As of 2012, there is no medication that has been proven effective for treating cannabis use disorder; research is focused on three treatment approaches: agonist substitution, antagonist, and modulation of other neurotransmitter systems. Dronabinol is an agonist that is legally available; in some cases and trials, it reduced symptoms of withdrawal and reduced cannabis use. Entacapone was well-tolerated and decreased cannabis cravings in a trial on a small number of patients. Acetylcysteine (NAC) decreased cannabis use and craving in a trial. Atomoxetine in a small study showed no significant change in cannabis use, and most patients experienced adverse events. Buspirone shows promise as a treatment for dependence; trials show it reducing cravings, irritability and depression. Divalproex in a small study was poorly tolerated and did not show a significant reduction in cannabis use among subjects.

Psychological intervention includes cognitive behavioral therapy (CBT), motivational enhancement therapy (MET), contingency management (CM), supportive-expressive psychotherapy (SEP), family and systems interventions, and twelve-step programs.

Evaluations of Marijuana Anonymous programs, modelled on the 12-step lines of Alcoholics Anonymous and Narcotics Anonymous, have shown small beneficial effects for general drug use reduction. In 2006, the Wisconsin Initiative to Promote Healthy Lifestyles implemented a program that helps primary care physicians identify and address marijuana use problems in patients.

Early treatment of acute withdrawal often includes medical detoxification, which can include doses of anxiolytics or narcotics to reduce symptoms of withdrawal. An experimental drug, ibogaine, is also proposed to treat withdrawal and craving.

Neurofeedback therapy has shown statistically significant improvements in numerous researches conducted on alcoholic as well as mixed substance abuse population. In chronic opiate addiction, a surrogate drug such as methadone is sometimes offered as a form of opiate replacement therapy. But treatment approaches universal focus on the individual's ultimate choice to pursue an alternate course of action.

A number of medications have been approved for the treatment of substance abuse. These include replacement therapies such as buprenorphine and methadone as well as antagonist medications like disulfiram and naltrexone in either short acting, or the newer long acting form. Several other medications, often ones originally used in other contexts, have also been shown to be effective including bupropion and modafinil. Methadone and buprenorphine are sometimes used to treat opiate addiction. These drugs are used as substitutes for other opioids and still cause withdrawal symptoms.

Antipsychotic medications have not been found to be useful. Acamprostate is a glutamatergic NMDA antagonist, which helps with alcohol withdrawal symptoms because alcohol withdrawal is associated with a hyperglutamatergic system.

Psychedelics, such as LSD and psilocin, may have anti-addictive properties.

Behavioral programming is considered critical in helping those with addictions achieve abstinence. From the applied behavior analysis literature and the behavioral psychology literature, several evidence based intervention programs have emerged: (1) behavioral marital therapy; (2) community reinforcement approach; (3) cue exposure therapy; and (4) contingency management strategies. In addition, the same author suggest that Social skills training adjunctive to inpatient treatment of alcohol dependence is probably efficacious. Community reinforcement has both efficacy and effectiveness data. In addition, behavioral treatment such as community reinforcement and family training (CRAFT) have helped family members to get their loved ones into treatment. Motivational Intervention has also shown to be an effective treatment for substance dependence.

Therapists often classify patients with chemical dependencies as either interested or not interested in changing.

Treatments usually involve planning for specific ways to avoid the addictive stimulus, and therapeutic interventions intended to help a client learn healthier ways to find satisfaction. Clinical leaders in recent years have attempted to tailor intervention approaches to specific influences that affect addictive behavior, using therapeutic interviews in an effort to discover factors that led a person to embrace unhealthy, addictive sources of pleasure or relief from pain.

From the applied behavior analysis literature and the behavioral psychology literature, several evidenced-based intervention programs have emerged (1) behavioral marital therapy (2) community reinforcement approach (3) cue exposure therapy and (4) contingency management strategies. In addition, the same author suggests that social skills training adjunctive to inpatient treatment of alcohol dependence is probably efficacious.

From the applied behavior analysis literature, behavioral psychology, and from randomized clinical trials, several evidenced based interventions have emerged: behavioral marital therapy, motivational Interviewing, community reinforcement approach, exposure therapy, contingency management They help suppress cravings and mental anxiety, improve focus on treatment and new learning behavioral skills, ease withdrawal symptoms and reduce the chances of relapse.

