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Anti-addiction vaccines



Despite intensive efforts to eradicate it, addiction to both legal and illicit drugs continues to be a major worldwide medical and social problem. Anti-addiction vaccines can produce the antibodies to block the effects of these drugs on the brain, and have great potential to ameliorate the morbidity and mortality associated with illicit drug intoxications. This review provides a current overview of anti-addiction vaccines that are under clinical trial and pre-clinical research evaluation. It also outlines the development challenges, ethical concerns, and likely future intervention for anti-addiction vaccines.
Anti-addiction vaccines
Xiaoyun Shen
, Frank M. Orson
and Thomas R. Kosten
Immunology, Allergy & Rheumatology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA;
of Psychiatry, Baylor College of Medicine, Houston, TX 77030, USA;
Veterans Affairs Medical Center, 2002 Holcombe, Houston, TX 77030, USA
* Corresponding author: Thomas R. Kosten (
F1000 Medicine Reports 2011, 3:20 (doi:10.3410/M3-20)
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Despite intensive efforts to eradicate it, addiction to both legal and illicit drugs continues to be a
major worldwide medical and social problem. Anti-addiction vaccines can produce the antibodies to
block the effects of these drugs on the brain, and have great potential to ameliorate the morbidity and
mortality associated with illicit drug intoxications. This review provides a current overview of anti-
addiction vaccines that are under clinical trial and pre-clinical research evaluation. It also outlines the
development challenges, ethical concerns, and likely future intervention for anti-addiction vaccines.
Globally, UNODC (United Nations Office on Drugs and
Crime) estimates that, in 2009, between 149 and
272 million people, or 3.36.1% of the population
aged 1564, used illicit substances at least once in the
previous year. About half of those are estimated to have
been current drug users (i.e., they used illicit drugs at
least once during the month prior to the date of
assessment). Of the current drug users, it is estimate d
that there is a range of 1539 million problem drug
users globally. This subgroup of drug users is most likely
to come to the attention of healthcare services and law
enforcement authorities, and has been estimated to
cause the main public-health and public-order burden.
After cannabis, amphetamine grou p substances are the
most common, followed by cocaine and opiates. The last
three drugs are highly addictive and cause enormous
economic, health, and behavior problems [1].
Current medications for drug abuse have only had limited
success for drugs such as cocaine, nicotine, methamphe-
tamine, and heroin. The recent advent of human trials of
vaccines against abused drugs is therefore a welcome
development. The antibodies generated from anti-drug
vaccines can bind the target drug and form the antibody-
drug compound molecules that are too large to cross the
bloodbrain barrier. This reduces the rate and quantity of
drug entry into the brain and inhibits the psychoactive
effects of the drug [2-6]. If this antibody capacity is
sufficiently large, it can lead to a reduction in drug use
or limit the possibility of a drug relapse. Anti-addiction
vaccines are designed for the following goals: (a) helping
addicts achieve initial abstinence; (b) preventing relapse
after a drug-dependent patient completes withdrawal and
is attempting to remain drug-free; (c) enhancing beha-
vioral therapies when combined with other anti-addiction
medications; and (d) potentially preventing addiction in
high-risk populations.
The history of anti-addiction vaccines starts nearly
40 years ago. The proof of principle for an anti-addiction
vaccine was first demonstrated by two studies. In 1972,
Berkowitz and colleagues [7] published their creation of a
morphine vaccine in animals. Using rats, they adminis-
tered a morphine hapten linked to bovine serum albu-
min (BSA, a carrier protein) and created anti-morphine
antibodies. These antibodies reduced the concentration of
free morphine in the plasma of their vaccinated rats. In
1974, Bonese created a similar vaccine in primates, and
the vaccinated rhesus monkey primates decreased their
self-administration of heroin [8]. Unfortunately, this work
did not move forward to human use, at least in part
because other neuropharmacological approaches that
blocked abstinence symptoms (methadone) or prevented
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Published: 03 October 2011
© 2011 Faculty of 1000 Ltd
relapse (naltrexone) were introduced and preferred by
patients [9,10]. More recently, given the lack of success of
these and other approaches, anti-addiction vaccines have
now been trialed in humans.
The data from cocaine and nicotine vaccine trials suggest
that many patients may not produce a sufficient
antibody response for clinical efficacy, but those patients
who do attain high levels of antibodies are helped to
remain abstinent [11-12]. If extending this technology
to other abused substances is suc cessful, it will be a
tremendous benefit to have innovative pharmacothera-
pies rapidly available, especially as new designer drugs
are introduced. Indeed, anti-addiction vaccines are in
various stages of development for quite a broad array of
abused drugs, including cocaine, nicotine, methamphe-
tamine, and heroin [13-15]. Vaccine efficacy depends
on many critical factors, such as antibody specificity,
affinity, and antibody concentration (titer), which are
affected by the design of the vaccine conjugate, the dose
of the vaccine, the adjuvant selection, the frequency of
vaccinations, the time interval between immunizations,
and maybe the poorly understood geneti c variations
among individuals.
Cocaine vaccines
Background and development
Cocaine addiction is a global health problem. In the
United States alone, government surveys indicate that
2.4 million or more Americans aged 12 years or older are
current users of cocaine [16]. Its use has penetrated all
levels of society, and the ills it has created are evident in
both crime (abo ut 30% of federal and state prisoners
were regular cocaine users before incarceration) and
health statistics (from overcrowded emergency rooms to
individual acute psychotic reactions, heart attacks, or
strokes). A therapeutic vaccine is particularly critical for
cocaine addiction since there is currently no US Food
and Drug Administration (FDA)-approved pharma-
cot herapy to encourage wit hdrawal, or pre vent the
relapses that consistently derail most addicts recovery
efforts [17]. The current cocaine vaccines development
started in 1994 under Dr. Barbara Fox at the ImmuLogic
Pharmaceutical Corporation with support from the
National Institute of Drug Abuse [2]. It was produced
by attaching the cocaine to the surface of an antigenic
carrier protein, which for this first generation vaccine was
deactivated cholera toxin B subunit protein combined
with the FDA-approved human adjuvant alum. Both the
carrier protein and adjuvant used in this cocaine trial are
different from those used in the first animal morphine
vaccine studies, although the proof of principle is the
same. Along with other labs, these early studies showed
that conjugate cocaine vaccines could elicit strong
antibody responses that blocked the pharmacological
effects of the drug.
Clinical trials
In 1996, a Yale University group was the first to use a
cocaine conjugate vaccine in humans, and Phase I and IIa
studies with this cocaine vaccine (TA-CD) were com-
pleted by 2005 [17]. In the phase IIa studies, where
human laboratory trials assessed dosing requirements
and short-term risks, m ost pat ient s made clinically
relevant quantities of cocaine-specific antibody, and so
far have had few side effects [18,19]. The estimate of the
needed antibody level was based on the results of a
human laboratory study demonstrating that TA- CD
substantially decreased the intoxicating effects of smok-
ing cocaine in those generating antibody levels above
20 μg/ml [20]. A later Phase IIb study (a randomized
human outpatient trial to assess clinical efficacy) showed
that 40% of the patients made sufficiently high antibody
levels (over 43 μg/ml) after vacc ination and significantly
reduced their cocaine use for over 2 months.
The response to cocaine vaccines occurs in two phases.
