Daryl Shorter, MD

In this age of chat rooms and social media, an ever-growing number of psychiatric patients use the internet to find their treatment community online. Interactive forums, Youtube.com, and personal blogs are now connecting psychiatric patients in ways that were never before available. One treatment focus for these online communities is complicated withdrawal from psychiatric medications. This article discusses this phenomenon in relation to the well-established forums of benzodiazepine and antidepressant withdrawal.

Online forums, such as www.benzobuddies.org and www.survivingantidepressants.org, provide a platform for patients to support each other as they move through their withdrawal symptoms. These interactive sites feature different strategies for managing a wide range of withdrawal-related symptoms. Other sections provide inspiration for users through sharing stories about a successfully completed withdrawal experience. The traffic moving through these sites is mostly from within the US and is substantial: 

 receives on average 250,000 hits a month and 

 receives approximately 150,000 hits each month.

 It is interesting to note that the patient 

 from these websites are generating early clinical data that researchers are using to learn more about unexpectedly difficult withdrawal symptoms and syndromes.

Beyond these forums there is a vivid and expansive community of thousands on Youtube.com, where participants have shared their personal withdrawal experiences. Some participants have created daily videos to chronicle the process: a generic search for the terms “antidepressant withdrawal” or “benzo withdrawal” will bring up 7000 and 14,000 personal video blogs, respectively.

While it might initially seem that these communities and video blogs are simply artifacts of the internet culture, a closer look at the stories told on these forums suggests a different message. The message is that physicians have been unprepared for these withdrawal disorders and are unable to treat or even guide patients through complicated withdrawal from these substances.

Medication withdrawal is difficult to assess in the relatively brief 6- to 12-week randomized controlled trials that lead to FDA approvals and marketing. The costs, clinical challenges, and desire to do no more than is needed to show relative safety and efficacy have limited these studies’ duration. Such short durations do not typically allow time for participants to develop any level of significant physiological dependence or to produce a difficult or even detectable withdrawal syndrome. These trials, which usually focus on determining efficacy, often have adequate methodology or statistical power to identify and characterize only very common and relatively severe withdrawal syndromes.

Because of these challenges in acquiring the necessary data for educating physicians about any potential withdrawal syndromes, medications come onto the market with many unknowns about their longer-term effects and discontinuation syndromes. Many unidentified problems beyond withdrawal syndromes can take years to become fully appreciated-often requiring an accumulation of published case reports or other observational studies before they become widely known to the medical community.

For instance, although the first benzodiazepine was released onto the market in the US in 1960, it was not until 1988 that health authorities finally 

 the true extent and impact of the dependence and addictive potential of these agents.

 The clear surprise to physicians was the 

 and duration of withdrawal symptoms found with normal therapeutic doses.

A similar situation was described for antidepressant discontinuation when it was initially presented to physicians as a minor preventable 

 It would take many more years before the complexity and severity of antidepressant withdrawal began to take shape and the information 

The pharmacodynamics and pharmacokinetics of the medication and an individual’s genetics all play significant roles in the timing, duration, and severity of withdrawal. These multiple factors lead to the observed heterogeneity in withdrawal syndromes. This challenge has spurred publication of increasingly refined diagnostic guidelines to help clinicians recognize these syndromes. It is uncertain how many clinicians are aware of the variety of presentations of withdrawal syndromes and the range of medications that can produce these syndromes. If clinicians are unaware of the complexity of such syndromes, they may misdiagnose these withdrawal syndromes as manifestations of the underlying original mental illness, a new physical condition, or perhaps an adverse effect of a different medication.

Recognition that a patient has incurred an iatrogenic complication is essential in the recovery process. A correct diagnosis will inform the decision of how to manage the withdrawal. Clinicians can engage patients in a discussion about the variety of existing treatment options. They can choose to wait out the withdrawal syndrome, if it is tolerable, reinstate treatment, or try a slower medically supervised withdrawal treatment regimen. They might also opt to use other pharmacotherapies for symptomatic treatment.