In children and adolescents, cognitive behavioral therapy (CBT) and family therapy currently has the most research evidence for the treatment of substance abuse problems. Well-established studies also include ecological family-based treatment and group CBT. These treatments can be administered in a variety of different formats, each of which has varying levels of research support Research has shown that what makes group CBT most effective is that it promotes the development of social skills, developmentally appropriate emotional regulatory skills and other interpersonal skills. A few integrated treatment models, which combines parts from various types of treatment, have also been seen as both well-established or probably effective. A study on maternal alcohol and drug use has shown that integrated treatment programs have produced significant results, resulting in higher negative results on toxicology screens. Additionally, brief school-based interventions have been found to be effective in reducing adolescent alcohol and cannabis use and abuse. Motivational interviewing can also be effective in treating substance use disorder in adolescents.

Alcoholics Anonymous and Narcotics Anonymous are one of the most widely known self-help organizations in which members support each other not to use alcohol. Social skills are significantly impaired in people suffering from alcoholism due to the neurotoxic effects of alcohol on the brain, especially the prefrontal cortex area of the brain. It has been suggested that social skills training adjunctive to inpatient treatment of alcohol dependence is probably efficacious, including managing the social environment.

Residential drug treatment can be broadly divided into two camps: 12-step programs and therapeutic communities. Twelve-step programs are a nonclinical support-group and faith-based approach to treating addiction. Therapy typically involves the use of cognitive-behavioral therapy, an approach that looks at the relationship between thoughts, feelings and behaviors, addressing the root cause of maladaptive behavior. Cognitive-behavioral therapy treats addiction as a behavior rather than a disease, and so is subsequently curable, or rather, unlearnable. Cognitive-behavioral therapy programs recognize that, for some individuals, controlled use is a more realistic possibility.

One of many recovery methods are 12-step recovery programs, with prominent examples including Alcoholics Anonymous, Narcotics Anonymous, Drug Addicts Anonymous and Pills Anonymous. They are commonly known and used for a variety of addictions for the individual addicted and the family of the individual. Substance-abuse rehabilitation (rehab) centers offer a residential treatment program for some of the more seriously addicted, in order to isolate the patient from drugs and interactions with other users and dealers. Outpatient clinics usually offer a combination of individual counseling and group counseling. Frequently, a physician or psychiatrist will prescribe medications in order to help patients cope with the side effects of their addiction. Medications can help immensely with anxiety and insomnia, can treat underlying mental disorders (cf. self-medication hypothesis, Khantzian 1997) such as depression, and can help reduce or eliminate withdrawal symptomology when withdrawing from physiologically addictive drugs. Some examples are using benzodiazepines for alcohol detoxification, which prevents delirium tremens and complications; using a slow taper of benzodiazepines or a taper of phenobarbital, sometimes including another antiepileptic agent such as gabapentin, pregabalin, or valproate, for withdrawal from barbiturates or benzodiazepines; using drugs such as baclofen to reduce cravings and propensity for relapse amongst addicts to any drug, especially effective in stimulant users, and alcoholics (in which it is nearly as effective as benzodiazepines in preventing complications); using clonidine, an alpha-agonist, and loperamide for opioid detoxification, for first-time users or those who wish to attempt an abstinence-based recovery (90% of opioid users relapse to active addiction within eight months or are multiple relapse patients); or replacing an opioid that is interfering with or destructive to a user's life, such as illicitly-obtained heroin, dilaudid, or oxycodone, with an opioid that can be administered legally, reduces or eliminates drug cravings, and does not produce a high, such as methadone or buprenorphine – opioid replacement therapy – which is the gold standard for treatment of opioid dependence in developed countries, reducing the risk and cost to both user and society more effectively than any other treatment modality (for opioid dependence), and shows the best short-term and long-term gains for the user, with the greatest longevity, least risk of fatality, greatest quality of life, and lowest risk of relapse and legal issues including arrest and incarceration.

In a survey of treatment providers from three separate institutions, the National Association of Alcoholism and Drug Abuse Counselors, Rational Recovery Systems and the Society of Psychologists in Addictive Behaviors, measuring the treatment provider's responses on the "Spiritual Belief Scale" (a scale measuring belief in the four spiritual characteristics of AA identified by Ernest Kurtz); the scores were found to explain 41% of the variance in the treatment provider's responses on the "Addiction Belief Scale" (a scale measuring adherence to the disease model or the free-will model of addiction).

In the United States there are four approved medications for alcoholism: disulfiram, two forms of naltrexone, and acamprosate. Several other drugs are also used and many are under investigation.