The initial phase lasts about 812 weeks during which an
initial series of five vaccinations results in a relatively
high level of antibodies in about 40% of vaccinated
addicts and another 35% have antibody levels sufficient
to block one or two cocaine doses, the latter of which is
especially useful for relapse prevention in patients
already abstinent [18]. The antibodies are produced to
cocaine as well as cholera toxin B, since the polyclonal
antibody response includes the cocaine chemically
attached to the cholera toxin. Virtually everyone will
produce substantial antibody responses to the cholera,
but the reasons why about 25% of patients produce low
or minimal levels of anti-cocaine antibodies are not
known. This non-response issue i s being actively
investigated with a variety of very interesting leads
related to human genetics and the production of
immunological tolerance for particular substances.
The antibody levels may decline substantially in the
second phase (beyond 12 weeks) in the patients who
produced therapeutic levels of antibody to cocaine in the
initial phase, and a booster vaccination is often needed.
Rather than needing the full series of five vaccinations
again, however, a single vaccination may be sufficient to
elevate antibody levels back to their therapeutic levels for
about 3 months. Thus, for a period of protection lasting
2 years, patients would need to get about six additional
boosters given as one every 3 months. Exposure to cocaine
alone will not provoke an increase in antibodies because
the cocaine molecule is unable to activate memory B cells
by cross-linking the antibodies expressed on their surface.
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F1000 Medicine Reports 2011, 3:20
However, after boosting with the conjugate vaccine, newly
produced antibodies in sufficient quantity will be able to
very rapidly (within seconds) bind most of a usual dose of
cocaine when it enters the bloodstream, and again prevent
the cocaine from leaving the blood vessels and entering
the brain, heart, or other organs. This reduces the typical
drug effects on the various organ systems in the body.
Because the antibodycocaine complex is too large to pass
thorough the bloodbrain barrier, the cocaine is then
metabolized in the blood and liver to inactive metabolites
by one of three mechanisms: spontaneous hydrolysis,
tissue esterases (especially in the liver), or butyryl
cholinesterase (in the bloodstream) [21]. These metabo-
lites do not bind to the cocaine antibodies because of their
different chemical structures and are simply excreted from
the body.
Phase I and II studies with the cocaine vaccine were very
succes sful, in part because the cocaine was rapidly
sequestered and metabolized. This resulted from the
advantageous combination of a good antibody response
from the cholera toxin carrier and the spontaneous and
enzymatic hydrolysis of cocaine into inactive metabo-
lites. This type of rapid metabolism does not exist in the
blood stream for other abused drugs, such as nicotine or
methamphetamine. When these other drugs are bound
by antibodies, the drug is slowly metabolized in the liver
or other tissue sites, or excreted unchanged [22]. As a
result, these other compounds circulate in the blood-
stream much longer when bound by antibody.
Current status
The notable success o f the first placebo-controlled
clinical trial of a cocaine vaccine [18], as well as the
relative ease with which these vaccines can be manu-
factured, has encouraged a multi-site study of the cocaine
vaccine to move forward quickly. Currently, the cocaine
vaccine (TA-CD) is being evaluated in an ongoing multi-
site, Phase IIb clinical trial. This 4-month, double-blind,
randomized, placebo-controlled, multi-center study is
comparing the effect of the cocaine vaccine to place bo in
reducing cocaine use in 300 treatment-seeking, cocaine-
dependent individuals. Patients receive five vaccinations
over a period of 12 weeks and some subjects will likely
attain therapeutic antibod y levels in weeks 68, after the
first three injections. Based on the success of this vaccine
in earlier clinical trials, this cocaine vaccine shows
promise to be one of the first anti-addiction vaccines to
be ap proved by the FDA for human use.
Nicotine vaccines
Background and development
Smoking is a global healthcare problem. The World
Health Organization estimates that there are 1.3 billion
smokers worldwide today and more than 5 million
tobacco-related deaths each year [23]. If current smoking
patterns continue, smoking will cause some 10 million
deaths each year by 2020 [24]. To date, three medica-
tions are FDA-approved for smoking cessation: nicotine
replacement therapy, sustained-release bupropion, and
varenicline [25,26]. Despite the relative efficacy of these
first-line medications, long-term absti nence rates remain
disappointingly low, plus, many drug abusers relapse
after one quit attempt using the available pharma-
cotherapies. The CDC (Centers for Disease Control and
Prevention) estimates that, among the 45 million adult
smokers in the United States, almost 75% want to quit,
but less than 5% of those who try to quit remain smoke-
free after 12 months [27]. Thus, efforts to develop new
treatments including nicotine vaccines are continuing.
Nicotine does not have the advantage of a serum enzyme
that breaks it down into an inactive metabolite in the
bloodstream. Lacking such a serum enzyme would make
a successful nicotine vaccine more difficult if the only
goal was to prevent deliberate override of the antibody
levels. However, nicotine vaccines may nonetheless prove
as effective as cocaine vaccines because the antibody
levels needed for blocking nicotine effects are about ten
times lower for nicotine than cocaine, and those being
vaccinated are typically very motivated to stop smoking
and do not have the ambivalence about abstinence that is
common among cocaine and other illicit drug users
[11,28]. An early nicotine vaccine significantly reduced
drug distribution to the brain from single nicotine doses,
even after animals were chronically treated with total
nicotine daily doses that exceeded the estimated binding
capacity of antibody by 33-fold [28]. This reflected the
fact that nicotine metabolism was able to continue
despite a portion of the drug being bound to antibody,
permitting some antibody to be available for binding
an additional nicotine dose. This remarkably greater
efficacy than binding capacity is probably due to the
rapid on and off binding rates for nicotine as a small
molecule that is bound by a single antibody-combining
site. Nevertheless, having quantitatively high antibody
responses to clinical vaccines is critical to success. Overall,
nicotine vaccines could have significant success relatively
soon since they can be manufactured relatively inexpen-
sively, the total smoking population worldwide is very
large, motivation to quit smoking is relatively strong, and
finally patients are quite unlikely to try to deliberately
override the antibody capacity, unlike cocaine patients.
The low cost of a nicotine vaccine will also facilitate
widespread distribution of the vaccine for public health
purposes to a wide range of less wealthy populations
in both developed and developing nations healthcare
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Clinical trials
Because of the substantial market for smoking cessation
products, development of a vaccine against nicotine
addiction has caught the intere st of the pharmace utical
industry. As a result, thr ee pharmaceutical companies
have moved nicotine vaccines forward to hum an
studies [29].
Phase II trials with NIC002 (also known as Nicotine
Qbeta or CYT002-NicQb) from Cytos Biotechnology/
Novartis were conducted in 341 smokers, and the
outcome data were available from 239 study subjects
who were divided into low, medium, and high respon-
ders according to their nicotine antibody levels. There
was no difference in abstinence rates among the low and
medium responders and placebo groups. The top third
of the responders had higher abstinence rates at the 6-
and 12-month follow ups [30]. However, side effects
(including flu -like symptoms) occurred in 69.4% of
subjects. In 2007, Cytos Biotechno logy entered into a
licence agreement with Novartis and, in 2008, Novartis
began a new Phase II trial in 200 cigarette smokers with a
reformulated vaccine with fewer side effects. However,
interim analysis showed that the primary endpoint
(continuous abstinence from smoking from weeks
812 after start of treatment) was not achieved, possibly
because NIC002 failed to induce sufficiently high anti-
body titers [31].
Celtic Pharma completed a Phase II, double-blind,
randomized, placebo-controlle d, multicenter, dose-
ranging study of 100 or 250 μg of TA-NIC (a recombinant
cholera toxin conjugate vaccine) to assess the efficacy and
safety of the vaccine as an aid to smoking cessation in
2009, but the results have not yet been released [32].