The ability to tolerate the dysphoric moods and physical symptoms associated with psychotropic medication withdrawal is undoubtedly linked to a patient’s baseline psychological resilience and the strength of his or her support system. Therapies targeted at bolstering psychological resilience such as cognitive behavioral therapy (CBT) can be useful in helping patients cope with withdrawal. For instance, CBT might be useful in challenging patients’ beliefs that discontinuation symptoms are a sign that they are incapable of coping without the medication. CBT could transform this self-belief to the more accurate understanding that these symptoms are common and often time limited.

 highlights 3 main complexities in managing antidepressant withdrawal. First, no clear sociodemographic and clinical characteristics appear to be associated with increased vulnerability to severe withdrawal; second, although gradual tapering of antidepressants is a reasonable clinical strategy, it often will not prevent the onset of severe withdrawal symptoms; and third, antidepressant withdrawal appears to be associated with a variety of other iatrogenic complications such as the onset of hypomania/mania and other persistent mood instabilities.

 discuss the difficulty of managing benzodiazepine withdrawal. Three of these difficulties are illustrative:

1 The onset of severe withdrawal symptoms sometimes does not respond to re-initiation of medication.

2 Persistent withdrawal reactions can last years.

3 Unavoidable severe withdrawal symptoms may occur despite slow withdrawal over several months or years.

When the risks of treatments are not identified in the clinical trials that bring them onto market, these risks are not cautioned against in widely circulated medication guidelines. As a result, the prescribing physician will overestimate potential benefits and neglect patients’ vulnerabilities to the adverse effects of treatment. Expert 

 in psychiatric journals are available to help clinicians correctly weigh the risks and benefits of using benzodiazepines and antidepressants in the management of depression and anxiety disorders.

Although many people do not have substantial difficulties withdrawing from these medications, it is clear that withdrawal syndromes are not rare. Reports of withdrawal syndromes are becoming increasingly common on patient websites, and the widespread use of these types of medications poses a substantial public health concern.

The ubiquity of social media in the past 10 years and informal online communities have led adolescents to utilize these as the 

 As young patients continue to turn to these sources for mental health guidance, mental health professionals need to familiarize themselves with and interface with these online communities.

An important ethical issue to consider is who should conduct research into drug-related problems that emerge following licensing? Burdening pharmaceutical companies to conduct such research before granting them license to sell would certainly slow down the development of many new and helpful medications. Yet, who is responsible for conducting the urgent and resource-heavy research needed to help guide clinicians in managing the variety of unexpected iatrogenic complications of these medications?

Given the current state of our understanding of complex withdrawal syndromes, increased awareness of these syndromes among providers is of utmost importance. These syndromes need further research, or more patients will continue to turn away from the medical establishment to look for support from other patients on the internet.

is Assistant Professor of Psychiatry, and Director, Psychiatry Residency Program

is Professor of Psychiatry, Neuroscience, Pharmacology, Immunology, and Rheumatology, and Vice-Chair, Psychiatry for Research, Baylor College of Medicine, Houston, TX

https://www.similarweb.com/website/survivingantidepressants.org#overview

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/www.similarweb.com/website/benzobuddies.org#referrals

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 Nielsen M, Hansen E, GÃ¸tzsche P. What is the difference between dependence and withdrawal reactions? A comparison of benzodiazepines and selective serotonin re-uptake inhibitors. 

Withdrawing benzodiazepines in patients with anxiety disorders

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 Wilson E, Lader M. A review of the management of antidepressant discontinuation symptoms. 

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 Oldt A. Adolescents turn to social media when in need of mental health care; 2017. 

https://www.healio.com/psychiatry/suicide/news/online/%7B3af3e975-2bc3-4069-b96f-bc60551bae48%7D/adolescents-turn-to-social-media-when-in-need-of-mental-health-care

Articles

In this age of chat rooms and social media, an ever-growing number of psychiatric patients use the internet to find their treatment community online.

Online Communities for Drug Withdrawal: What Can We Learn?

