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Ketamine is a dissociative anesthetic that acts on the central nervous system by antagonizing the n-methyl-d-aspartate (NMDA) receptors. It is a rapid acting anti-depressant, but there is a lot more attention being paid to it’s efficacy in alcohol and drug abuse treatment.

Ketamine has been shown in some studies to prolong abstinence from alcohol and drug use disorders. It also has been found to reduce cocaine craving and self-administration in untreated patients.

The mechanisms by which this works has been through the disruption of relevant neural networks which blocks reconciliation of drug-related memories, neuroplasticity and neurogenesis, and enhancing psychological therapy.

We know that addiction is a chronic relapsing disorder with cravings, drug seeking, and unpleasant withdrawal symptoms upon cessation of the drug. Relapse rates with current therapies are between 40-80%.

Pre-clinical research on Ketamine has shown effectiveness in alcohol intake in a rat model:

Alcohol-preferring rats could self-administer
0.08% weight/volume saccharin, 10% weight/volume ethanol or
water. After intraperitoneal administration of either ketamine or
memantine, operant responding and motor activity were assessed.
A dose of 20 mg/kg of ketamine reduced ethanol administration
significantly (33.3% less than vehicle-treated rats) without affecting
motor activity and water consumption. Importantly, coadministration
of rapamycin blocked ketamine-mediated reduction
of alcohol intake, but not that of memantine (Sabino et al.,
2013). Similarly, ketamine’s antidepressant effects are suppressed
by rapamycin. mTOR activation is required for the anti-alcohol effect of ketamine, but not memantine, in alcohol-preferring rats

Also:

Both ketamine and NBQX attenuate alcohol drinking in male Wistar rats.

The devastating consequences of alcohol-use disorder (AUD) on the individual and the society are well established. Current treatments of AUD encompass various strategies, all of which have only modest effectiveness. Hence, there is a critical need to develop more efficacious therapies. Recently, specific glutamatergic receptors have been identified as potential novel targets for intervention in AUD. Thus, the current study was designed to evaluate the effects of acute administration of sub-anesthetic doses of ketamine, an NMDA receptor antagonist, as well as NBQX, an AMPA/kainate receptor antagonist on alcohol intake and its possible behavioural consequences. Adult male Wistar rats were trained in drinking in dark paradigm (3 weeks), and following stable alcohol intake, ketamine, NBQX as well as their combination were injected prior to a 90 min drinking session. In addition to alcohol intake, sucrose preference (overnight), and locomotor activity and forced swim test (FST) were also evaluated before and following alcohol intake. Both doses of ketamine (5 and 10 mg/kg) and NBQX (5 and 10 mg/kg) significantly attenuated percent alcohol intake. The combination of the higher dose of ketamine and NBQX, however, did not significantly affect percent alcohol intake. Moreover, animals exposed to alcohol showed decreased sucrose intake (reflective of anhedonia), decreased locomotor activity and swimming in the FST (reflective of helplessness), that were not affected by ketamine and/or NBQX. These results suggest that selective antagonism of the NMDA or AMPA/kainate receptors may be of therapeutic potential in AUD.

Addiction is characterised by disruptions in learning and memory. Addicts develop cue-specific responses to drug-related
cues. One preclinical study examined the effects of ketamine administration on reconsolidation
where memories are rendered more labile following reactivation. After morphine CPP ( conditioned place preference) was induced, rats were intraperitoneally administered 60 mg/kg of ketamine after being reexposed to the conditioned context or while they were in their home cages. After ketamine administration, preference for morphine decreased significantly in the first retest.  This has been interpreted as evidence that ketamine successfully disrupted reconsolidation of the environment-drug memory.