The most adva nced nicotine product is NicVAX (a
bacterial exo prote in conjugate vaccine) by Nabi Bio-
pharmaceuticals/GlaxoSmithKline. During 2004 to
2006, Nabi conducted five Phase I/II clinical studies
involving more than 475 subjects and demonstrated
that NicVAX was well-tolerated, highly immunogenic,
gave a dose-dependent increase in antibody concen-
trations, and showed a clinical proof of concept for
efficacy in smoking cessation (cli nical response rates
were highly correlated with antibody concentrati on).
Significantly, the data in the Phase IIb proof-of-
concept study showed a correlation between antibody
concentration and the ability of subjects not only to
quit smoking but also to remain abstinent up to
12 months [32].
In 2007, Nabi announced the successful completion of
our Phase IIb trial of NicVAX. The Phase IIb study was a
double-blind, placebo-controlled, dose-ranging study
designed to establish proof of concept and the optimal
dose and regimen for the Phase III program. The trial
enrolled a total of 301 heavy smokers who smoked an
average of 24 cigarettes per day prior to enrollment. The
30% of participants who developed the highest level of
nicotine antibodies (61 of 201) showed a continuous
abstinence at 8 weeks, between weeks 1926 compared
with subjects who received placebo, and abstinence rate
was almost three times that of the placebo group after
12 months (16% in 400 μg group, 14% in the 200 μg,
and 6% in the placebo group). In addition, vaccinated
smokers who failed to quit but showed a high antibody
response smoked a median of only 10 cigarettes per day
while in the study, compared to their own baseline value
of 20 cigarettes per day before treatment. In the
remaining 70% of vaccinated participants, abstinence
rates were no better than placebo. These trials did not
demonstrate nicotine vaccines to be superior to placebo
when including all vaccinated subjects because only a
third of those vaccinated develop sufficient levels of
antibody to block the effects of nicotine [32].
However, in July 2008, Nabi reported results of an
improved immunization schedule, which was based on
the 400 μg dose and six applications of the vaccine.
Based on this schedule, 80% of the subjects achieved the
target antibody level at 14 weeks, which compares to
only 50% of subjects with the prior immunization
schedule. Nabi started a Phase III trial in 2008, which
was a double-b linded, place bo-controlled trial with
1,000 patients. The primary endpoint of the study was
the abstinence rate for 16 weeks ending at 12 months.
Abstinence was evaluated by self-reported cigarette
consumption and biologically verified by exhaled
carbon dioxide. Secondary endpoints included the
abstinence rate at various time intervals, safety, and
immunogenicity and the effect of NicVAX on withdrawal
symptoms, cigarette consumption, smoking satisfaction,
and nicotine dependency. Nabi has announced the
results of the first NicVAX(R) Phase III clinical trial recently;
the smoking cessation immunotherapy failed to meet its
primary endpoint of significantly greater abstinence in
those vaccinated compared with the placebo group [32].
However, this assessment was done several months after
the anti-nicotine antibody levels had fallen well below
expected therapeutic levels. Nabi is awaiting the results
of a second Phase III trial, but it has suffered similar
design problems; that is, treatment efficacy was assessed
after the active agent responsible for the therapeutic
effect (e.g., high antibody levels to nicotine) had been
gone for several months [33].
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Development considerations
Nicotine vaccines could have an important advantage in
that they can have a prolonged effect on the immune
system (for 612 months), and this could reduce the
relapse rate. Another advantage of the vaccine approach
is that daily administration of the drug is not required;
only occasio nal booster shots are needed to maintain
an adequate antibody titer. However, there has been
inconsistency in the degree of antibody response; some
people do not achieve adequate antibody titers. Possible
disadvantages of nicotine vaccines inc lude the necessity
for multiple injections and the time delay before an
effective immune response is achieved. Nicotine vaccines
are in Phase I and III trials and, if successful, they will
contribute to the fight against tobacc o addiction in an
innovative way.
Vaccines for methamphetamine addiction
Methamphetamine is a highly addictive and toxic drug of
abuse with potent central and peripheral sympathomi-
metic effects [34]. Its potent effects include an elevation
of pulse rate and blood pressure, and an increased level
of alertness. Pharmacokinetic studies have shown t hat both
cocaine and methamphetamine have fast uptake (reaching
peak brain concentrations within several minutes); the
drug clearance from the human brain is fast for cocaine, but
slow for methamphetamine (hours) [35]. Methampheta-
mine has a plasma half-life of 12 hours, and the drug may
last between 4 and 24 hours [36]. It has been shown that
abuse of the drug leads to high levels of accumulation of
methamphetamine in most body organs, in humans [37]
as well as non-human primates [38]. This widespread and
long-lasting drug distribution parallels its long-lasting
behavioral effects, and is likely to contribute to various
medical complications including stroke, insomnia, excit-
ability, seizures, panic attacks, psychosis, and aggressive
behavior [39,40].
Methamphetamine use and addiction has grown at
alarming rates over the past two decades in the United
States and in Southeast and East Asi a [41,42], and the
high rate of relapse in the patients undergoing metham-
phe tamine withdrawal underscores the difficulty in
developing an effective therapy for methamphetamine
addiction [43]. According to the 2008 National Sur vey
on Drug Use and Health, 850,000 Americans aged 12 or
older used methamphetamine at least once in the year
prior to being surveyed , with past-month users reaching
314,000 [44]. The National Drug Threat Assessment
states that methamphetamine is a principal drug threat
to the United States and that 31% of state and local law
enforcement agencies nationwide consider it as the
principal drug threat [45]. Currently, there are no FDA-
approved medications for treating methamphetamine
addiction, so a successful vaccine against methampheta-
mine could have a substantial impact on addiction, as
well as on reducing one of the major risks for HIV
transmission worldwide.
Over the past decade, a number of labs have been
working on evaluating the best composition of a vaccine
for methamphetamine by considering hapten design,
selection of the carrier protein, the chemical positioning
of a linker between the target antigen and the carrier
protein, and choice of the best adjuvant, which is crucial
for proper immune stimulation both in terms of amount
of antibody elicited and antibody specificity [46-48].
Jandas group has recently reported three methampheta-
mine conjugates that are able to generate substantial
antibody titers (45-108 μg/mL) and moderate affinity
(82, 130, and 169 nM) [47]. The data from our lab have
shown that high titer antibodies can be elicited and
maintained for 3 months by administration of metham-
phetamine conjugates in rodents, depending on the
conjugate construction and the adjuvants used. This
elevated antibody level is associated with the reduction
of methamphetamine-stimulated locomotor activity in
the vaccinated animals (Orson, unpublished data).
Furthermore, our data have suggested that methamphe-
tamine binding to antibody is equivalent to high affinity
monoclonal methamphetamine antibody [4-6] in
enzyme-linked immunosorbent inhibition assays, using
polyclonal antibodies generated by KLH-S-Meth or
OMPC-S-Meth (Orson, unpublished data).
In parallel, Owens and his colleagues have been
evaluating a passive immunotherapy approach using
the monoclonal antibodies for methamphetamine.
Passive immunotherapy involves the administration of
the preformed antibodies via intravenous, subcutaneous,
or intramuscular injection. The antibodies can be in the
form of polyclonal serum or purified IgG from animals
that were immunized with a drug-protein vaccine [49].