[Acknowledgment-the authors acknowledge The 

American Academy of Addiction Psychiatry 

(AAAP) for helping to bring this article to fruition. The AAAP is a professional membership organization for learning and sharing about the science of Addiction Psychiatry translating the research into clinical practice. As relentless advocates for those suffering from the devastation of substance use disorders and mental health disorders, AAAP is driven to transform lives through a commitment to using evidenced-based research to continually improve clinical approaches and outcomes for patients.]

Illicit drug use is on the rise in the US. According to the National Survey on Drug Use and Health, 27 million people aged 12 years or older were illicit drug users in 2014-an increase from the 2002 to 2013 numbers. Results also indicate that 1.5 million people aged 12 years or older who were current users of cocaine (in all forms) included about 354,000 users of crack cocaine.

[[{"type":"media","view_mode":"media_crop","fid":"48873","attributes":{"alt":"Â© marcos mesa mam Wordley/shutterstock.com","class":"media-image media-image-right","id":"media_crop_8280155473152","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"5864","media_crop_rotate":"0","media_crop_scale_h":"150","media_crop_scale_w":"168","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"font-size: 13.008px; line-height: 1.538em; float: right;","title":"Â© marcos mesa mam Wordley/shutterstock","typeof":"foaf:Image"}}]]According to the National Institute on Drug Abuse, the national cost of illicit drug use is $11 billion in health care and $193 billion overall (including costs related to crime and lost productivity).

 Improving treatments for illicit drug use may have a widespread effect on the affected individual, on his or her family, and on society as a whole.

There are no FDA-approved pharmacotherapies for cocaine use disorder. In this article we review the off-label use of promising medications for cocaine use disorder (

). These treatments can be divided into 3 categories: dopaminergic agents, noradrenergic agents, and those with mixed mechanisms of action. Among these treatment targets are proteins with relatively frequent genetic variants that appear to mediate enhanced responses to specific pharmacotherapies. These proteins include metabolic enzymes, receptors, and receptor transducers that mediate the coupling of receptors to second messenger systems such as cyclic adenosine monophosphate.

We will focus specifically on dopamine Î²-hydroxylase (DÎ²H), dopamine receptor, ankyrin repeat and kinase domain-containing 1 (ANKK1), and Î±

Dopaminergic agents include levodopa-carbidopa, dextroamphetamine, and lisdexamfetamine. Levodopa-carbidopa has been studied for the treatment of cocaine use disorder because of its ability to increase brain dopamine levels and subsequently correct cocaine-induced hypodopaminergia. Levodopa is able to cross the blood-brain barrier but is administered with carbidopa (a peripheral decarboxylase inhibitor) to slow the breakdown of levodopa and allow a greater portion of it to enter the brain rather than being metabolized to inactive compounds.

The DÎ²H gene polymorphism rs1611115 has been studied for pharmacogenetics matching with levodopa.

 This functional, regulatory polymorphism leads to a substantial 10- to 100-fold reduction in the amount of the DÎ²H enzyme. With substantially lower DÎ²H levels, the conversion of dopamine to norepinephrine is much slower and lower than normal. For patients with the low DÎ²H activity genotypes (CT/TT) who were treated with levodopa, the odds of having cocaine-positive urine samples decreased significantly, compared with placebo. Individuals with the normal DÎ²H activity genotype (CC) showed no differential levodopa response between active agent and placebo.

Dextroamphetamine, an amphetamine derivative, has also been studied for its ability to correct hypodopaminergia and decrease D2 receptor binding observed with chronic cocaine use.

 However, dextroamphetamine does this via reversal of the dopamine transporter, which results in indirect enhancement of dopaminergic function.

Lisdexamfetamine dimesylate is a prodrug consisting of dextroamphetamine covalently bonded to the amino acid lysine. Following oral administration, red blood cells convert lisdexamfetamine into dextroamphetamine (the active drug) by enzymatic rate-limited hydrolysis of lysine from amphetamine. The kinetics of the rate limiting is such that the medication has long-lasting effectiveness but a slow onset, similar to a sustained-release amphetamine preparation.

 Study participants who received lisdexamfetamine reported less need for cocaine than those given placebo.