Effects of scopolamine and ketamine on reconsolidation of morphine conditioned place preference in rats

Persistent memory associated with addictive drugs contributes to the relapse of drug abuse. The current study was conducted to examine the effects of scopolamine and ketamine on reconsolidation of morphine-induced conditioned place preference (CPP). In experiment 1, after morphine CPP was acquired, rats were injected with ketamine (60 mg/kg, intraperitoneally) and scopolamine (2 mg/kg, intraperitoneally), respectively, after reexposure to an earlier morphine-paired context or in their home cages. The CPP was reassessed 24 and 48 h after reexposure. An additional group of rats received saline following reexposure to the earlier morphine-paired context. In experiment 2, two groups of rats were only given saline during the CPP training and subsequent administration of ketamine or scopolamine during the reexposure. In experiment 1, rats failed to exhibit morphine CPP when ketamine and scopolamine were administered only after reexposure to a morphine-paired context. CPP was not abolished by ketamine or scopolamine administration in the animals’ home cages. Also, the animals receiving only saline injections showed strong morphine CPP 24 h after a short exposure to the morphine-paired context. In experiment 2, ketamine or scopolamine treatment alone did not induce CPP or aversion. Administration of scopolamine and ketamine, after reexposure to a drug-paired context, resulted in the disruption of morphine CPP, suggesting the potential effects of scopolamine and ketamine in disrupting memory associated with environmental cues and addictive drugs.

The capacity of ketamine to treat addiction was not investigated scientifically until decades later when Krupitsky and
Grinenko (1997), published work that reported the use of ketamineto reduce relapse in recently detoxified alcoholics. These
published results were a review of 10 years of previous research.The procedure that was investigated was referred to as Ketamine Psychedelic Therapy (KPT) and had been applied since the mid-80sin the former Soviet Union, until ketamine was banned in Russia 1998.  Ten Year Study of Ketamine Psychedelic Therapy (KPT) of Alcohol Dependence [

KPT consisted of three stages. The first step was the preparation,during which patients underwent a preliminary psychotherapy session where a psychotherapist discussed with them the content of the psychedelic experience. They were told that under the influence of ketamine, they would view the world symbolically, realise about the negative aspects of alcohol dependence and see the positive sides of sobriety. They were also told that they would become aware of unconscious mental concepts about the negative aspects of their addiction, such as their personal problems and their self-identity. These insights would help them to accept new life values, purposes and meaning of life and in turn e to overcome
their alcoholism. The second stage was the ketamine session in which ketamine was intramuscularly injected and the psychotherapist interacted with the patient. The psychotherapist verbally guided the patient, with the aim of creating new meaning and purpose in life. At moments of highly intense psychedelic experience, the smell of alcohol was introduced to the individuals. The idea was to enhance the negative emotional valence of the thoughts related to alcohol during the session. Finally, group psychotherapy was performed after the session. The aim of this session was to help patients integrate
insights of psychedelic experience into their lives. It is reported that this procedure was used in
over 1000 alcoholics with no reported complications.In Krupitsky and Grinenko, 1997 report, relapse rates in a group
of recently detoxified alcohol dependent patients undergoing KPT (n ¼ 111) were compared with another group of alcohol dependent patients who were treated with treatment as usual (n ¼ 100). Both groups underwent alcohol detoxification before treatment. After these sessions, the KPT group received an intramuscular injection of ketamine (2.5 mg/kg) along with the corresponding preparation. The control group received ‘conventional, standard methods of treatment’ in the same hospital. Only 24% of the control group remained abstinent after a year, whereas 66% of the KPT group did not relapse during the same period (p < .01).

In a further study, 70 detoxified heroin-dependent patients were randomised into two KPT groups, who were injected different doses of ketamine, in a double-blind manner (Krupitsky et al., 2002). One group (n ¼ 35) received 0.2 mg/kg i.m. of ketamine, which was considered an active placebo, whereas the experimental group (n ¼ 35) received 2.0 mg/kg i.m. After two years, the higher dose of ketamine resulted in a greater rate of abstinence (17% vs 2% abstinent subjects, p < .05). Additionally, the experimental group had a larger positive change in nonverbal unconscious emotional attitudes and a greater and longer-lasting reduction in craving for heroin. The authors therefore concluded that effectiveness of ketamine
was dose dependent. Ketamine psychotherapy for heroin addiction: immediate effects and two-year follow-up