- Benzodiazepines, while useful in the management of acute alcohol withdrawal, if used long-term can cause a worse outcome in alcoholism. Alcoholics on chronic benzodiazepines have a lower rate of achieving abstinence from alcohol than those not taking benzodiazepines. This class of drugs is commonly prescribed to alcoholics for insomnia or anxiety management. Initiating prescriptions of benzodiazepines or sedative-hypnotics in individuals in recovery has a high rate of relapse with one author reporting more than a quarter of people relapsed after being prescribed sedative-hypnotics. Those who are long-term users of benzodiazepines should not be withdrawn rapidly, as severe anxiety and panic may develop, which are known risk factors for relapse into alcohol abuse. Taper regimes of 6–12 months have been found to be the most successful, with reduced intensity of withdrawal.

- Acamprosate may stabilise the brain chemistry that is altered due to alcohol dependence via antagonising the actions of glutamate, a neurotransmitter which is hyperactive in the post-withdrawal phase. By reducing excessive NMDA activity which occurs at the onset of alcohol withdrawal, acamprosate can reduce or prevent alcohol withdrawal related neurotoxicity. Acamprosate reduces the risk of relapse amongst alcohol dependent persons.

- Disulfiram (Antabuse) prevents the elimination of acetaldehyde, a chemical the body produces when breaking down ethanol. Acetaldehyde itself is the cause of many hangover symptoms from alcohol use. The overall effect is severe discomfort when alcohol is ingested: an extremely fast-acting and long-lasting uncomfortable hangover. This discourages an alcoholic from drinking in significant amounts while they take the medicine.

- Naltrexone is a competitive antagonist for opioid receptors, effectively blocking the effects of endorphins and opioids. Naltrexone is used to decrease cravings for alcohol and encourage abstinence. Alcohol causes the body to release endorphins, which in turn release dopamine and activate the reward pathways; hence when naltrexone is in the body there is a reduction in the pleasurable effects from consuming alcohol. Evidence supports a reduced risk of relapse among alcohol dependent persons and a decrease in excessive drinking. Nalmefene also appears effective and works by a similar manner.

- Calcium carbimide works in the same way as disulfiram; it has an advantage in that the occasional adverse effects of disulfiram, hepatotoxicity and drowsiness, do not occur with calcium carbimide.

The Sinclair method is a method of using naltrexone or another opioid antagonists to treat alcoholism by having the person take the medication about an hour before they drink alcohol, and only then. The medication blocks the positive reinforcement effects of ethanol and hopefully allows the person to stop drinking or drink less.

Evidence does not support the use of selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), antipsychotics, or gabapentin.

Alcoholics may also require treatment for other psychotropic drug addictions and drug dependences. The most common dual dependence syndrome with alcohol dependence is benzodiazepine dependence, with studies showing 10–20 percent of alcohol-dependent individuals had problems of dependence and/or misuse problems of benzodiazepine drugs such as valium or clonazopam. These drugs are, like alcohol, depressants. Benzodiazepines may be used legally, if they are prescribed by doctors for anxiety problems or other mood disorders, or they may be purchased as illegal drugs "on the street" through illicit channels. Benzodiazepine use increases cravings for alcohol and the volume of alcohol consumed by problem drinkers. Benzodiazepine dependency requires careful reduction in dosage to avoid benzodiazepine withdrawal syndrome and other health consequences. Dependence on other sedative-hypnotics such as zolpidem and zopiclone as well as opiates and illegal drugs is common in alcoholics. Alcohol itself is a sedative-hypnotic and is cross-tolerant with other sedative-hypnotics such as barbiturates, benzodiazepines and nonbenzodiazepines. Dependence upon and withdrawal from sedative-hypnotics can be medically severe and, as with alcohol withdrawal, there is a risk of psychosis or seizures if not managed properly.

Treatments for alcohol dependence can be separated into two groups, those directed towards severely alcohol-dependent people, and those focused for those at risk of becoming dependent on alcohol. Treatment for alcohol dependence often involves utilizing relapse prevention, support groups, psychotherapy, and setting short-term goals. The Twelve-Step Program is also a popular process used by those wishing to recover from alcohol dependence.

