin that triggers angiotensin21 and oxidation that produces aldosterone21 are further risk factors.19 Other causes of clinical variable hypertension are physiologic variables.22 The first is vascular tone, which establishes the elastic properties of veins and arteries, vessel diameter, and vascular resistance.22 Additional variables causing high blood pressure are inotropic state and heart rate.22 Hypertension can result also from the use of drugs, medications, and other substances such as oral contraceptives, nonsteroidal anti-inflammatory drugs, licorice, cocaine, and amphetamines.23

Self Administration of Psychostimulants

Several studies in rodents have shown that suppression or reduction of circulating corticosterone decreases the reinforcing effects of psychostimulants as measured by self-administration. For example, suppression of glucocorticoids by adrenalectomy abolishes acquisition of cocaine self-administration over a wide range of cocaine doses (27,28), an effect that is reversed by corticosterone replacement. Other dose-response studies have shown that adrenalectomy induces a vertical downward shift of the dose-response curve to cocaine (29) during the maintenance phase (Fig. 2A). This reduction in drug effects is reversed dose-dependently by exogenous administration of corticosterone to adrenalec-tomized rats and the response to cocaine is fully restored when stress levels of corticos-terone are reached (Fig. 2B). Blockade of corticosterone secretion by metyrapone also reduces self-administration of cocaine, in both the acquisition and retention phases (27,28). Another corticosterone...

Hypersensitivity Myocarditis

Adverse effects of prescribed medications may include hypersensitivity and toxic myocarditis. Unlike toxic reactions, hypersensitivity may occur in individuals with prior uneventful exposure to the drug and is not dose related. The myocarditis is histologically characterized by a perivascular and interstitial infiltrate of the myocardium by eosinophils, leukocytes, and, rarely, multinucleated giant cells or granulomas with little or no myocyte necrosis.17 Commonly implicated drugs are sulfonamides, penicillins, methyldopa, phenytoin, and tri-cyclic antidepressants (Table 11-3).17'18 Cocaine may also rarely produce a hypersensitivity myocarditis. Unlike the hypereosinophilic syndrome, peripheral eosinophilia is typically absent.19 Prolonged continuous infusion of dobutamine has also been associated with hypersensitivity myocarditis.20 Hypersensitivity myocarditis is rarely recognized clinically and is often first discovered at postmortem examination. However, it may be diagnosed by...

Relapse in Psychostimulants Self Administration

Thus, cocaine-induced reinstatement of cocaine self-administration is only minimally decreased by adrenalectomy (43), and is not modified by ketoconazole, a corticosterone synthesis inhibitor that reduces circulating levels of corticosterone (44). Instead, corticosterone plays a significant role in cue-induced reinstatement of seeking. Thus, treatment with ketoconazole prevents conditioned cue-induced reinstatement of cocaine-seeking behavior produced by contingent exposure to a light and tone previously paired with cocaine during self-administration (for review, see ref. 45). Furthermore, as we will see in the next section, corticosterone also seems to play an important role in stress-induced reinstatement.

Methodological Considerations

Although most studies examining the effects of adrenalectomy on the behavioral responses to drugs are consistent, some studies have not observed decreased drug effects following ablation of the adrenal glands. For example, as mentioned previously, adrenalectomy does not decrease sensitization to the locomotor effects of cocaine when it is performed after a sensitizing paradigm (18,19). In addition, adrenalectomy does not reduce cocaine facilitation of brain stimulation (46) or drug-induced reinstatement of seeking behavior (for review, see ref. 43). The nature of this discrepancy is unclear. However, it is important to point out that corticosterone levels at the time of adrenalectomy (i.e., circulating levels of corticosterone at the time when the adrenal glands are removed) could play a fundamental role in determining whether adrenalectomy will or not reduce drug effects. Thus, it has been shown (12,47) that adrenalectomy has no effects on the locomotor response to cocaine or on the...