In 2007, Krupitsky’s lab compared the impact of a single vs three KPT sessions (dose: 2.0 mg/kg, i.m.) (Krupitsky et al., 2007). Fifty nine detoxified heroin dependent patients first received a KPT session. After this, 6 participants relapsed and abandoned the treatment. The remaining participants were randomised into two groups: one received a further two KPT sessions (n ¼ 26) in monthly intervals, whereas the other underwent two counseling sessions (n ¼ 27) also in monthly intervals. After a year, 50% in the 3-session KPT group remained abstinent compared to 22% in the single KPT (p < .05) (Krupitsky et al., 2007). This clearly demonstrates the superior efficacy of three KPT sessions in comparison to
one KPT session, which indicates that the KPT sessions are beneficial.  Single Versus Repeated Sessions of Ketamine-Assisted Psychotherapy for People with Heroin Dependence 

In a private psychiatric practice in the US, another psychiatrist has successfully conducted KPT since 1994. He has not only treated patients with drug addiction, but also individuals with other types of addictions (e.g. food addiction) and other psychological disorders. His reported anecdotal, clinical findings are positive, having adhered strictly to the original protocol.  Ketamine Enhanced Psychotherapy: Preliminary Clinical Observations on Its Effectiveness in Treating Alcoholism. Kolp, Eli,Friedman, Harris L.,Young, M. Scott,Krupitsky, Evgeny The Humanistic Psychologist, Vol 34(4), 2006, 399-422

Abstract:

Ketamine is a dissociative anesthetic widely used by physicians in the United States and also a psychedelic drug that physicians can legally prescribe off-label within the United States for other therapeutic purposes. It has been used in Russia and elsewhere to successfully treat alcoholism and other psychological or psychiatric problems, but has not been researched for this purpose in the United States. Results of a series of clinical trials using ketamine for treating alcoholism in the United States are retrospectively reported, along with 2 case studies of how psychotherapy facilitated by this substance helped two individuals achieve abstinence through ketamine’s transpersonal effects. Considering the massive problems caused by alcoholism, the need to begin formal research studies on ketamine psychotherapy for alcoholism is emphasized.

In 2014, 8 cocaine dependent males disinterested in treatment received 3 infusions in a double-blind, cross-over design: 0.41 mg/ kg ketamine, 0.71 mg/kg ketamine, and 2 mg lorazepam (an active benzodiazepine control, which induces mild subjective and anxiolytic effects) (Dakwar et al., 2014b). Infusions lasted 52 min and were separated by 48 h. Before and after each infusion, motivation to quit cocaine and cue-induced craving were assessed. Relative to the lorazepam, motivation to quit cocaine was enhanced and cueinduced craving for cocaine was reduced by the 0.4 mg/kg ketamine (both ps ¼ 0.012), and this latter effect was augmented by the 0.71 mg/kg ketamine dose. During the psychedelic experience,
dissociation and mystical-type effects were assessed. As predicted, the higher dose of ketamine led to greater mystical experiences. Strikingly, these mystical-type experiences, but not the dissociative effects, were found to mediate motivation to quit. However, the small non-treatment-seeking sample, the absence of an inactive placebo and the cross-over design, limit the results.Having said that, the participants showed a significant reduction in the frequency and amount of cocaine
consumed in normal life in the 4 weeks following the experiment, compared to baseline. Dakwar, E., Levin, F., Foltin, R.W., Nunes, E.V., Hart, C.L., 2014b. The effects of subanesthetic ketamine infusions on motivation to quit and cue-induced craving in cocaine-dependent research volunteers. Biol. Psychiatry 76, 40e46. https://doi. org/10.1016/j.biopsych.2013.08.009.

Also, more cocaine research from the same group is here:

Cocaine self-administration disrupted by the N-methyl-D-aspartate receptor antagonist ketamine: a randomized, crossover trial E DakwarMolecular Psychiatry volume22pages76–81 (2017) |

Abstract:

Repeated drug consumption may progress to problematic use by triggering neuroplastic adaptations that attenuate sensitivity to natural rewards while increasing reactivity to craving and drug cues. Converging evidence suggests a single sub-anesthetic dose of the N-methyl-D-aspartate receptor antagonist ketamine may work to correct these neuroadaptations and restore motivation for non-drug rewards. Using an established laboratory model aimed at evaluating behavioral shifts in the salience of cocaine now vs money later, we found that ketamine, as compared to the control, significantly decreased cocaine self-administration by 67% relative to baseline at greater than 24 h post-infusion, the most robust reduction observed to date in human cocaine users and the first to involve mechanisms other than stimulant or dopamine agonist effects. These findings signal new directions in medication development for substance use disorders.