Youth treatment and intervention should focus on eliminating or reducing the effects of adverse childhood experiences, like childhood maltreatment, since these are common risk factors contributing to the early development of alcohol abuse. Approaches like contingency management and motivational interviewing have shown to be effective means of treating substance abuse in impulsive adolescents by focusing on positive rewards and redirecting them towards healthier goals. Educating youth about what is considered heavy drinking along with helping them focus on their own drinking behaviors has been shown to effectively change their perceptions of drinking and could potentially help them to avoid alcohol abuse.

Completely stopping the use of alcohol, or "abstinence," is the ideal goal of treatment. A strong social network and family support maybe important in achieving this goal.

Some people who abuse alcohol may be able to reduce the amount they drink, also called "drinking in moderation." If this method does not work, the person may need to try abstinence. Abstinence has been regularly achieved by many alcoholics in Alcoholics Anonymous.

Mindfulness-based intervention programs (that encourage people to be aware of their own experiences in the present moment and of emotions that arise from thoughts) can reduce the consumption of alcohol.

The symptoms of stimulant use disorder include failure to control usage and frequency of use, an intense craving for the drug, increased use over time to obtain the same effects, known as a developed tolerance, and a continued use despite negative repercussions and interference in one’s everyday life and functioning. Furthermore, a disorder is noted when withdrawal symptoms occur because of a decrease in the drug amount and frequency, as well as stopping the use of the drug entirely. These withdrawal symptoms can last for days, weeks, months, and on rare occasions, years, depending on the frequency and dosages used by the individual. These symptoms include, but are not limited to, increased appetite, decreased energy, depression, loss of motivation and interest in once pleasurable activities, anxiety, insomnia, agitation and an intense craving for the drug. Unless intensive medical and psychological treatment is sought after, there is a very high likelihood of relapse among the user.

MAO inhibitor drugs block an enzyme system resulting in increased stores of monoamine neurotransmitters. More common antidepressants such as tricyclic antidepressants and SSRIs block reuptake transporters causing increased levels of norepinephrine or serotonin in synapses. Mood stabilizers include lithium and many anticonvulsants, such as carbamazepine and lamotrigine are also used for mood disorders. This would demonstrate little to zero cross-tolerance with serotonergic or lithium treatment.

Only a small proportion of those with co-occurring disorders actually receive treatment for both disorders. Therefore, it was argued that a new approach is needed to enable clinicians, researchers and managers to offer adequate assessment and evidence-based treatments to patients with dual pathology, who cannot be adequately and efficiently managed by cross-referral between psychiatric and addiction services as currently configured and resourced. In 2011, it was estimated that only 12.4% of American adults with co-occurring disorders were receiving both mental health and addictions treatment. Clients with co-occurring disorders face challenges accessing treatment, as they may be excluded from mental health services if they admit to a substance abuse problem, and vice versa.

There are multiple approaches to treating concurrent disorders. Partial treatment involves treating only the disorder that is considered primary. Sequential treatment involves treating the primary disorder first, and then treating the secondary disorder after the primary disorder has been stabilized. Parallel treatment involves the client receiving mental health services from one provider, and addictions services from another.

Integrated treatment involves a seamless blending of interventions into a single coherent treatment package developed with a consistent philosophy and approach among care providers. With this approach, both disorders are considered primary. Integrated treatment can improve accessibility, service individualization, engagement in treatment, treatment compliance, mental health symptoms, and overall outcomes. The Substance Abuse and Mental Health Services Administration in the United States describes integrated treatment as being in the best interests or clients, programs, funders, and systems. Green suggested that treatment should be integrated, and a collaborative process between the treatment team and the patient. Furthermore, recovery should to be viewed as a marathon rather than a sprint, and methods and outcome goals should be explicit.

Although many patients may reject medications as antithetical to substance-abuse recovery and side effects, they can be useful to reduce paranoia, anxiety, and craving. Medications that have proven effective include opioid replacement therapies, such as lifelong maintenance on methadone or buprenorphine, to minimize risk of relapse, fatality, and legal trouble amongst opioid addicts, as well as helping with cravings, baclofen for alcoholics, opioid addicts, cocaine addicts, and amphetamine addicts, to help eliminate drug cravings, and clozapine, the first atypical antipsychotic, which appears to reduce illicit drug use amongst stimulant addicts. Clozapine can cause respiratory arrest when combined with alcohol, benzodiazepines, or opioids, so it is not recommended to use in these groups.

Currently, stimulants are used medicinally to treat certain types of asthma, the common cold, depression, obesity and a wide variety of physical pain and ailments. Most commonly, stimulants such as Adderall and Ritalin are prescribed for both children and adults diagnosed with attention deficit hyperactivity disorder (ADHD). Additionally, stimulant medications are available such as Provigil which are given to individuals diagnosed with narcolepsy.