Effects of Stress on the Behavioral Response to Psychostimulants

Stress-induced corticosterone secretion mediates stress-induced sensitization to cocaine. (A) Stress (food restriction) increases the locomotor response to an injection of cocaine (10 mg kg). Blockade of stress-induced secretion of corticosterone by treatment with metyrapone (100 mg kg) prevents this stress-induced effect. (B) Food restriction increases dopamine levels in response to cocaine (10 mg kg). Blockade of stress-induced secretion of corticosterone by treatment with metyrapone (100 mg kg) prevents this stress-induced effect. (Modified from Marinelli et al. 13 and Roug -Pont et al. 71 ). Fig 3. Stress-induced corticosterone secretion mediates stress-induced sensitization to cocaine. (A) Stress (food restriction) increases the locomotor response to an injection of cocaine (10 mg kg). Blockade of stress-induced secretion of corticosterone by treatment with metyrapone (100 mg kg) prevents this stress-induced effect. (B) Food restriction increases dopamine levels in...

Locomotor Response to Psychostimulants

Several studies have shown that stress-induced sensitization to the locomotor effects of psychostimulants depends on the increase in corticosterone levels induced by the stressor. Thus, treatments that block stress-induced corticosterone secretion, but maintain basal levels of the hormone, have been shown to inhibit stress-induced sensitiza-tion. For example, adrenalectomy associated with replacement of basal levels of glucocorticoids (via subcutaneous corticosterone pellets) prevents the increase in locomotor response to amphetamine observed after food-restriction stress (53). A similar effect is seen on the locomotor response to amphetamine following social isolation (68), restraint stress (69), or different repeated stressors (70). These findings are confirmed by the observation that pharmacological blockade of stress levels of corticosterone (with acute or repeated metyrapone treatment) also decreases sensitization to the psychomotor effects of cocaine or amphetamine (15,71) (Fig....

Neurotransmitter Transporters 751 Dopamine Transporter

The dopamine transporter (DAT) is an important molecule for controlling dopaminergic turnover in the brain. Moreover, it is an important initial site of action for psychostimulants such as amphetamine and cocaine. Chronic ethanol treatment affects the function of the DAT A single photon emission computer tomography (SPECT) study on Finish alcohol-dependent patients found a 30 decrease in the DAT while these patients were intox-icated.137 However, another human positron emission tomography (PET) study with the radioligand 11C d-threo-methylphenidate showed no significant difference in DAT densities between alcohol-dependent patients and normal healthy volunteers.138 The divergence among the data might be related to different blood ethanol levels that were not controlled in these studies. Further investigations will help to clarify the functional meaning of this molecule.

Tonicclonic status epilepticus

The annual incidence of tonic-clonic status epilepticus varies considerably from study to study depending on the population analysed estimates have ranged from 4 to 28 cases per 100 000 persons (2000-14 000 new cases each year in the United Kingdom).4-7 It is most frequent in the young, in whom it also tends to be longer lasting. Status epilepticus is also commoner in epileptic patients with mental handicap, or with structural cerebral pathology (especially in the frontal lobes). In established epilepsy, status epilepticus can be precipitated by drug withdrawal, intercurrent illness, or metabolic disturbance, or the progression of the underlying disease, and is more common in symptomatic than in idiopathic epilepsy. About 5 of all epileptic adult clinic patients will have at least one episode of status epilepticus in the course of their epilepsy,1 and in children the proportion is higher (10-25 ).1,8 Most status epilepticus episodes, however, do not develop in known epileptic...

Relapse in Psychostimulant Self Administration

Following extinction training, reinstatement of drug-seeking behavior can be elicited by exposure to different stressors such as foot shock or food restriction (see refs. 77-79). Regarding foot shock stress, it was shown that basal levels of corticosterone are necessary for foot shock to induce cocaine seeking, but that stress-induced increase in corticosterone does not play an important role on this type of reinstatement. Thus, adrenalectomy decreases foot shock-induced reinstatement, but basal levels of corti-costerone are sufficient to reverse this effect (43). Similarly, in a different study, treatment with ketoconazole has been shown to decrease foot shock-induced reinstatement while only partially decreasing stress-induced corticosterone secretion (80). Studies on foot shock-induced reinstatement show that this behavior is blocked by administration of CRH antagonists (43,81) or D2-adrenergic receptor agonists (82), suggesting that extra-hypothalamic CRH and the central...