 Although cocaine use did not differ between the lisdexamfetamine and placebo groups, lisdexamfetamine recipients reported significantly less craving than those given placebo.

Noradrenergic agents include doxazosin, disulfiram, and nepicastat. Doxazosin, which blocks noradrenergic alpha-1 receptors, has been studied in the treatment of cocaine use disorder for its ability to reduce the acute effects of cocaine. When rapidly titrated, doxazosin significantly reduced cocaine use and increased the percentage of participants who achieved 2 or more consecutive weeks of abstinence.

 Slow titration of doxazosin was found to be similar to that of placebo. This suggests that the medication effect is due, in part, to the rapid titration to the optimal dose, rather than to a longer duration of receiving the optimal dose.

A subsequent study of doxazosin (under review) not only replicated its efficacy for reducing cocaine use, but also showed that this efficacy was enhanced in patients with relatively common genetic variants in the alpha-1 receptor, which appears to change the G-protein coupling of this receptor to the cyclic adenosine monophosphate second messenger system.

Disulfiram also acts on both the noradrenergic and dopaminergic systems by inhibiting the enzyme (DÎ²H) that converts dopamine to norepinephrine through chelation of the copper needed for its activity. Disulfiram at 250 mg daily has significantly reduced cocaine use in several clinical trials.

 More recently, disulfiram has been studied in conjunction with polymorphisms in the genes that encode for DÎ²H, as well as the ANKK1, the dopamine receptor D2 (DRD2), and the Î±1-adrenoceptor gene variations.

The reduction in cocaine use with disulfiram was associated with a specific functional regulatory genetic polymorphism in the gene that codes for DÎ²H (rs1611115). Patients who have 2 of the alleles associated with normal levels of DÎ²H (CC) responded to disulfiram, while those with the genotypes encoding lower levels of DÎ²H (CT and TT) showed no difference from placebo.

genes are associated with dopamine D2 receptor sensitivity to dopamine. Patients with CT or TT variants of the ANKK1 genotype had a significant decline in cocaine-positive urine samples on disulfiram; patients who received placebo showed no treatment effect; patients with the CC variant of the ANKK1 genotype showed no effect on treatment with disulfiram or placebo. Using the DRD2 genetic variants, the GT/TT genotype group showed a significant decrease in the number of cocaine-positive urine samples on disulfiram, whereas the GG genotype group showed only a marginal decrease. Moreover, genotype pattern analysis revealed that individuals carrying at least 1 minor allele in either gene (

) responded better to disulfiram treatment than did individuals carrying only the major alleles.

Disulfiram inhibition of DÎ²H decreases brain norepinephrine levels, leading to a subsequent reduction in stimulation of adrenoceptors. The gene 

-adrenoceptor has a functional polymorphism (rs1048101) in exon 2 and codes for 2 types of receptors based on a single amino acid substitution of ARG for CYS. The more common CYS receptor appears to have a more efficient G-protein coupling to the cyclic adenosine monophosphate second messenger system than does the ARG receptor variant.

 We found that the more common variant with CYS was associated with a significant difference from placebo in response to disulfiram, while the ARG variant showed no difference between disulfiram and placebo.

Because we had already found that the DÎ²H CC genotype was associated with an enhanced pharmacogenetic response to disulfiram, we decided to combine both the DÎ²H-CC and ARDA1A-TT/TC genotypes to form a group of patients with both of these potentially responsive genotypes.

 The patients with the responsive polymorphisms for disulfiram again showed a significantly enhanced reduction in cocaine urine samples compared with a minimal change on placebo. In the remaining patients, including those with only 1 of these 2 responsive polymorphisms, no difference was seen between disulfiram and placebo. Thus, the optimal response to disulfiram appears to be among those patients with both the “normal” CYS polymorphism of the alpha-1 adrenergic receptor and the genetically normal, rather than low, DBH levels.

Nepicastat, a potent and selective DÎ²H inhibitor, has also been investigated, but it did not change the kinetics, metabolism, or clearance of cocaine or its metabolites.