Neural plasticity is defined as the cellular and structural reorganisation
of the brain. Synaptogenesis is a crucial mechanism for
plasticity, since for change to happen within brain circuitry new
synapses between neurons must be formed. Surface expression of
AMPARs and upregulation of other synaptic proteins are involved in
the process of synaptogenesis. Diminished glutamatergic synaptic
transmission and reduced plasticity are thought to be associated
with addiction. Existing models suggest that ketamine’s blockade of NMDA receptors
increases synaptogenesis by stimulating protein synthesis
and the insertion of AMPA receptors. Hence, ketamine’s
effects help to reverse the glutamatergic changes associated
with depression and addiction. 

Animal models of addiction, depression and other psychiatric disorders
have been linked to a reduction in adult neurogenesis . It has been suggested that in addiction
the loss of neurogenesis, especially in cortical and hippocampal
regions, may contribute to levels of self-administration and the
vulnerability of relapsing. The reduction of neurogenesis in addiction is supported in
humans by the reduction in BDNF serum levels. In a study, 37
subjects with diagnosis of alcohol dependence showed significantly
reduced BDNF serum levels compared to healthy individuals
. Similarly, cocaine- and heroin-dependentpatients have significantly lower serum BDNF levels and these
seem to recover during withdrawal. Rapid and transient up-regulation of the neuroplasticity marker
BDNF is implicated as a critical component of the antidepressant
mechanism of ketamine . BDNF knock-out mice do not show anti-depressant response to
ketamine in animal models of depression.

Recent research has
demonstrated that ketamine increases peripheral plasma BDNF in
depressed people who respond to treatment but not in treatment
non-responders or patients receiving an active placebo. These BDNF increases in depressed people given ketamine
are robustly correlated with the drug’s antidepressant effects.

It has been found there is a dispersion in normal brain connectivity and the disruption of the usual pattern of communication  in depression and addictions. . The integrity of functional networks decreased, being the
change maximal in functional hubs such as the thalamus, putamen
and high-level association cortices. In particular, connectivity
within the Default Mode Network was reduced between the posterior
cingulate cortex and the mPFC .
The connectivity between the parahippocampal and the retrosplenial
cortex also decreased as well as the segregation between
other major functional networks such as the salience, attention and
different visual networks Infusions of ketamine have shown to decrease connectivity
between and within resting-state consciousness networks.
Connectivity between the mPFC and the rest of the Default
Mode Network (via the posterior cingulate cortex) has been found
to be reduced, along with the integrity and activity of the salience
and visual networks are also affected. Since it is known
that connectivity with the mPFC is elevated in depression , the reduction of connectivity in the Default Mode
Network observed during the psychedelic experience might be a
mechanism that helps treat depressive states, which are very
common in addicts and predictive of relapse.

Given addiction is highly co-morbid with depression   and ketamine’s role within psychiatry changed
dramatically when it was discovered to be an anti-depressant, we
now briefly describe the research concerning ketamine and
depression. In 2000, the first clinical trial hinted at the potential of
ketamine as a treatment for depression. Four subjects diagnosed
with depression were intravenously administered 0.5 mg/kg of
ketamine in a randomised, double-blind design. The results were
compared to the injection of saline solutions in 3 subjects with an
equivalent diagnosis. Comparison on the Hamilton Rating Scale for
Depression (HAM-D) showed moderate evidence for a greater
reduction in scores after ketamine infusion compared to saline
(Berman et al., 2000). The reduction was rapid and outlasted the
subjective effects of ketamine, lasting for 3 days after infusion.
Despite the small sample size and the limited follow-up, this result
and anti-depressant effects observed in animal models of depression
encouraged researchers in the field to perform more studies in humans . Since then, over 30 studies have
examined the antidepressants effects of ketamine in patients with
treatment-resistant major depressive and bipolar disorders.