The Mesolimbic Dopamine System

Injection of corticosterone induces reinstatement of drug-seeking behavior. Administration of corticosterone induces an increase in the number of responses (nose pokes) in the device previously associated with cocaine (active hole), without modifying responding in the device without scheduled consequences (inactive hole). Peak effects are obtained for doses of corticosterone that are similar to those observed during stress the descending limb of the curve is obtained for supra-physiological doses of corticosterone. (Modified from Deroche et al. 29 ). Fig 4. Injection of corticosterone induces reinstatement of drug-seeking behavior. Administration of corticosterone induces an increase in the number of responses (nose pokes) in the device previously associated with cocaine (active hole), without modifying responding in the device without scheduled consequences (inactive hole). Peak effects are obtained for doses of corticosterone that are similar to those observed during stress...

Why Do Glucocorticoid Hormones and Drugs of Abuse Interact

In conclusion, glucocorticoid hormones are an essential component of our capacity to endure stressful situations, probably by attenuating their aversive impact. The role of these hormones in drug abuse is likely related to the long-lasting sensitization they induce in the reward system when repeatedly activated during stress. Consequently, understanding the molecular mechanisms that mediate such long-lasting effects of glucocorticoids could help us to better understand addiction and to develop new treatments of this condition.

Assessment and management of lifethreatening manifestations

The essential approach to an agitated patient necessitates physical control. Restraining the patient with multiple personnel, soft cloth restraints, and benzodiazepines may be lifesaving and necessary before continuing evaluation of the airway, breathing, and circulation. Is the airway protected Is the respiration depressed or shallow Is the patient in circulatory collapse High-flow oxygen, cardiac monitoring, and intravenous access must be established while obtaining vital signs, including a core temperature. Determination of bedside glucose is a priority. Blood should be sent for a complete blood count, electrolytes, blood urea nitrogen, creatinine, and arterial blood gas. Liver function studies (serum aspartate aminotransferase and serum alanine aminotransferase) should be performed, and creatinine phosphokinase levels should be determined. An ECG should be obtained to evaluate myocardial ischemia or infarction, atrial or ventricular dysrhythmias, and conduction abnormalities....

Myocardial ischemia

Those patients who have chest pain following cocaine use have a 6 per cent incidence of myocardial infarction which is comparable with that of other groups (Hollander. etal 1994). About 40 per cent of patients using cocaine complain of chest pain. Pleuritic or sharp chest pain is usually deemed 'non-cardiac'. Approximately one-third of cocaine abusers who have myocardial infarctions report the pain as pleuritic or sharp. Infarctions that may be silent, occurring in young patients (typically 19-40 years) with or without ECG changes or underlying atherosclerotic disease, makes the assessment more complex than that of traditional chest pain patients. Although giving clinically atypical presentations, cocaine has a classic pathophysiology for myocardial ischemia increased myocardial demand in the face of diminished oxygen supply. Cocaine abusers have increased oxygen demand with high sympathetic stimulation and development of left ventricular hypertrophy. Oxygen supply is diminished...

Aneurysmal Subarachnoid Hemorrhage

There is a strong temporal association between cocaine use and both ischemic and hemorrhagic cerebrovascular events. The use of sympathomimetic drugs, such as cocaine or metamphetamine, tends to increase the incidence and decrease the age at which rupture occurs in patients harboring aneurysms aneurysmal size at rupture also tends to be smaller.

The Development of Sensitization

Ferent psychostimulants may preferentially involve one or the other scenario (28,29). Thus, there is evidence for an action by amphetamine directly in the VTA, with less involvement from the PFC, while cocaine-induced behavioral sensitization appears to rely more on effects in the PFC (although an action directly in the VTA has also been shown). A distinction between amphetamine and cocaine is perhaps more dramatically emphasized by the fact that dopamine receptor antagonists can prevent the development of sensitization to amphetamine, but are generally ineffective at preventing cocaine sen-sitization (30,31). Given the role of dopamine transporter blockade in the acute motor stimulant effect of cocaine, this is a remarkable observation and presumably points to a critical role for cocaine blockade of the serotonin or norepinephrine transporter(s) in the development of sensitization. Another important factor is the involvement of environmental stimuli that are associated with the drug...