 In addition, the lack of effects of nepicastat on the cardiovascular and pharmacokinetic profiles evoked by cocaine suggests that the selective targeting of nepicastat for the DÎ²H enzyme would improve the safety profile of this compound compared with the non-selective DÎ²H inhibitor disulfiram. In an as yet unpublished study, nepicastat significantly reduced several cocaine-induced positive subjective effects.

Among mixed mechanism agents that have been investigated for the treatment of cocaine use disorder, the most successful has been modafinil.

 Modafinil inhibits dopamine and norepinephrine transporters and increases extracellular levels of glutamate. It has been studied for its impact on cocaine use and its ability to decrease symptoms of cocaine abstinence syndrome.

 Patients treated with modafinil reported low levels and shorter durations of cocaine craving intensity on the Brief Substance Craving Scale. Patients were also more likely to rate themselves as “very much improved” on the Clinical Global Impression Scale, compared with placebo.

 No pharmacogenetics analyses have been undertaken with modafinil, but clearly the functional polymorphisms for the dopaminergic, noradrenergic, and possibly glutaminergic systems deserve study.

The medical comorbidities associated with cocaine use disorder include greater risk of infectious diseases and greater rates of health care utilization.

 The treatment of cocaine use disorder needs FDA-approved medications, but the evolving pharmacotherapies have not been uniformly successful and may need to be applied to subgroups of patients to be optimally effective.

The emergence of effective pharmacotherapies requires matching medications to optimal patient groups. Genetic markers can be used to advance identification of patients for this type of personalized medicine. Thus, in addition to targeting multiple neurotransmitter systems, current pharmacotherapy research incorporates pharmacogenetics to identify subpopulations that might preferentially respond to specific medications. New challenges include matching medications such as modafinil, which targets multiple neurotransmitter systems, to genetically selected subgroups of patients.

Dr Andry is Addiction Psychiatry Fellow, Dr Shorter is Assistant Professor, and Dr Kosten is JH Waggoner Chair and Professor of Psychiatry, Neuroscience, Pharmacology, Immunology & Pathology and Co-Director, Dan Duncan Institute for Clinical and Translational Research at the The Menninger Department of Psychiatry & Behavioral Sciences, Baylor College of Medicine in Houston, TX. Dr Kosten is also Editor of the 

. The authors report no conflicts of interest concerning the subject matter of this article.

Center for Behavioral Health Statistics and Quality. Behavioral Trends in the United States: Results From the 2014 National Survey on Drug Use and Health

. Washington, DC: US Department of Health and Human Services; 2015. HHS Publication No. SMA 15-4927, NSDUH Series H-50.

http://www.drugabuse.gov/related-topics/trends-statistics

 Shorter D, Domingo CB, Kosten TR. Emerging drugs for the treatment of cocaine use disorder: a review of neurobiological targets and pharmacotherapy. 

 Liu S, Green CE, Lane SD, et al. The influence of dopamine Î²-hydroxylase gene polymorphism rs1611115 on levodopa/carbidopa treatment for cocaine dependence: a preliminary study. 

 Pennick M. Absorption of lisdexamfetamine dimesylate and its enzymatic conversion to d-amphetamine. 

 Mooney ME, Herin DV, Specker S, et al. Pilot study of the effects of lisdexamfetamine on cocaine use: a randomized, double-blind, placebo-controlled trial. 

 Shorter D, Lindsay JA, Kosten TR. The Alpha-1 Adrenergic Antagonist Doxazosin for Treatment of Cocaine Dependence: a pilot study. 

 Kosten TR, Wu G, Huang W, et al. Pharmacogenetic randomized trial for cocaine abuse: disulfiram and dopamine beta-hydroxylase. 

 Carroll KM, Nich C, Ball SA, et al. Treatment of cocaine and alcohol dependence with psychotherapy and disulfiram. 

 George TP, Chawarski MC, Pakes J, et al. Disulfiram versus placebo for cocaine dependence in buprenorphine-maintained subjects: a preliminary trial. 