Ketamine has shown a 65-70% response rate in treating
depression within 24 h, which contrasts with the ~47% response
rate of conventional monoaminergic antidepressants after weeks
or months . Furthermore,
ketamine’s antidepressant actions are almost immediate and last
for approximately a week ,
whereas conventional antidepressive medications take weeks to
have an effect, are given daily and most of them fail to exert long lasting
effects . Furthermore, studies
have consistently shown that after a ketamine infusion there is a
significant reduction in suicidal ideation which also lasts for several
days.Depression and addiction’s co-expression is almost ubiquitous
People with alcohol, opioids, cannabis and
cocaine use disorders show notably higher rates of depression than
the average of the general population. Furthermore, high levels of depression and anxiety
may predispose relapse to: heroin, alcohol, cannabis and cocaine.

Memories and their creation and alteration is felt to be at the heart of cues and triggers and relapse in addiction. Once consolidated, memories are thought to be stored in a
stabilised state after initial acquisition. Shortly after reactivation
(i.e. remembered) of consolidated memories, these are rendered
transiently unstable and labile, before they then re-stabilise. This
process has been named reconsolidation . After reconsolidation,
the memories are stored again, but they may have been slightly
altered or updated. Each time memories are reactivated the latest
version is retrieved and they are again susceptible to change. During reconsolidation memories may be vulnerable to
manipulation and disruption. This was first demonstrated in animals
using fear conditioning. Rodents were trained to associate a
neutral stimulus with a shock such that the neutral stimulus elicited
a fear response. Researchers eliminated this fear response by
pharmacologically disrupting the reconsolidation process . Reward memories can also be disrupted such that a
neutral stimulus that once elicited appetitive behaviour no longer
does so. Therefore, non-pharmacological and drug therapies that
aim at weakening drug-cue memories via manipulation of reconsolidation
are of interest. Preclinical studies have shown that ketamine affects reconsolidation
of drug memories. . A recent review has suggested that ketamine (along with other psychedelics)
may be able to disrupt maladaptive appetitive memories
(Fattore et al., 2017).  Psychedelics and reconsolidation of traumatic and appetitive maladaptive memories: focus on cannabinoids and ketamine

Article ABSTRACT:

Rationale

Clinical data with 3,4-methylenedioxymethamphetamine (MDMA) in post-traumatic stress disorder (PTSD) patients recently stimulated interest on the potential therapeutic use of psychedelics in disorders characterized by maladaptive memories, including substance use disorders (SUD). The rationale for the use of MDMA in PTSD and SUD is being extended to a broader beneficial “psychedelic effect,” which is supporting further clinical investigations, in spite of the lack of mechanistic hypothesis. Considering that the retrieval of emotional memories reactivates specific brain mechanisms vulnerable to inhibition, interference, or strengthening (i.e., the reconsolidation process), it was proposed that the ability to retrieve and change these maladaptive memories might be a novel intervention for PTSD and SUD. The mechanisms underlying MDMA effects indicate memory reconsolidation modulation as a hypothetical process underlying its efficacy.

Objective

Mechanistic and clinical studies with other two classes of psychedelic substances, namely cannabinoids and ketamine, are providing data in support of a potential use in PTSD and SUD based on the modulation of traumatic and appetitive memory reconsolidation, respectively. Here, we review preclinical and clinical data on cannabinoids and ketamine effects on biobehavioral processes related to the reconsolidation of maladaptive memories.

Results

We report the findings supporting (or not) the working hypothesis linking the potential therapeutic effect of these substances to the underlying reconsolidation process. We also proposed possible approaches for testing the use of these two classes of drugs within the current paradigm of reconsolidation memory inhibition.

Furthermore, a meta-analysis of pre-clinical
studies found evidence suggesting that NMDAR antagonists can
be used to target reward memory reconsolidation, and more successfully
than adrenergic antagonists such as propranolol (Das
et al., 2013)  Das, R.K., Freeman, T.P., Kamboj, S.K., 2013. The effects of N-methyl d-aspartate and B-adrenergic receptor antagonists on the reconsolidation of reward memory: a meta-analysis. Neurosci. Biobehav. Rev. 37, 240-255.:

Abstract

Pharmacological memory reconsolidation blockade provides a potential mechanism for ameliorating the maladaptive reward memories underlying relapse in addiction. Two of the most promising classes of drug that interfere with reconsolidation and have translational potential for human use are N-methyl-d-aspartate receptor (NMDAR) and B-Adrenergic receptor (B-AR) antagonists. We used meta-analysis and meta-regression to assess the effects of these drugs on the reconsolidation of reward memory in preclinical models of addiction. Pharmacokinetic, mnemonic and methodological factors were assessed for their moderating impact on effect sizes. An analysis of 52 independent effect sizes (NMDAR = 30, B-AR = 22) found robust effects of both classes of drug on memory reconsolidation, but a far greater overall effect of NMDAR antagonism than B-AR antagonism. Significant moderating effects of drug dose, relapse process and primary reinforcer were found. The findings suggest that reward memory reconsolidation can be robustly targeted by NMDAR antagonists and to a lesser extent, by B-AR antagonists. Implications for future clinical work are discussed.

Highlights

► Meta-analysis of NMDAR and B-adrenergic antagonists in preclinical reward reconsolidation. ► Larger effects of NMDAR (r = .613) than B-adrenergic (r = .24) antagonists were found. ► ‘Relapse process’, trace type, reinforcer and drug dose moderated effect sizes. ► NMDAR antagonists particularly might be of clinical use in treating addiction.

 

.

                                 Mystical experiences and psychedelic effects

Mystical experiences and psychedelic effects provoked by
classic psychedelic drugs have been shown to be psychologically
beneficial in long-term studies.They have not only been linked with positive
outcomes in various treatments, but also to ‘life-changing’,
‘spiritually meaningful’ and ‘eye opening’ events.In the ketamine studies described
above, anecdotal and qualitative reports suggest that the subjective
psychedelic experience seemed to help patients. For example, to
help them: undergo a cathartic process, improve relationships with
the world and other people, maintain positive psychological
changes and enhance self-awareness and personal growth.During KPT, patients reported a feeling of ‘resolution’ and
‘catharsis’ of some psychological problems, mainly those related to
alcohol. Furthermore, the degree of mystical experience was also
linked to the insight and impact of KPT reported by patients
. Interestingly, the intensity of the negative experiences (experiences associated
with negative emotions, fear and horror) during the
ketamine session was associated with longer remission. This was
blindly and quantitatively assessed by analysing patient’s selfreports.
Moreover, spirituality, self-concept, emotional attitudes
to other people and positive changes in life values and purposes
were improved after the ketamine experience.

Notably, ketamine’s mystical experiences, but not dissociative
effects, were found to mediate ketamine’s increase motivation to
quit 24 h after the infusion in cocaine addicts .
Moreover, consistent with previous studies, it was also observed
that mystical experiences were positively dose-dependent. This
study therefore provides evidence that the mystical experience
induced by ketamine is important in its therapeutic mechanism
. Speculatively, mystical experiences may help
to rapidly shift patients’ mindsets towards the integration and
acceptance of a sober lifestyle.

The acute disruptions of the functional networks, especially the
alterations to the default mode network, are related to the psychedelic
experience. In fact, the degree of network dissolution in
LSD and psilocybin is correlated with the intensity of the psychedelic
experience . The disruption to the default mode network may engender a reduction
in rumination and maladaptive repetitive thoughts. Psychological
therapies for addiction often aim to help the patient consider
different ways of life, especially those without the drug, and a
pharmacological agent such as ketamine which expedites that
process may be useful in treating addiction.

Speculatively, ketamine can
provide a unique mental state during and after acute drug effects
that facilitates and enriches therapeutic experiences, which in turn
may improve efficacy and lengthen treatment effects. Furthermore, synaptogenesis
and neurogenesis are putatively critical in learning new
information . The uptake of psychological therapy may
therefore be facilitated after ketamine infusions due increases in
synaptogenesis and neurogenesis, and thus improved learning of
relapse-reducing strategies, such as those used in relapseprevention
based cognitive behavioural therapy (CBT). In fact, the
idea that neurogenesis and synaptogenesis work synergistically
with psychological therapies is becoming recognised as a new
approach in the treatment of mental disorders . Theoretically, the administration of ketamine (which can
produce a ‘psychedelic’ experience) may open people’s minds so
they are more able to embrace what is presented during therapy as
well as enhancing the uptake of new therapeutic content.