The Expression of Sensitization

One of the hallmark observations in the field of sensitization is that the capacity of a psychostimulant to increase extracellular dopamine in the nucleus accumbens is augmented, and that this augmentation increases progressively during withdrawal (13,14,49). This increase has been shown to arise in early withdrawal, in part from desensitization of autoreceptors. However, as in the VTA, this desensitization of D2 receptors is transient. At later withdrawal times an enduring elevation in vesicular release of dopamine predominates and occurs via an increase in calcium signaling, probably involving CaMKII (50,51). Some studies have also reported an increase in the releasibility of glutamate in the nucleus accumbens (52,53). However, this enhanced release is associated with a reduced basal level of extracellular glutamate, and when the reduced basal levels are normalized, an acute drug challenge no longer elevates glutamate (54). These data point to the likelihood that the presynaptic...

Association of REM sleep behaviour disorder with psychiatric disorders and stress

Psychiatric disorders are rarely associated with REM sleep behaviour disorder. (1236) Fluoxetine treatment of obsessive-compulsive disorder,(37) or cessation of use or abuse of REM-suppressing agents (viz. ethanol, amphetamine, cocaine, imipramine(38)) can trigger REM sleep behaviour disorder. Tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, and venlafaxine can induce or aggravate REM sleep behaviour disorder. In four cases, major stress involving divorce, automobile accident, sea disaster, or public humiliation triggered REM sleep behaviour disorder. (2,12

Other Pharmacological Actions

Orthostatic hypotension and high resting pulse rates can result from the use of the low-potency phenothi-azines. Mean arterial pressure, peripheral resistance, and stroke volume are decreased, while pulse rate is increased. Abnormal electrocardiograms (ECGs) have been observed, especially following thioridazine administration. These findings include prolongation of the QT interval and abnormal configurations of the ST segment and T waves, the latter being rounded, flattened, or notched. These effects are readily reversed upon drug withdrawal.

Other Adverse Effects

Opacities of the cornea and lens due to deposition of fine particulate matter are a common complication of chlorpromazine therapy but regress after drug withdrawal. The most serious ocular complication is pigmentary retinopathy associated with high-dose thioridazine administration it is an irreversible condition leading to decreased visual acuity and possibly blindness.

Physical examination

A normal initial examination of the abdomen does not exclude a significant intra-abdominal injury because some injuries may not cause pain or tenderness for up to 12 to 24 h. In addition, alcohol, illicit drug use, or a head or spinal cord injury may preclude a reliable examination. Close observation and frequent re-evaluation of the abdomen, preferably by the same observer, is important for detecting such injuries early. Fractures of the pelvis or the lower rib cage may also hinder adequate examination of the abdomen, because pain from these areas may be elicited when palpating the abdomen.

Extent and Pattern of Abuse

While some stimulants, such as amphetamine and methylphenidate, are taken orally, others are either volatilized for inhalation or snorted as the solid (nasal insufflation). It is necessary to convert cocaine and methamphetamine to their free base so that they can be volatilized. Methamphetamine and cocaine are also abused via the intravenous route.

Pharmacological Aspects

Acute drug administration produces feelings of euphoria, elation, and alertness. Intravenous injections of cocaine and amphetamine can produce a very intense rush of sensations that resemble sexual orgasm. At small doses cognition increases and mood is elevated. As the dose of drug escalates during a run, the overall activity of the individual changes from task performance to one generally characterized by stereotypical movements. The person starts performing certain behaviors repeatedly. Some grind or gnash their teeth. Many continuously touch or pick at their face or extremities. At this stage the individual becomes suspicious and may develop anxiety or paranoia. Acute toxic paranoid psychosis can develop, but it usually requires a longer period of abuse than a single acute session.