The monoclonal antibodies injected passively bind the
abused drug and act by the same pharmacokinetic as the
polyclonal antibody-produced vaccines. In vivo phar ma-
cokinetics have shown that high concentrations of anti-
methamphetamine monoclonal antibodies can produce
a sustainable equilibrium shift of methamphetamine out
of the brain and into the blood stream, as measured by
substantial reductions in methamphetamine brain
concentrations over time accompanied by substantial
increases in methamphetamine serum concentrations
[5,6]. The rate of association and dissociation of the
antibody binding to the drug may also infl uence the rate
of drug entry to, and exit from, the brain. By slowing
methamphetamines entry into the brain, the antibodies
may be effective in reducing the amount of drug in the
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brain, thereby reducing the pharmacological effects of
the drug. These antibody-induced reductions in metham-
phetamine volu me of distribution, clearance from the
blood stream, and substantially increased serum protein
(predominantly antibody) binding are why antibody
medications are classified as pharmacokinetic antago-
nists; that is, they f avorably change the concentration-
time course of methamphetamine in brain and other
organ systems. In addition, the passive administration of
high-affinity monoclonal antibodies has also shown to
reduce methamphetamine self-administration in rats
[50] and to reduce locomotor activity in rats given low
and moderate doses of methamphetamine, but not at
doses that significantly exceeded the antibody-binding
capacity for high-dose methamphetamine [51,52].
Development considerations
While the published human cocaine/nicotine studies
support the feasibility of anti-methamphetamine vaccines,
the methamphetamine vaccines that generate efficacious
levels of antibodies with sufficient binding affinity to the
drug are not yet sufficiently characterized to proceed to
clinical studies. Hapten design, carrier protein, and use of
adjuvants are critical for development of an efficacious
vaccine. The OMPC (outer membrane protein complex of
the bacterium Neisseria meningitidis group B) and KLH
(keyhole limpet hemocyanin) are the highly immuno-
genic foreign carrier proteins that have been commonly
used in vaccine formulation [53], and our preliminary
data indicated that OMPC is particularly attractive as a
carrier for the anti-addition conjugate vaccines, since it
elicits early, high-level antibody responses to the drug.
The methamphetamine vaccines may be evaluated in
combination with the currently licensed adjuvants includ-
ing aluminum salts (alum), MF59, and monophosphoryl
lipid A [53]. The influence of average antibody-binding
affinity and kinetics from these vaccines can be examined
using techniques including surface plasmon resonance,
isothermal titration calorimetry, and fluoresenced ther-
mopheresis. Animal models, such as methamphetamine
self-administration and the locomotor assay, can be
applied to evaluate the vaccines against repeated self-
dosing with methamphetamine and to assess the degree to
which the antibodies can inhibit the reinforcement effects
of methamphetamine.
Vaccines for opiate addiction
All opioids, including morphine, heroin, and prescrip-
tion analgesics such as Vicodin and OxyContin, have
extremely high abuse potential. Dependence on these
drugs has been termed a chronic, relapsing disease,
[54] and is associated with a multitude of health and
social problems, such as increased risk for HIV, mortality,
crime, unemployment, and breakdown of int erpersonal
relationships [55]. Global heroin consumption was 340
metric tons in 2008, of which Europe (excluding Russia
and Turkey) consumed the most (88 metric tons, 26% of
global consumption), followed by Russia (70 tons; 21%),
China (45 tons; 13%) and the United States (22 tons; 6%)
[1]. In 2007, 3.8 million Americans reported using heroin
at some point in their lives, with 58% of the 366,000
current-year users meeting criteria for dependence or
abuse [56].
Both methadone maintenance and naltrexone are cur-
rently used as treatment for opiate dependence [9,10].
However, it has been shown that less than 25% of heroin
addicts remain abstinent after methadone maintenance
treatment [57] and 60% of heroin addicts lapse following
inpatient treatment [58]. In addition, these therapies are
associated with a number of problems, such as high
attrition rates within the first month [59], and reliance on
methadone clinics for the three-times-weekly administra-
tion. Besides, methadone is a full-opioid agonist itself,
therefore it is susceptible to abuse and overdose, including
adverse reactions such as respiratory depression. Further-
more, both methadone maintenance and naltrexone
programs are very costly (in 1996 alone, the United States
spent approximately $21.9 billion dollars on heroin
addiction [60], and so are less feasible in some countries
[55]. Therapeutic vaccines have the potential as treatments
to address these problems.
As discussed above, the first anti-ad diction vaccine
development was directed to vaccines for opiate addic-
tion [7,8]. Other early studies also showed that certain
morphine protein conjugates could produce antibodies
with specificity to heroin and 6-acetylmorphine, as well as
morphine itself, and that the binding specificity may differ
depending on the hapten used [61-63]. Opiate vaccines
are now being revisited, almost 40 years after they were
initially studied [64-67], in order to offer an option to
produce long-lasting morphine/heroin antibodies that are
specific for heroin and its psychoactive metabolites at a
sufficient level to block the pharmacological effects. These
antibodies would act as an opiate antagonist without the
aforesaid negative side effects associated with naltrexone/
naloxone. Anton and Lef [65] demonstrated that a 6
linked morphine-tetanus toxoid vaccine was able to
trigger and establish adequate antibody titers and prevent
reacquisition of heroin self-administration in rats. How-
ever, similar to the earlier study [8], a total of four boosts
were required over a 60-day period to reach adequate
titers, and biweekly boosts were needed to keep titer levels
high over the period of a year. Recently, Janda and his
colleagues have published their study using vaccines with
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heroin-like and morphine-like haptens linked to the
adjuvant KLH (keyhole limpet hemocyanin). The results
showed that the polyclonal antibodies from a heroin-like
vaccine had micromolar affinity to 6-acetyl morphine,
heroin, and morphine and prevented rodents from
acquiring the habit of heroin self-administration or
showing the anti-nociceptive effects of heroin. Conversely,
antibodies generated by morphine-like vaccine only had
adequate affinity for morphine and a reduced binding for
heroin, but no affinity for 6-acetyl morphine; in addition,
the morphine-like vaccine was not effective for pre-
empting heroin administration [67].
Our recent studies have demonstrated that high to
moderate levels of anti-morphine antibodies are elicited
by morphineKLH conjugates together with either alum or
monophosphoryl lipid A in rodents [68,69]. In agreement
with the previous studies [61-63], our study has shown
that polyclonal antibodies generated by morphine vaccines
were able to bind to morphine and its metabolites (6-acetyl
morphine, 3-glucuronide morphine, and 6-glucuronide
morphine), but with nanomolar affinity [69]. This cross
reactivity is critically important, since heroin is a prodrug
that is rapidly converted to the pharmacologically active
opiates 6-acetyl morphine and morphine by esterases
present in both the periphery and the central nervous
system [70]. In addition, our efficacy studies demonstrated
a significant inhibition of morphine-induced analgesia
[68,69] and conditioned rewarding effects of morphine
[69] in the immunized animals. These behavioral changes
in the vaccinated rats were at least in part due to seque-
stration of the drug in the blood and reduction of the drug
levels in the brain by antibodies [70].
Although morphine and heroin can both be blocked by
antibodies from a single type of vaccine, at least five
different vaccine types may be needed to block all the
types of synthetic opiates that have now been manu-
factured as alternatives to morphine due to their widely
varying chemical structures. Because prescription opiate
abuse has overtaken heroin as the major opiate abuse
problem in the United States, a vaccine approach to
blocking heroin abuse will be less effective in the clinic.