These drugs block dopamine receptors and some also block serotonin receptors (such as chlorpromazine, the first antipsychotic used clinically). Having been on one or more antipsychotics for any appreciable amount of time results in dramatically reduced sensitivity to others with similar mechanisms of action. However, an antipsychotic with a substantial disparity in pharmacology (e.g. haloperidol and quetiapine) may retain significant efficacy.

Preventing or reducing the harm has been called for via increased taxation of alcohol, stricter regulation of alcohol advertising and the provision of brief Interventions. Brief Interventions for alcohol abuse reduce the incidence of unsafe sex, sexual violence, unplanned pregnancy and, likely, STD transmission. Information and education on social norms and the harms associated with alcohol abuse delivered via the internet or face-to-face has not been found to result in any meaningful benefit in changing harmful drinking behaviours in young people.

According to European law, individuals who are suffering from alcohol abuse or other related problems cannot be given a license, or if in possession of a license cannot get it renewed. This is a way to prevent individuals driving under the influence of alcohol, but does not prevent alcohol abuse per se.

An individual's need for alcohol can depend on their family's alcohol use history. For instance, if it is discovered that their family history with alcohol has a strong pattern, there might be a need for education to be set in place to reduce the likelihood of reoccurrence (Powers, 2007). However, studies have established that those with alcohol abuse tend to have family members who try to provide help. In many of these occasions the family members would try to help the individual to change or to help improve the individual's lifestyle.

The National Institute on Drug Abuse (NIDA) says that "even though anabolic steroids do not cause the same high as other drugs, steroids are reinforcing and can lead to addiction. Studies have shown that animals will self-administer steroids when given the opportunity, just as they do with other addictive drugs. People may persist in abusing steroids despite physical problems and negative effects on social relationships, reflecting these drugs’ addictive potential. Also, steroid abusers typically spend large amounts of time and money obtaining the drug; another indication of addiction. Individuals who abuse steroids can experience withdrawal symptoms when they stop taking them, including mood swings, fatigue, restlessness, loss of appetite, insomnia, reduced sex drive, and steroid cravings, all of which may contribute to continued abuse. One of the most dangerous withdrawal symptoms is depression. When depression is persistent, it can sometimes lead to suicidal thoughts. Research has found that some steroid abusers turn to other drugs such as opioids to counteract the negative effects of steroids."

Complications of benzodiazepine abuse include drug-related deaths due to overdose especially in combination with other depressant drugs such as opioids. Other complications include: blackouts and memory loss, paranoia, violence and criminal behaviour, risk-taking sexual behaviour, foetal and neonatal risks if taken in pregnancy, dependence, withdrawal seizures and psychosis. Injection of the drug carries risk of: thrombophlebitis, deep vein thrombosis, deep and superficial abscesses, pulmonary microembolism, rhabdomyolysis, tissue necrosis, gangrene requiring amputation, hepatitis B and C, as well as blood borne infections such as HIV infection (caused by sharing injecting equipment). Long-term use of benzodiazepines can worsen pre-existing depression and anxiety and may potentially also cause dementia with impairments in recent and remote memory functions.

Use is widespread among amphetamine users, with those that use amphetamines and benzodiazepines having greater levels of mental health problems and social deterioration. Benzodiazepine injectors are almost four times more likely to inject using a shared needle than non-benzodiazepine-using injectors. It has been concluded in various studies that benzodiazepine use causes greater levels of risk and psycho-social dysfunction among drug misusers.

Poly-drug users who also use benzodiazepines appear to engage in more frequent high-risk behaviors. Those who use stimulant and depressant drugs are more likely to report adverse reactions from stimulant use, more likely to be injecting stimulants and more likely to have been treated for a drug problem than those using stimulant but not depressant drugs.

Individuals with a substance abuse history are at an increased risk of misusing benzodiazepines.

Several (primary research) studies, even into the last decade, claimed, that individuals with a history of familial abuse of alcohol or who are siblings or children of alcoholics appeared to respond differently to benzodiazepines than so called "genetically healthy" persons, with males experiencing increased euphoric effects and females having exaggerated responses to the adverse effects of benzodiazepines.