Stage of established status epilepticus 306090 minutes

Action of benzodiazepines occurs with prolonged administration, requiring higher doses that are potentially dangerous. There may also be recurrence of seizures on drug withdrawal. Chlormethiazole, which is not licensed in the United States, is an easily administered agent. Infusions, however, can be complicated by hypotension, cardiac depression, and respiratory arrest and, like benzodiazepines, this drug shows a propensity for dangerous accumulation with prolonged administration.36,37 Of other alternatives, paraldehyde is difficult to use as an intravenous preparation, decomposes in light, and in overdose there are potentially serious toxic side effects. It may be useful in premonitory stages per rectum, but in established status epilepticus where an intravenous infusion is indicated, its use is limited.36 There have been uncontrolled studies of the use of intravenous sodium valproate at this stage at high doses of at least 15 mg kg followed by an infusion of 1 mg kg h 38 experience...

Risk of suicide after attempted suicidedeliberate selfharm

Prospectively, suicide attempters have a high risk of committing suicide. Between 10 and 15 per cent eventually die because of suicide. (35) Mortality by suicide is higher among suicide attempters who have made previous attempts 38,39) The risk of suicide after attempted suicide deliberate self-harm for males is nearly twice the female risk, the risk being particularly high in the first year. (4 ,41) Alcohol and drug abuse and related social deterioration are risk factors for subsequent suicide, (42) as are psychiatric diagnosis (affective disorders, schizophrenia, personality disorders), and a highly lethal non-impulsive index suicide attempt.

Viral Diseases Hivaids

It is important to integrate HIV prevention and care, and the challenges are immense worldwide, fewer than one in five people at risk of becoming infected with HIV has access to basic prevention services. Of people living with HIV, only one in ten has been tested and is aware of the infection. For prevention interventions to achieve the results necessary to get ahead of the epidemic, projects with short-term horizons must translate into long-term programmatic strategies. In settings in which HIV is largely sexually transmitted, information and education campaigns can save lives. For example, intensive prevention programmes in the Mbeya region of the United Republic of Tanzania led to an increase in the use of condoms and the treatment of sexually transmitted infections between 1994 and 2000 those changes were accompanied by a decline in HIV prevalence among 15-24-year-old women from 21 to 15 in the same period 10). In settings in which HIV transmission is linked more closely to...

Clinical presentation

The possibility of acute traumatic rhabdomyolysis must be raised under several circumstances in which muscle damage may not be clinically apparent. Muscle compression secondary to coma, post-trauma or postseizure, or postural syndrome is sufficient to generate acute rhabdomyolysis. Electrocution or thundershock may also cause muscle necrosis. Postexertional rhabdomyolysis may occur after strenuous physical exercise, particularly in unprepared military recruits or occasional sportsmen. Other etiological and contributing factors include hypothermia, heat stroke, metabolic derangements, drug or cocaine abuse, acute or chronic alcoholism, and hereditary or acquired myopathies (T .ble,. ).

Donor Selection Organ Specific

Careful and complete documentation of the circumstances surrounding the death of the donor is essential. A history of blunt chest trauma raises the question of myocardial contusion, which can be ruled out with a combination of myocardial specific enzymes, ECG, and direct inspection of the chest wall and heart. A history of sudden death without known cause raises the question of a primary cardiac event such as an arrhythmia or myocardial infarction. Even with a clear history of a closed head injury due to a fall or motor vehicle accident, it is important to determine if a sudden cardiac event could have precipitated the accident. The role of any toxin exposure contributing to the cause of death (e.g., cocaine, alcohol, or carbon monoxide) may increase the risk of myocardial damage. Documentation of the duration or estimated duration of any down time prior to resuscitation is important to determine the possibility of ischemic injury to the