The promise of ketamine in the treatment of addiction is supported
by research with large treatment effect sizes, especially in
comparison to existing treatments. In recently detoxified alcoholics,
ketamine treatment increased one-year abstinence rates in
alcoholics from 24% in the control to 66% in the ketamine group
(Krupitsky and Grinenko, 1997) and reduced cocaine self administration
by 67% relative to baseline in non-treatment
seeking cocaine users (Dakwar et al., 2016). These results clearly
demonstrate profound effects of ketamine administration (with
and without therapy) on drug and alcohol use, of an order of
magnitude which is 2 or 3 times more effective than existing
pharmacotherapies.

Ketamine for the treatment of addiction Evidence and potential mechanisms

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Fentanyl was involved in nearly half of New York’s overdose deaths in 2016. In Baltimore, fentanyl was involved in closer to three-quarters of the 574 overdose deaths in the first nine months of 2017.

Annals article with cocaine and fentanyl induced amnesia

An Unusual Amnestic Syndrome Associated With Combined Fentanyl and Cocaine Use

Uzoma B. Duru, MD; Gauri Pawar, MD; Jed A. Barash, MD; Liv E. Miller, PsyD; Indrani K. Thiruselvam, PhD; Marc W. Haut, PhD

Background: Between 2012 and 2016, a total of 14 persons in Massachusetts with a history of substance use developed an unusual amnestic syndrome that included acute, complete, and bilateral hippocampal lesions on magnetic resonance imaging (1).
Objective: To describe an additional patient whose characteristics may extend our understanding of this syndrome.
Case Report: In May 2017, a 30-year-old man was transferred from a local hospital in his native Maryland to a tertiary medical center in West Virginia for persistent memory impairment. According to family members, the patient had a history of heroin use, was recently discharged from a residential addiction treatment program, and had been abstinent from drugs for more than a month. Now back home, he returned late 1 evening and was difficult to arouse the next morning when his family found him in his room with drug paraphernalia. Because the patient was asking repetitive questions as he became more alert, he was taken to the local hospital.
A serum toxicology screen identified cocaine, but results of a urine toxicology screen were negative. Computed tomography of the brain revealed bilateral, symmetrical hypodensities in the hippocampi and basal ganglia. Serum aspartate and alanine aminotransferase levels were minimally elevated (42 and 50 U/L, respectively). The patient was transferred to the tertiary medical center, where his amnesia was characterized as anterograde. Magnetic resonance imaging of the brain found diffusion-weighted hyperintensities involving all of both hippocampi as well as the fornices, mamillary bodies, and globus pallidus (Figure). Cerebrospinal fluid findings and results of an assay for carbon monoxide in the blood were unrevealing.
FIGURE.

Trace diffusion-weighted imaging findings on brain magnetic resonance imaging. Axial trace diffusion-weighted imaging shows bright signal involving the bilateral hippocampi (panels A through C, arrows), fornices and mamillary bodies (panel B, arrowheads), and globus pallidus (panel C, arrowheads).

Image: L170575ff1_Figure_Trace_diffusion-weighted_imaging_findings_on_brain_magnetic_resonance_imaging