 Spellicy CJ, Kosten TR, Hamon SC, et al. ANKK1 and DRD2 pharmacogenetics of disulfiram treatment for cocaine abuse. 

 Shorter D, Nielsen DA, Huang W, et al. Pharmacogenetic randomized trial for cocaine abuse: disulfiram and Î±1A-adrenoceptor gene variation. 

 De La Garza R 2nd, Bubar MJ, Carbone CL, et al. Evaluation of the dopamine Î²-hydroxylase (DÎ²H) inhibitor nepicastat in participants who meet criteria for cocaine use disorder. 

Prog Neuropsychopharmacol Biol Psyhciatry

 Kampman KM, Lynch KG, Pettinati HM, et al. A double blind, placebo controlled trial of modafinil for the treatment of cocaine dependence without co-morbid alcohol dependence. 

There are no FDA-approved pharmacotherapies for cocaine use disorder. Here: a review of the off-label use of promising medications for this addiction.

Emerging Treatments and Pharmacogenetics for Cocaine Use Disorder

Substance use disorders (SUD) are recognized worldwide as causes of negative medical, psychological, and social outcomes, and they result in significant personal consequences for affected persons, their families, and society at large. Treatment of SUD has focused on a combination of pharmacotherapy and behavioral therapies in an effort to improve patients’ chances of successfully entering and maintaining recovery.

Antidrug vaccines are a potentially important class of medications currently under investigation. They represent yet another frontier in the ongoing quest for novel pharmacological strategies that could be easily integrated into treatment plans to reduce substance use and establish abstinence. Ultimately, these vaccines reflect an important shift in our conceptualization of drugs of abuse, ie, that these substances are “foreign” and that the body’s own defenses can be used against them.

Drugs of abuse act centrally on the reward and reinforcement pathways of the brain. After introduction into the body, via oral, intranasal, inhalation, or intravenous route, these substances rapidly enter the brain to activate target neurotransmitter systems. One factor of particular importance in addiction pharmacology relates to the size of the molecule, because substances of abuse must be small enough to traverse the blood-brain barrier. Once in the brain, the initial common pathway of the addictive process is through stimulation of dopamine release from the ventral tegmental area to the nucleus accumbens; this, in part, determines the addictive liability of a substance.

Although the use of a vaccine to treat chemical dependency-an illness characterized by its multifactorial etiology and biopsychosocial underpinnings-sounds like a concept from the pages of a science fiction novel, the field of addictions treatment is much closer than many may realize. Interestingly, the idea of treating SUD using immunological means was introduced almost 40 years ago.

In 1972, based on an animal study, Berkowitz and Spector

 published their findings on the creation of a morphine vaccine. In rats, administration of a morphine hapten–bovine serum albumin (a carrier protein) was found to result in the creation of antimorphine antibodies. These antibodies were observed to reduce the plasma concentration of the drug in rats and to decrease self-administration of heroin in rhesus monkeys.

 highlighted the ability of antibodies to sequester substances of abuse within the circulatory system. The researchers first characterized the pharmacokinetics and clearance of phencyclidine (PCP) in dogs.

 They followed this study by creating antigen-binding fragments through a process of passive immunization. Goats were immunized with PCP, which generated high-affinity antibody proteins that were then collected from the animal serum and purified. In their final experiment, they administered PCP to dogs and used the PCP-specific antigen-binding fragments to bind the drug, confining it to the plasma and limiting its distribution into tissue.

What is already known about antidrug vaccines? 
? They are medically safe and effective in reducing abuse of cocaine and nicotine in humans through a mechanism of competitive antagonism.

What new information does this article add? 
? It provides a brief summary of the studies done with these vaccines over the past 15 years when they were first tested in humans and updates the status of their development in ongoing multisite randomized clinical trials.

What are the implications for psychiatric practice? 
? Addictions, particularly nicotine dependence in psychotic patients, are the most common disorders in psychiatric practice. Nicotine has a few pharmacotherapies, but no blocking therapies, and the efficacy of existing treatments is relatively limited. Medical safety issues have also arisen with varenicline, the most effective agent, which is a partial blocker. Cocaine addiction has no FDA-approved therapies. For both these disorders, vaccines are significant additions to the treatment options and should be available commercially within a few years.