Vesicular Monoamine Transporter VMAT Null Mice

However, it was possible to study the VMAT-2 heterozygous mice, and to compare their behavior and physiology to the wild-type animals. The idea was to consider that the VMAT-2 density in vesicles is not in excess, something that was actually confirmed later vesicles from manipulated synapses (41,42). Therefore, it was observed that amphetamine (36,38), but also cocaine, the D1 D2 agoniste apomorphine, and alcohol (38), all produced a higher motor response in VMAT-2 heterozygous mice as compared to their control littermates. This supersensitivity to dopamine agonists is presently not understand, but is probably of the same kind as was observed on reserpin-ized rats (33). This presensitized state is also evidenced using a locomotor sensitization protocol, where the VMAT-2 heterozygous mice do not sensitize to chronic administration of cocaine for 1 wk. This lack of sensitization actually happened because the heterozygous animals have a locomotor activity on the first day of the protocol...

Immediate Questions

Does patient take any drugs (legal or illegal) Contraceptives, diet pills, cold medicine containing pseudoephedrine, antirejec-tion drugs (particularly cyclosporine), corticosteroids, NSAIDs, erythropoietin, cocaine, amphetamine, and phencyclidine (PCP) can increase BP

The Discovery Of Htlv1

The human T-cell lymphoma leukemia viruses types 1 and 2 (HTLV-1 HTLV-2) belong to a group of primate T-cell lymphoma leukemia viruses (PTLV) which, together with bovine leukemia virus (BLV), comprise an oncogenic genus of retroviruses (Figure 12-1). Both viruses are transmitted perinatally, sexually, and by blood transfusions and the sharing of needles during intravenous drug abuse. Both viruses can infect all subsets of human lymphocytes and cause polyclonal, oligoclonal,

Tuberculosis Clinical picture

Tuberculosis patients quite frequently present with neuropsychiatric symptoms, which can be related to very different circumstances. First, clinicians should bear in mind that tuberculosis infection often develops in patients who previously had a severe psychiatric pathology, such as alcoholism or intravenous drug abuse, or in the chronic mentally ill. Also, the most common psychiatric symptoms, such as emotional lability and depression, could be related, among other factors, to the feeling of invalidity that accompanies the illness, and its social stigma. In addition, the preventive treatment of those in contact with the patient can trigger feelings of guilt. In some cases, tuberculosis leads to chronic respiratory disease, which is also associated with depressive symptoms, suicidal ideation, and cognitive impairment, particularly in debilitated patients.

Lessons From Mutant Animals And Genetic Diseases

Among the PSD-95 family, the most interesting phenotype observed so far is that of PSD-95 mutant mice, whose spatial learning is impaired although LTP is enhanced and LTD is defective33. The behavioral sensitization induced by chronic cocaine administration is also eliminated in these mice99 and the maturation of orientation preference in the visual cortex fails to mature100. These in vivo results demonstrate that PSD-95 is important for the regulation of synaptic plasticity.

The Controversy Over Cannabinoid Dependence

As for cannabis dependence, there is both clinical and epidemiological evidence in heavy, chronic users. Some of these individuals report problems in controlling cannabis use, and they continue to use despite experiencing adverse personal consequences (4-6). It has been reported that the cannabis dependence syndrome is analogous to the alcohol dependence syndrome (7-9). Cannabis dependence as defined in DSM-III was the most common form of illicit drug dependence in one large epidemiological study (9). The risk of becoming dependent on cannabis is probably more like that for alcohol than for nicotine or the opioids (10), with around 10 of those who ever use cannabis meeting criteria for dependence (10,11). Persons who use cannabis on a daily basis over periods of weeks to months are at greatest risk of becoming dependent. It has been estimated that the risk of dependence among near-daily cannabis users (according to approximated DSM-III criteria) is one in three (12). From Molecular...

Ecology and Epidemiology

Zygomycetes are mostly opportunistic pathogens responsible for infections in immunocompromised patients or patients with other predisposing factors. Integrity of the skin barrier as well as innate immunity mediated by mononuclear and poly-morphonuclear phagocytes prevent development of infection in an immunocompe-tent individual. Therefore, risk factors for zygomycosis comprise conditions in which these defense mechanisms are altered. The clinical presentation of the disease will vary depending upon the risk factors (Roden et al., 2005). Diabetes mellitus, and particularly in patients with ketoacidosis, is a well-known and common risk factor for zygomycosis. In these patients sinus and rhinocerebral infections are the most common. Iron is an important growth factor for zygomycetes and iron overload has been identified as a risk factor for zygomycosis. Paradoxically, deferoxamine therapy used for treatment of iron and aluminum overload in dialysis patients has also been recognized as...