However, in the developing world, such as Southeast
Asia, the Middle East (Iran) and Mexico, where
morphine and heroin are the opiates most commonly
abused, an effective vaccine would be life-saving and very
cost effective. By building on previous research, design-
ing methodologically sound studies and systematically
assessing patient outcomes during the clinical trial and
612 month follow-ups , such vaccines can hopefully win
FDA approval and then assist in combating this serious
public-health issue.
Challenges and implications
Challenges in delivering clinically effective
anti-addiction vaccines
An efficacious vaccine elicits good quality antibodies that
maintain at sufficient levels throughout a sustained
period of several months after the initial vaccination
series and then after each booster vaccination. Clinical
trials of cocaine and nicotine vaccines so far have
reported mod est efficacy. The abstinence rates among
those vaccinated against nicotine have been no better
than placebo overall, but the rates have been superior to
placebo in the third who achieved therapeutic antibody
levels. So, enhancing the proportion of responders and
the magnitude of antibody responses will be critical for
making this approach broadly useful. Increasing the
number of doses and/or the size of the dose may
improve immunogenicity [33], but improved adjuvants
may offer the best route for increasing responses.
However, these changes may also increase adverse effects
so that the safety and efficacy of the revised dosage
schedules will need to be established. Nicotine vaccines
will need to be shown to be more effective than nicotine
replacement therapy, bupropion, varenicline, and any
new cessation aids in order to be adopted.
The cocaine vaccine was conceived primarily as an agent
for patients who could abstain from cocaine use for a
limited period of time but needed help with maintaining
that abstinence. This could work by inhibition of a
phenomenon that occurs across addictions called the
priming effect [71]. In the absence of an anti-cocaine
mechanism, cocaine use after a period of abstinence
markedly intensifies craving and increases the risk for
continuing into a binge pattern of abuse and relapse.
However, it was noted in Phase IIb cocaine trials that
some subjects who continued high-level cocaine use did
not appear to override the antibody blockade of cocaine
effects [18]. Therefore, anti-addiction vaccines may, in
high responders at least, also inhibit deliberate attempts
to override the vaccines blockade by using more than an
initial one or two drug doses.
The behavioral challenges for any successful vaccination
program start with the need to have 23 months where
the patient can be brought to a treatment site for five
vaccinations. During these 23 months, the patients
could be vulnerable to relapse if they have already
discontinued drug use. While this drug abuse alone does
not interfere with the vaccines ability to induce the
required antibody production, it is critica l that the
patient gets these vaccinations at appropri ate times over
the 3 months (e.g., 2, 4, 8, and 12 weeks after the initial
vaccination) and continued abuse may result in failure to
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F1000 Medicine Reports 2011, 3:20
appear for these follow-up visits. Thus, other treatment
interventions will be valuable to insure that compliance
with the schedule of vaccinations is maintained and such
interventions could vary from residential substance
abuse care to outpatient contingency management in
which patients are paid to come for the vaccinations with
an escalating pay schedule for each vaccination obtained.
Alternatively, monoclonal antibodies could provide
passive immunity while the acquired immunity is built
up, although such antibodies are expensive and can
produce adverse side effects [72].
Ethical and legal challenges
Apart from development hurdles, ethical, legal, and
regulatory challenges are the barriers to implementation
of these innovative treatments. Vaccines themselves are
generally considered high risk with a low profit margin
by the pharmaceutic al industry, in large part because of
the extended liability that a company can incur with the
prolonged legal exposure produced through vaccination.
Also, the fundamental stigma of substance abuse, viewed
as a moral failure rather than a brain disease, pervades
many aspects of treatment for substance abuse. When
addiction is considered a failure of will power or as
willful misconduct, then treatment is generally directed
toward the behavioral disorde r, with little consideration
given to direct medical intervention, so that even the
addict may not recognize the potential benefit of
therapeutic vaccination. The economic correlate of this
perception within the pharmaceutical industry is that
these patients would provide a poor return on invest-
ment for the costs and risks of developing an immuno-
logical intervention. This misperception has been
countered to a significant extent for tobacco smoking,
possibly because of its legality and worldwide preva-
lence, and as a result, nicotine vaccines are in clinical
trials by three companies.
Vaccines may have potential use as preventive agents in
high-risk populations; however, certain ethical concerns
need to be considered carefully before implementation
in these contexts [72,73]. For examples, the treatment
may be provided as an alternative to imprisonment to
persons who have been charged with or convicted of an
offence to which their drug dependence has contributed,
its main justification being that treating offenders drug
dependence will reduce their chance of reoffending
[74,75]. Anothe r example could be vaccinating adoles-
cents against nicotine. If the adolescents then subse-
quently smoked ten times mor e cigarettes in order to
overcome the nicotine blockade, the result of such high
levels of smoking for prolonged periods would be a
massive increase of ingested carcinogens, which the
vaccine does not block. Another possible application
would be to use the vaccines in drug-abusing pregnant
women to protect the fetus and mother from drug
exposure and its complications. Finally, parents might
request that their children be vaccinated to prevent future
drug abuse, even though the risks of future drug abuse
for them as individuals might not be well defined [73].
The ethical and legal challenges have made FDA
approval for an anti-addiction vaccine extremely com-
plicated, and the precise requirements for FDA approval
are not clear because no such vaccine has yet been
approved [74]. FDA approval requires demonstration of
not only clinical efficacy, but also medical safety. The
preventive use of a vaccine in healthy young people
requires stronger evidence of safety and efficacy than
shorter-term use to reduce relapse in adults who are drug
dependent. Obtaining eviden ce to meet r egulatory
requirements for such use has become very expensive
to accomplish [74,75]. As a result, FDA approval has
been of great concern to those companies who might
manufacture, license, and sell these vaccines.
The results from human studies of the first cocaine
vaccine and three nicotine vaccines are promising, and
preclinical development of efficacious methampheta-
mine and opiate vaccines is rapidly progressing. Blocking
immediate behavioral and toxic drug effects is valuable,
but even more promising from the addiction perspective
is the inhibition of drug reinforcement, or craving, which
will be necessary to help prevent relapse to drug use
by individuals motivated to quit. Ethical, legal, and
regulatory challenges are the barriers to implementation
of anti-addition vaccines, and future development
strategies may include examining additional ways to
increase antibody levels in high proportions of immu-
nized individuals to improve vaccine efficacy. Advances
in vaccine conjugate design, carrier protein use, and
especially adjuvant optimization will significantly
enhance the quantity and quality of the antibodies
produced, allowing drug vaccines to become useful
clinical tools for the treatment of substance abuse.
FDA, US Food and Drug Administration; KLH, keyhole
limpet hemocyanin; OMPC, outer membrane protein
complex of the bacterium Neisseria meningitidis group B.
Competing interests
The authors declare that they have no competing interests.
Supported by the Department of Veterans Affairs (VA)
Meri t Review Program and VISN 16 Mental I llness
Page 8 of 11
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F1000 Medicine Reports 2011, 3:20
Research, Education and Clinical Center(MIRECC), the VA
National Substance Use Disorders Quality Enhancement
Research Initiative (QUERI), and the National Institute on
Drug Abuse grants K05 DA 0454 (TRK), P50-DA18197
(TRK), 5R01DA030338 (FMO), 1X02DA032939 (TRK,
FMO, XYS), R01DA026859 (FMO, XYS).
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... It could be argued that preventive use of vaccines violates the minor's right to express their free will. On the other hand, such an argument is pretty similar to those raised by parents who claim vaccination requirements usurp their due process rights to make parental decisions on behalf of their children (Shen et al., 2011). ...