Since that time, additional studies of passive immunization for treatment of SUD have been conducted. Antibodies specific for methamphetamine, heroin, and morphine were shown to bind these drugs in the circulation, to reduce euphoric effects and symptoms of toxicity, and to protect against overdose. These agents are akin to other immunoglobulin treatments for a wide array of illnesses, including malignancies and infectious diseases.

Antidrug vaccines work via active immunization, where administration of the vaccine triggers an immunological response against the agent.

 Immunological memory is created, whereby re-exposure to the agent (ie, through booster injection) results in amplification of the initial response. Because the immune system has been primed by vaccination, later introduction of the agent produces an antigen-specific, IgG-mediated antibody response. These antibodies bind the substance of abuse and create immune complexes too large to cross the blood-brain barrier; as such, they trap the drug in the circulation and allow it to be cleared from the system. The individual’s subjective experience (ie, euphoria) and reward are reduced, which also affects the reinforcing nature of the drug.

Drugs of abuse do not typically cause the user to mount an immunological response with the creation of antibodies capable of binding and clearing the substance. Thus, in creating antidrug vaccines, the targeted substance of abuse (ie, drug hapten) must be conjugated to a molecule that carries immunogenicity-such as a foreign carrier protein (eg, inactivated cholera toxin, bovine serum albumin). The effectiveness of the vaccine is then measured by its ability to create antibodies with specificity and high binding affinity for the drug of abuse and the robustness of the antibody response, ie, the concentration of antibody produced.

Clinical trials of substance abuse vaccines that target both cocaine and nicotine dependence are ongoing. Phase 1 and 2 clinical trials of these new medications are discussed below.

The cocaine vaccine, TA-CD, is a cocaine hapten conjugated to inactivated cholera toxin B (

). The vaccine induces a cocaine-specific antibody response. Antibody-bound cocaine molecules are then broken down by cholinesterases in the circulation, which convert cocaine into inactive metabolites that are subsequently excreted.

In the phase 1 trial (N = 34), TA-CD demonstrated an ability to induce the creation of cocaine-specific antibodies in all vaccinated subjects.

 Participants reported attenuation in their subjective experience and euphoria from smoked cocaine.

 The antibody levels did not persist beyond 1 year; the immunological effect appeared to last approximately 2 to 4 months following the final vaccination, as evidenced by a decline in the level of circulating antibody within that time span.

Overall, the safety profile for the vaccine was quite favorable. Almost all recipients (33 of 34) reported local pain and/or tenderness at the injection site, with no difference between active-treatment and placebo groups. Treatment-related systemic adverse effects that occurred in both groups included tachycardia, elevated temperature, and hypertension.

 It is important to note that there were no serious adverse effects during the 12 months of follow-up.

In the phase 2a trial (N = 18), TA-CD was administered at 2 dose levels (100 µg × 4 injections, or 400 µg × 5 injections). The vaccine demonstrated an ability to elicit an immunological response in participants from both the low- and high-dose groups.

 Participants from both groups developed cocaine-specific antibodies that persisted for at least 6 months.

 Mean antibody levels were higher in the high-dose group. Persons in this group were also more likely to remain abstinent at 6-month follow-up (89% of the low-dose group experienced a relapse vs 43% of the high-dose group). Sixteen of 18 participants (89%) successfully completed the study; there were no hospitalizations, deaths, or serious adverse effects.

 The 2 participants who did not complete the study received only 1 vaccination and did not report any adverse effects before discontinuing treatment.

In the initial phase 2b trial (N = 115), either TA-CD, at a single dose level (360 µg × 5 injections), or placebo was administered to cocaine-dependent, methadone-maintained participants. Those who received the vaccine were analyzed according to response and stratified into high- and low-antibody–producing groups. The high-antibody group showed a greater percentage of cocaine-free urine samples.