Special Issues In Organ Transplantation

The most salient psychosocial issue and controversy in liver transplantation is the transplantation of patients with alcoholic liver cirrhosis. There is slowly emerging data on the most important questions initially asked about liver transplantation in alcoholics. These scientific questions have always existed in the context of the larger questions of ethics, moralization and the reality of public perception. The scientific questions have been about survival, return to drinking and quality of life. The ethical question goes as follows if we have a scarce resource like donor livers should we allow alcoholics who presumably shoulder a greater responsibility for their illness to receive equal consideration for transplantation The fact is that alcohol cirrhosis and recently hepatitis C, which in some cases is the consequence of IV drug abuse, are the most common causes for cirrhosis. As the waiting lists rise, it will be important to have data to support the rationale in transplantation...

Bloodborne Pathogens In the Workplace Debra L Hunt Jerry J Tulis MD

Treponema pallidum, the causative agent of syphilis, is found in highest numbers during the secondary, hematogenous stage, but is also found intermittently in blood if syphilis is left untreated. During 1990, the rate for primary and secondary syphilis in the United States (20.3 per 100,000) was the highest since the 1940s (149). Outbreaks have been linked epidemiologically to increased crack-cocaine use and HIV infection. The increasing numbers of patients with syphilis and HIV increases the possibilities for occupational exposures and infection. Nosocomial transmission of syphilis has occurred by needlesticks, blood transfusions, and tattooing (150, 151).

Geneexpression Analysis

New tools for measuring the expression of genes on a large scale are now available with oligonucleotide or cDNA microarrays and by proteomic technologies (Avissar & Schreiber, 2002). Advances in genomics and proteomics make it possible to screen very large numbers of candidate genes and proteins. One example of this approach was a study in which methamphetamine-treated rats were used as a model for mania (Niculescu et al., 2000). Gene expression in specific brain regions was compared in treated and untreated animals by oligonucleotide microarrays. Amphetamine administration led to changes in the expression of several genes in rat cortex, and the human homologues of these genes were considered candidates for a role in the pathogenesis of bipolar disorder, including a G-protein coupled receptor kinase (GRK3). This was selected for further examination, as it was mapped to a region of chromosome 22 where linkage to bipolar disorder had previously been reported and weak evidence for...

Clinical effects of hypnotics

In many cases of more severe insomnia, the cause is a physical complaint such as pain, breathlessness, or pruritus. The treatment is for that of the primary complaint. In many other cases, the insomnia is either a symptom of psychiatric distress, anxiety, or depression, or it is iatrogenic, caused by the very drugs prescribed to relieve the insomnia. In the first instance, treatment is directed towards the primary condition in the second, a careful regimen of drug withdrawal or substitution and subsequent withdrawal must be planned, as discussed earlier for anxiolytic medication. Some drugs, of which caffeine is the most common, induce insomnia. (54

Ltype calciumchannel blockers

Verapamil and the phenylalkylamines are charged and gain access to the inside of the calcium channel less readily than most of the dihydropyridines which are uncharged (except amlodipine). These different membrane properties and binding characteristics result in a profile of effects for the dihydropyridines compared with the phenylalkylamines, including the following increased lipid solubility anticonvulsant effects on kindling and hyperfusion models and clinical seizures the ability to block cocaine hyperactivity behavioural sensitization, and its associated dopamine overflow in the nucleus accumbens (whereas verapamil is inactive) positive effects in two animal models of depression (including the forced swim test and learned helplessness model) decreased glycine inhibition of 3H-5,7-dichlorokynurenic acid binding similar to that of other antidepressant modalities and, possibly, a different effectiveness on mood in some bipolar patients.

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