... The smoker, vaccinated by anti-nicotine vaccine, may be urged to smoke ten times more cigarettes in order to overcome the nicotine blockade; the result of such high levels of smoking for prolonged periods would be a massive increase of ingested carcinogens, which the vaccine does not block. Finally, parents might request that their children be vaccinated to prevent future drug abuse, even though the risks of future drug abuse for them as individuals might not be well defined (Shen et al., 2011). ...
... Vaccine efficacy depends on many critical factors, such as antibody specificity, affinity, and antibody concentration (titer), which are affected by the design of the vaccine conjugate, the dose of the vaccine, the adjuvant selection, the frequency of vaccinations, the time interval between immunizations, and maybe the poorly understood genetic variations among individuals (Shen et al., 2011). ...
Full-text available
Medicine in the developed world is becoming progressively more commercialized since patients (or, more accurately, medical consumers) are increasingly becoming the driving force of what we call medical progress. The doctors are primarily obliged to treat and help patients, but will always have also (commercial) temptation before him: to facilitate the consumer's desires and, with a warm heart, shoot to the far borders of medical knowledge and technology. A good example illustrating dilemma of beneficial vs commercial medicine are ethical challenges of some new vaccines developed recently. Since their earliest introduction in the late 18th century, vaccines have undoubtedly saved the lives of millions, while also fundamentally changing the way modern medicine is practiced. Many diseases that were once widespread are now eradicated, yet vaccine development faces ongoing challenges, including some important ethical considerations. Today there are over 300 vaccines in development and included in clinical trials. Among them, anti-addiction vaccines (Cocaine, Nicotine, Fentanyl, Heroin, Oxycodone) received a burst of media attention, because these vaccines could help people in recovery from addiction; however, many ethical and legal questions may arise before clinical use.
... In the last decade, a considerable progress in development of novel vaccines based on Hc conjugates against various malignancies such as leukemia, metastatic breast cancer, oral cancer and melanoma [13][14][15] as well as some fungal and viral infections [16] and antidrug abuse [17] was made. Conjugation of peptides, carbohydrates, toxins, opioids or other small molecules to Hcs may alter or enhance their immunogenicity and activity [12]. ...
Two oxygen-transporting proteins known for their immunostimulating and anticancer properties, namely hemocyanin from Helix lucorum (HlH) and hemocyanin from Rapana thomasiana (RtH), have been modified for the first time with rosmarinic acid (RA). We prepared two conjugates RA–HlH and RA–RtH containing 47 and 50 rosmarinic acid residues, respectively. The conformational analysis showed that the secondary structure of RA–HlH is less ordered than that of the native HlH, and for the modified protein we observed a decrease in α-helical structures in the favor of random coils, unordered structures, and aggregates. Calorimetric studies showed an increase in the thermal stability of RA–HlH in comparison with the native HlH which is in agreement with the observed structural changes. On the other hand, the conformation of RA–RtH was very similar to that of the native RtH although some rearrangements in the molecule were found. Interestingly, the modification of RtH with RA resulted in a decrease in its thermal stability. A 48-h in vitro experiment showed that tested in concentrations up to 0.7 mg mL−1 the two modified hemocyanins did not inhibit the cell growth of human fibroblasts.
... Las proteínas portadoras más usadas son la albúmina sérica bovina (BSA, del inglés, bovine serum albumen), la KLH (del inglés, Keyhole limpet haemocyanin) y el toxoide tetánico (TT), entre otras. La unión de los anticuerpos específicos a la droga evita que ésta cruce la barrera hematoencefálica, lo que detiene los procesos neurofarmacológicos de la droga y rompe el ciclo de recompensa-adicción, como se esquematiza en la Figura 1 (Kinsey, Jackson, & Orson, 2009;Kosten & Owens, 2005;Montoya, 2012;Moreno & Janda, 2009;Shen, Orson, & Kosten, 2011). ...
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Introducción: por lo común, la adicción a las drogas se trata con psicoterapia y farmacología que evita la unión de las sustancias psicoactivas a receptores específicos en el cerebro. El resultado de estos tratamientos no ha sido del todo satisfactorio, por lo que el desarrollo de terapias más eficaces representa un reto constante para tratar las adicciones. Una alternativa a la farmacología antiadictiva es la vacunación activa dirigida contra las sustancias de abuso. Objetivo: esta revisión reúne la información disponible sobre los fundamentos y avances científicos en la generación de una terapia inmunológica, que coadyuve al tratamiento de la adicción a sustancias como la heroína-morfina, la cocaína, la nicotina y la anfetamina. Método: se consideraron los reportes científicos disponibles en PubMed –de 2005 a abril de 2017–, sobre los fundamentos, la metodología empleada, los estudios preclínicos y clínicos, y los resultados obtenidos en dichas investigaciones para generar vacunas contra las drogas. Resultados: las vacunas lograron mitigar los efectos producidos por las sustancias en los estudios preclínicos en modelos de estudio en animales; sin embargo, con pacientes humanos los resultados no han sido del todo satisfactorios. Discusión y conclusiones a pesar de los esfuerzos realizados por diferentes grupos de investigación y compañías farmacéuticas para generar vacunas terapéuticas contra el uso de diferentes drogas, ninguna ha alcanzado la fase III de estudios clínicos. En la actualidad, se continúa con los esfuerzos para lograr que las vacunas contra las adicciones alcancen su máxima eficiencia y eficacia, y contribuyan al tratamiento de la adicción a las drogas.
... It is possible that lower cocaine doses might have been more susceptible to perturbation by the vaccine; several laboratory studies testing pharmacological interventions in humans have demonstrated reductions in cocaine self-administration when intermediate doses of cocaine were available, whereas higher doses of cocaine were relatively unaffected (e.g., Haney et al., 2006;Rush et al., 2010). We also did not systematically test higher doses of cocaine to see if monkeys would attempt to override the effects of the vaccine which is a valid clinical concern (Haney and Kosten, 2004;Shen et al., 2011), although reacquisition in the two most resistant vaccinated monkeys occurred only when the cocaine dose was doubled. ...
Immunopharmacotherapy offers an approach for treating cocaine abuse by specifically targeting the cocaine molecule and preventing its access to the CNS. dAd5GNE is a novel cocaine vaccine that attenuates the stimulant and the reinforcing effects of cocaine in rats. The goal of this study was to extend and validate dAd5GNE vaccine efficacy in non-human primates. Six experimentally naïve adult female rhesus monkeys (Macaca mulatta) were trained to self-administer 0.1 mg/kg/injection intravenous (i.v.) cocaine or receive candy; then 4 monkeys were administered the vaccine and 2 monkeys were administered vehicle intramuscularly, with additional vaccine boosts throughout the study. The reinforcing effects of cocaine were measured during self-administration, extinction, and reacquisition (relapse) phases. Serum antibody titers in the vaccinated monkeys remained high throughout the study. There was no change in the preference for cocaine over candy over a 20-week period in 5 of the 6 monkeys; only one of the 4 (25%) vaccinated monkeys showed a decrease in cocaine choice. All 6 monkeys extinguished responding for cocaine during saline extinction testing; vaccinated monkeys tended to take longer to extinguish responding than control monkeys (17.5 vs. 7.0 sessions). Vaccination substantially retarded reacquisition of cocaine self-administration; control monkeys resumed cocaine self-administration within 6–41 sessions and 1 vaccinated monkey resumed cocaine self-administration in 19 sessions. The other 3 vaccinated monkeys required between 57 and 94 sessions to resume cocaine self-administration even in the context of employing several manipulations to encourage cocaine reacquisition. These data suggest that the dAdGNE vaccine may have therapeutic potential for humans who achieve cocaine abstinence as part of a relapse prevention strategy.