Whilst all benzodiazepines have abuse potential, certain characteristics increase the potential of particular benzodiazepines for abuse. These characteristics are chiefly practical ones—most especially, availability (often based on popular perception of 'dangerous' versus 'non-dangerous' drugs) through prescribing physicians or illicit distributors. Pharmacological and pharmacokinetic factors are also crucial in determining abuse potentials. A short elimination half-life, high potency and a rapid onset of action are characteristics which increase the abuse potential of benzodiazepines. The following table provides the elimination half-life, relevant potency to other benzodiazepines, speed of onset of action and duration of behavioural effects.

The self-medication theory suggests that people with severe mental illnesses misuse substances in order to relieve a specific set of symptoms and counter the negative side-effects of antipsychotic medication.

Khantizan proposes that substances are not randomly chosen, but are specifically selected for their effects. For example, using stimulants such as nicotine or amphetamines can be used to combat the sedation that can be caused by higher doses of certain types of (usually typical) antipsychotic medication. Conversely, some people taking medications with a stimulant effect such as the SNRI antidepressants Effexor (venlafaxine) or Wellbutrin (bupropion) may seek out benzodiazepines or opioid narcotics to counter the anxiety and insomnia that such medications sometimes evoke.

Some studies show that nicotine administration can be effective for reducing motor side-effects of antipsychotics, with both bradykinesia (stiff muscles) and dyskinesia(involuntary movement) being prevented.

ICD–10 criteria for dependence include experience of at least three of the following during the past year:

- a strong desire to take steroids

- difficulty in controlling use

- withdrawal syndrome when use is reduced

- evidence of tolerance

- neglect of other interests and persistent use despite harmful consequences

However, the following ICD-10-CM Index entries contain back-references to ICD-10-CM F55.3:

- Abuse

- hormones F55.5

- steroids F55.5

- drug NEC (non-dependent) F19.10

- hormones F55.5

- steroids F55.5

- non-psychoactive substance NEC F55.8

- hormones F55.5

- steroids F55.5

ICD-10 goes on to state that “although it is usually clear that the patient has a strong motivation to take the substance, there is no development of dependence or withdrawal symptoms as in the case of the psychoactive substances.”

Amphetamine dependence refers to a state of psychological dependence on a drug in the amphetamine class. In individuals with substance use disorder (problematic use or abuse with dependence), psychotherapy is currently the best treatment option as no pharmacological treatment has been approved. Tolerance is expected to develop with regular substituted amphetamine use. When substituted amphetamines are abused, drug tolerance develops rapidly.

Severe withdrawal associated with dependence from recreational substituted amphetamine use can be difficult for a user to cope with. Long-term use of certain substituted amphetamines, particularly methamphetamine, can reduce dopamine activity in the brain. Psychostimulants that increase dopamine and mimic the effects of substituted amphetamines, but with lower abuse liability, could theoretically be used as replacement therapy in amphetamine dependence. However, the few studies that used amphetamine, bupropion, methylphenidate and modafinil as a replacement therapy did not result in less methamphetamine use or craving.

In 2013, overdose on amphetamine, methamphetamine, and other compounds implicated in an "amphetamine use disorder" resulted in an estimated 3,788 deaths worldwide (3,425–4,145 deaths, 95% confidence).

Barbiturate dependence develops with regular use of barbiturates. This in turn may lead to a need for increasing doses of the drug to get the original desired pharmacological or therapeutic effect. Barbiturate use can lead to both addiction and physical dependence, and as such they have a high potential for abuse. Management of barbiturate dependence involves considering the affected person's age, comorbidity and the pharmacological pathways of barbiturates. Psychological addiction to barbiturates can develop quickly. The GABA receptor, one of barbiturates' main sites of action, is thought to play a pivotal role in the development of tolerance to and dependence on barbiturates, as well as the euphoric "high" that results from their abuse. The mechanism by which barbiturate tolerance develops is believed to be different from that of ethanol or benzodiazepines, even though these drugs have been shown to exhibit cross-tolerance with each other. The management of a physical dependence on barbiturates is stabilisation on the long-acting barbiturate phenobarbital followed by a gradual titration down of dose. The slowly eliminated phenobarbital lessens the severity of the withdrawal syndrome and reduces the chances of serious barbiturate withdrawal effects such as seizures. Antipsychotics are not recommended for barbiturate withdrawal (or other CNS depressant withdrawal states) especially clozapine, olanzapine or low potency phenothiazines e.g. chlorpromazine as they lower the seizure threshold and can worsen withdrawal effects; if used extreme caution is required.