 The safety profile of the vaccine was favorable: all severe adverse effects were deemed unrelated to the vaccine. At present, TA-CD is undergoing large-scale, multicenter, phase 2b clinical testing.

There are 3 nicotine conjugate vaccines, NicVAX, NicQb, and TA-NIC (

). NicVAX is composed of a nicotine hapten linked to Pseudomonas aeruginosa exoprotein A. NicVAX is currently in the second of 2 phase 3 clinical trials; in previous studies, it has been found to produce antibody titers in a linear dose-response fashion.

 The nicotine-specific IgG antibodies produced resulted in a reduction of smoking among vaccinated persons, rather than compensatory smoking behavior.

NicVAX was well tolerated from a safety standpoint. Local reactivity at the site of vaccination was seen in both placebo and treatment groups, which suggests that these events were related to the adjuvant, rather than vaccine, components. There were no significant differences between groups in terms of commonly reported systemic adverse effects (ie, malaise, headache, myalgia).

A nicotine hapten structurally similar to that used in NicVAX makes up the core of NicQb. With the NicQb vaccine, however, the nicotine hapten is conjugated to a virus-like particle formed by recombinant expression of the protein coat of bacteriophage Qb.

 Moreover, this vaccine is not mixed with an aluminum adjuvant, as is the case with most vaccines.

 In a phase 2 trial, there was no statistically significant difference in rates of continuous abstinence between vaccinated persons and controls (P > .05).

 However, when stratified according to antibody response, those with high antibody production had higher continuous abstinence rates than those who received placebo (56.6% vs 31.3%); the difference between the groups was statistically significant.

The safety of NicQb was found to be favorable overall, although there was a significantly higher rate of reported “flu-like symptoms” among recipients of the vaccine than among recipients of placebo (70% vs 12.5%). Other commonly reported adverse effects in the vaccine group included pyrexia (42% vs 8% in the control group), headache (40% vs 27%), nasopharyngitis (32% vs 26%), rigors (13.5% vs 0%), and myalgia (13.5% vs 5%).

Similar to the cocaine vaccine, TA-NIC is composed of a nicotine hapten conjugated with inactivated cholera toxin B. During the clinical trial to assess safety and immunogenicity of the vaccine, participants demonstrated the ability to mount an immunological response, with serum antibody levels that increased significantly (P > .05) after each subsequent dose. Higher quit rates were observed in the high-dose vaccine group than in the control group (38% vs 8%). Note, however, that because of the small cohort size, statistical analysis was not reported.

Antidrug vaccines represent an exciting area of development in the pharmacological treatment of chemical dependency. In addition to the clinical trials being conducted on vaccines for cocaine and nicotine dependence, preclinical development of vaccines for methamphetamine and heroin is ongoing. Future directions for vaccine trials will likely focus on the use of booster injections to prolong antibody effects and methods for combining immunotherapy with current behavioral approaches.

As we think about the implications of this treatment, alleviating the suffering of those struggling with active addiction might only be the first step. Although years away, there may be a day when those persons at increased risk for chemical dependency (because of factors such as family history) may elect to prophylactically receive antidrug vaccines in an effort to reduce their likelihood of progression to addiction. Therefore, it is important that our ongo-ing conversation about this pharmacotherapeutic option strike a balance between the practical implications of vaccines, ethical considerations of treatment, and financial realities within society.

Acknowledgments-Research support was provided by VA SUD-QUERI, DOD, NIH grants K05-DA0454, P50-DA18197.

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 Bonese KF, Wainer BH, Fitch FW, et al. Changes in heroin self-administration by a rhesus monkey after morphine immunisation. 

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Antidrug vaccines represent an exciting area of development in the pharmacological treatment of chemical dependency. In addition to the clinical trials being conducted on vaccines for cocaine and nicotine dependence, preclinical development of vaccines for methamphetamine and heroin is ongoing.

Daryl Shorter, MD

Articles

Online Communities for Drug Withdrawal: What Can We Learn?

Emerging Treatments and Pharmacogenetics for Cocaine Use Disorder

Antidrug Vaccines