... Currently, anti-drug vaccines are being studied for cocaine, nicotine, methamphetamine and heroin (Shen et al., 2011). The most advanced vaccines address cocaine and nicotine dependence, and have proved to be effective in helping patients to remain abstinent. ...
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Methiopropamine use in Europe has been detected since January 2011, but there is limited information on its acute toxicity. Here, we describe a case of analytically confirmed methiopropamine acute toxicity. A 27-year-old woman with no previous medical history was brought to the emergency department with palpitations, chest tightness, anxiety, nausea, vomiting and visual hallucinations following the use of a 'Quicksilver'. Toxicological analysis of her urine collected at presentation to the ED detected methiopropamine at a concentration of 400 ng/mL. Other drugs were also detected but at a much lower concentration. This is the first ever case report of analytically confirmed acute toxicity related to methiopropamine use. It confirms the potential for significant acute toxicity with cardiovascular, gastrointestinal and psychotic symptoms thus providing further information to help with managing these patients and allow legislative authorities to consider the need for its control.
... These antibodies can block illicit drugs from reaching the brain and therefore, reduce the morbidity and mortality associated with illicit drug intoxication [123]. Clinical trials are currently in progress to study this new intervention for treatment of stimulant addiction [124]. This new approach in still under investigation and has not been approved by the FDA at present time. ...
In this review the reader will be updated about the most recent guidelines for treatment of opioid abuse and dependence. The first phase of treatment which is managing the opioid withdrawal syndrome and detoxification will be described in details. The opioid agonist maintenance treatment with either methadone or buprenorphine for patients who fail abstinent based models will be elaborated. Opioid antagonists like naltrexone maintenance which are another form of treatment for patients who do not qualify for or desire opioid agonist maintenance treatment will also be elaborated. Treatment of special populations such as adolescents and opioid dependent pregnant women is included in this review. Psychotherapeutic interventions will be discussed with emphasis on contingency management (CM) since it is the most studied intervention in this population. Finally new approaches for treatment will be mentioned briefly.
... These antibodies can block illicit drugs from reaching the brain and therefore, reduce the morbidity and mortality associated with illicit drug intoxication [123]. Clinical trials are currently in progress to study this new intervention for treatment of stimulant addiction [124]. This new approach in still under investigation and has not been approved by the FDA at present time. ...
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Today tobacco use is the single greatest preventable cause of death in the world. Tobacco use is often incorrectly perceived to be solely a personal choice. This is contradicted by the fact that when fully aware of the health impact, most tobacco users want to quit but find it difficult to stop due to the addictiveness of nicotine. Henceforth, Nicotine replacement therapy (NRT) came into existence which temporarily replaces much of the nicotine from tobacco to reduce motivation to consume tobacco and nicotine withdrawal symptoms, thus easing the transition from cigarette smoking to complete abstinence. Various alternative nicotine sources (gum, transdermal patch, nasal spray, inhaler and sublingual tablets/lozenges) have been incorporated into tobacco cessation programs. Recent research is more focusing on rapid delivery of nicotine (Nicotine preloading, true pulmonary inhaler) and immunological approaches (nicotine vaccine) to tackle nicotine dependence. These NRTs are in general well tolerated and have minimal adverse effects.The review aims to summarize literature on various modes of nicotine replacement therapy methods currently used to treat nicotine dependence, and to give an overview about future possible approaches to treat tobacco use disorder.
Addiction to one or more drugs is a chronic and recurrent disease with a very high cost that affects the individual, his family, and his social environment. Drug abuse has rapidly increased all over the world. The drugs used to treat addictions act only temporarily, are expensive, and require correct compliance. Anti-addiction vaccines are a good alternative to the current treatment of addicts, and have as their purpose to decrease the physiological and psychological power of the drug, blocking its passage to the brain. Cocaine is the most problematic drug worldwide. There are 2.5 million addicts in the USA, and in Europe, Spain, and the United Kingdom it tops the list for consumption. Research into anti-cocaine vaccines started in the 1990's, with the first vaccines being tested on laboratory animals in 1994. The precursor of the current vaccine was prepared by conjugating succinyl cocaine with bovine serum albumin, and subsequently conjugated to the toxin B subunit from Vibrio cholerae and adding an aluminium adjuvant. This vaccine, called TA-CD, has been tested successfully, first in animals and then in humans, gradually perfecting its composition, initial doses and strength, with promising results. The results of a large clinical trial in cocaine addicts are awaited and, if appropriate, its approval by the FDA and European Agencies.
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Abstinent drug users often report that taking even a small amount of their previously abused drug increases their desire for the drug and can lead to a full relapse. This apparent "priming" effect of drugs has been studied in both laboratory animals and humans. In animals trained to self-administer drugs, small amounts of a previously self-administered drug readily reinstate responding. In humans, administration of a previously abused drug increases self-reported craving and desire for the drug. Priming effects also occur with other reinforcers (e.g., presentation of a food stimulus increases food-reinforced responding). This article examines the generality of priming phenomena, and it examines some of the learned or unlearned processes that underlie the effect. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
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Tobacco dependence is a chronic disease that often requires repeated interventions and multiple attempts to quit. To date, three medications are FDA-approved for smoking cessation: nicotine replacement therapy, sustained-release bupropion, and varenicline. These treatments are effective across a broad range of populations, and are recommended for all smokers, including those with psychiatric or addictive comorbidity. Less is known however concerning the benefit-risk profile of these medications in pregnant women and adolescents. With these limitations in mind, clinicians should encourage and offer counseling and a prescription of pharmacotherapy to every patient willing to make a quit attempt. Despite the relative efficacy of first-line medications, many smokers relapse after one given quit attempt, and alternative pharmacotherapies are needed. Clonidine and nortriptyline have been proposed as second-line medications. In addition, this review indentifies a series of promising drugs that hopefully will be available to complete our current armory.
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NicVAX, a nicotine vaccine (3'AmNic-rEPA), has been clinically evaluated to determine whether higher antibody (Ab) concentrations are associated with higher smoking abstinence rates and whether dosages and frequency of administration are associated with increased Ab response. This randomized, double-blinded, placebo-controlled multicenter clinical trial (N = 301 smokers) tested the results of 200- and 400-µg doses administered four or five times over a period of 6 months, as compared with placebo. 3'AmNic-rEPA recipients with the highest serum antinicotine Ab response (top 30% by area under the curve (AUC)) were significantly more likely than the placebo recipients (24.6% vs. 12.0%, P = 0.024, odds ratio (OR) = 2.69, 95% confidence interval (CI), 1.14-6.37) to attain 8 weeks of continuous abstinence from weeks 19 through 26. The five-injection, 400-µg dose regimen elicited the greatest Ab response and resulted in significantly higher abstinence rates than placebo. This study demonstrates, as proof of concept, that 3'AmNic-rEPA elicits Abs to nicotine and is associated with higher continuous abstinence rates (CAR). Its further development as a treatment for nicotine dependence is therefore justified.
textbook with separate chapters devoted to cocaine, naturally occurring stimulants, synthetic stimulants, hallucinnogens, narcotics, anabolic sterroids, diassociatieve anesthetics, solvent abute and marijuna. Also includes detailed information on the origin, history, and production techniques used to make these, with a detailed discussion of new synthetic cannabinoids and cathinones
These studies examined the effects of a high-affinity anti-(+)-methamphetamine monoclonal antibody (mAb; KD = 11 nM) on (+)-methamphetamine [(+)-METH] and (+)-amphetamine [(+)-AMP] serum and tissue disposition and serum protein binding following i.v. (+)-METH administration. Male Sprague-Dawley rats were pretreated with a buffer solution (control rats) or with anti-(+)-METH mAb [equimolar in binding sites to the (+)-METH dose]. The next day, both groups received a 1 mg/kg i.v. (+)-METH dose. At various time points after (+)-METH administration, rats were sacrificed (n = 3 per time point), and serum and tissues were collected. (+)-METH serum protein binding was increased from approximately 5% in controls to approximately 88 to 99% in the mAb-treated rats. The (+)-METH area under the concentration versus time curves from 0 to 4.5 h (AUC0-4.5 h) in mAb-treated rats showed an increase of >6600% for serum and a decrease of >60% for brain, compared with buffer-treated controls. Differential effects of anti-METH mAb on (+)-METH concentrations were observed in other tissues. For example, in the liver, anti-(+)-METH mAb caused significant increases in (+)-METH concentrations. The AUC0-4.5 h for (+)-AMP, a pharmacologically active metabolite, was decreased by approximately 50% in all tissues examined. These data show that pretreatment with an anti-(+)-METH mAb can significantly alter the disposition of (+)-METH and (+)-AMP in rats. Since the mAb has no significant cross-reactivity with (+)-AMP, the data suggest that the mAb reduced (+)-METH metabolic clearance through high-affinity binding to (+)-METH. Finally, rapidly equilibrating tissues, like the brain, appear to be preferentially protected by the mAb.
We consider the long-run odds that narcotics users remain abstinent after methadone treatment. A flexible split-hazard specification that allows for individual-level differences in both the long-run probability of eventual relapse and the short-run timing of relapse is developed. The model is applied to a comprehensive data set involving individual drug abuse and treatment histories for over 800 addicts. Our findings indicate (1) that the short-run success of methadone programs does not automatically translate into long-run abstinence, which suggests the need for aftercare, (2) the value of preventing a teenager or young adult from initiating, and (3) the possibility of identifying high-risk groups, both in terms of age of first daily use and in terms of ethnicity.
Heroin addiction is a wide-reaching problem with a spectrum of damaging social consequences. A vaccine capable of blocking heroin's effects could provide a long-lasting and sustainable adjunct to heroin addiction therapy. Heroin, however, presents a particularly challenging immunotherapeutic target, as it is metabolized to multiple psychoactive molecules. To reconcile this dilemma, we examined the idea of a singular vaccine with the potential to display multiple drug-like antigens; thus two haptens were synthesized, one heroin-like and another morphine-like in chemical structure. A key feature in this approach is that immunopresentation with the heroin-like hapten is thought to be immunochemically dynamic such that multiple haptens are simultaneously presented to the immune system. We demonstrate the significance of this approach through the extremely rapid generation of robust polyclonal antibody titers with remarkable specificity. Importantly, both the antinociceptive effects of heroin and acquisition of heroin self-administration were blocked in rats vaccinated using the heroin-like hapten.
(+)-Methamphetamine (METH) use and addiction has grown at alarming rates over the past two decades, while no approved pharmacotherapy exists for its treatment. Immunopharmacotherapy has the potential to offer relief through producing highly specific antibodies that prevent drug penetration across the blood-brain barrier thus decreasing reinforcement of the behavior. Current immunotherapy efforts against methamphetamine have focused on a single hapten structure, namely linker attachment at the aromatic ring of the METH molecule. Hapten design is largely responsible for immune recognition, as it affects presentation of the target antigen and thus the quality of the response. In the current paper we report the systematic generation of a series of haptens designed to target the most stable conformations of methamphetamine as determined by molecular modeling. On the basis of our previous studies with nicotine, we show that introduction of strategic molecular constraint is able to maximize immune recognition of the target structure as evidenced by higher antibody affinity. Vaccination of GIX(+) mice with six unique METH immunoconjugates resulted in high antibody titers for three particularly promising formulations (45-108 μg/mL, after the second immunization) and high affinity (82, 130, and 169 nM for MH2, MH6, and MH7 hapten-based vaccines, respectively). These findings represent a unique approach to the design of new vaccines against methamphetamine abuse.
To describe the rationale of vaccines against cocaine and nicotine, to review progress in developing and trialing vaccines to treat dependence on these drugs and to discuss some of the ethical issues that may arise from their use in legally coerced addiction treatment or for prevention of addiction in adolescents. Several randomized controlled trials of cocaine and nicotine vaccines for relapse prevention have produced mixed results. The studies demonstrate that it is possible to raise antibodies to cocaine and nicotine in humans. In abstinent patients who show high levels of drug antibodies, the rewarding effects of these drugs are attenuated. Phase 2 trials have not found nicotine vaccines to be superior to placebo because only a third of those vaccinated develop sufficient levels of antibody to block the effects of nicotine. Vaccines are a novel approach to relapse prevention that need to more reliably induce immunity in a larger proportion of vaccinated patients if they are to protect against relapse after achieving abstinence. Vaccines are unlikely to prevent addiction in adolescents. Their use under legal coercion should only be considered after considerable experience with their use in voluntary patients.
Background: Research on the clinical application of oral naltrexone agrees on several things. From a pharmacological perspective, naltrexone works. From an applied perspective, however, the medication compliance and the retention rates are very poor. Objectives: To evaluate the effects of naltrexone maintenance treatment versus placebo or other treatments in preventing relapse in opioid addicts after detoxification. Search strategy: We searched the Cochrane Central Register of Controlled Trials (CENTRAL - The Cochrane Library issue 6 2010), PubMed (1973- June 2010), CINAHL (1982- June 2010). We inspected reference lists of relevant articles and we contacted pharmaceutical producers of naltrexone, authors and other Cochrane review groups. Selection criteria: All randomised and controlled clinical trials which focus on the use of naltrexone maintenance treatment versus placebo, or other treatments to reach sustained abstinence from opiate drugs Data collection and analysis: Three reviewers independently assessed studies for inclusion and extracted data. One reviewer carried out the qualitative assessments of the methodology of eligible studies using validated checklists. Main results: Thirteen studies, 1158 participants, met the criteria for inclusion in this review.Comparing naltrexone versus placebo or no pharmacological treatments, no statistically significant difference were noted for all the primary outcomes considered. The only outcome statistically significant in favour of naltrexone is re incarceration, RR 0.47 (95%CI 0.26-0.84), but results come only from two studies.Comparing naltrexone versus psychotherapy, in the two considered outcomes, no statistically significant difference was found in the single study considered.Naltrexone was not superior to benzodiazepines and to buprenorphine for retention and abstinence and side effects. Results come from single studies. Authors' conclusions: The findings of this review suggest that oral naltrexone did not perform better than treatment with placebo or no pharmacological agent with respect to the number of participants re-incarcerated during the study period. If oral naltrexone is compared with other pharmacological treatments such as benzodiazepine and buprenorphine, no statistically significant difference was found. The percentage of people retained in treatment in the included studies is however low (28%). The conclusion of this review is that the studies conducted have not allowed an adequate evaluation of oral naltrexone treatment in the field of opioid dependence. Consequently, maintenance therapy with naltrexone cannot yet be considered a treatment which has been scientifically proved to be superior to other kinds of treatment.