Approximately 80 hours after presumed exposure, confirmatory urine testing was negative for fentanyl but revealed the presence of its metabolite norfentanyl (3.8 ng/mL). The patient had no known history of fentanyl use. Results of serum tests to detect designer opioids and synthetic cannabinoids and urine tests for buprenorphine, tramadol, and the metabolites of synthetic cannabinoids were negative.
Discussion: A man from Virginia who presented with a similar syndrome was evaluated at the same tertiary hospital in September 2015 (2). To our knowledge, these 2 patients constitute the first cluster of this amnestic syndrome to be documented outside of Massachusetts. This wider distribution implies that physicians in other states should be aware of this syndrome when evaluating patients with new-onset amnesia, particularly those with a history of substance use.
The identity of the offending agent is uncertain. Of the 16 patients with this syndrome, 15 had previously used or tested positive for opioids (12). However, none was tested specifically for fentanyl even though this drug is frequently mixed with other opioids and is not usually detected on routine screening (3). Therefore, to our knowledge this report is the first to associate fentanyl with this amnestic syndrome. Although isolated cocaine use has been associated with a similar presentation (4), the history and toxicology results in 8 of the 16 reported patients showed no evidence of cocaine use (12).
When administered to rats, fentanyl may cause acute neuronal degeneration in the hippocampus and affiliated limbic structures in association with hippocampal hypermetabolism (5). These observations suggest that fentanyl and cocaine together potentiate the underlying mechanism of injury, including the potential for both excitotoxic and hypoxic–ischemic processes; such an interaction may also explain some of the lesions identified outside the hippocampus (for example, those in the globus pallidus) in this patient and others.
We believe that clinicians who encounter patients with new-onset amnesia, particularly in the setting of substance use, should consider including in their evaluation diffusion-weighted magnetic resonance imaging of the head, routine toxicology screening, and neurologic consultation. When circumstances are consistent with this syndrome, we also suggest performing toxicology studies that are specific for fentanyl, its metabolites, and its analogues.

References

  1. Barash JA Somerville N DeMaria A Jr Cluster of an unusual amnestic syndrome—Massachusetts, 2012-2016 MMWR Morb Mortal Wkly Rep2017 66 76 9
  2. Massachusetts Department of Public Health. Data brief: an assessment of opioid-related deaths in Massachusetts (2013-2014). Accessed at www.mass.gov/eohhs/docs/dph/stop-addiction/chapter-55-opioid-overdose-study-data-brief-9-15-2016.pdf on 10 September 2017.
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    Test strips could help people who use drugs avoid fentanyl

    Baltimore Sun article regarding Fentanyl test strips

    People who buy heroin on the street don’t get warned that it may contain fentanyl, the potent opioid responsible for most overdose deaths in Maryland and nationwide.

    But a thin strip, akin to a pregnancy test, could quickly and reliably tell them.

    Those are the findings of researchers at Johns Hopkins and Brown universities, who went looking for a scientifically sound way to spot fentanyl in powder or pills so people could protect themselves by avoiding batches or reducing amounts they use. The researchers used a strip meant to test people’s urine for fentanyl.

    “They don’t want to die,” said Susan Sherman, associate professor in the health, behavior and society department at Hopkins’ Bloomberg School of Public Health.

    Public health officials prefer that everyone with a substance use problem get treatment but have pursued stopgap measures such as distribution of the overdose remedy naloxone to stem a growing tide of deaths. In Maryland, 1,705 people who overdosed and died in the first nine months of 2017 had fentanyl in their systems, up 56 percent from a year earlier.

    While the research shows the strips could work, it’s not clear whether they’ll prove useful. Drug users may not embrace them, they might cost too much or fail to identify fentanyl all the time, researchers and advocates say.

    The message from public health departments from Baltimore to New York is that it’s safest to assume every batch contains fentanyl.

    But some advocates already are handing out the strips through official and unofficial channels. The California Department of Public Health distributes them through almost a dozen needle exchange programs across the state. Advocates in New York give them out, while the New York City health department does not but said it was interested in the Hopkins-Brown research.

    For now, Stephanie Buhle, a department spokeswoman, said, “We encourage people who use drugs to take precautions to reduce their risk of overdose, including: carrying naloxone, using with another person, using a small amount to test potency first and not mixing drugs.”

    Fentanyl was involved in nearly half of New York’s overdose deaths in 2016. In Baltimore, fentanyl was involved in closer to three-quarters of the 574 overdose deaths in the first nine months of 2017.

    Baltimore’s health department aggressively distributes naloxone and developed a text system to alert users to places where fentanyl is likely being sold so they could avoid it. Dr. Leana S. Wen, health commissioner, sees potential in deploying strips.

    “In principle we support the idea of drug checking, but in practice it’s a complex issue and the last thing we want is people thinking testing is the answer,” Wen said. “We really need to assume it’s fentanyl. … But testing could amplify the message to take precautions.”

    The department plans to use the strips as they were intended, for urine tests, in a pilot at Mercy Medical Center and the University of Maryland Medical Center Midtown Campus. The department bought 3,500 strips, costing $1 each, to test overdose survivors with strips in the emergency room. It wants to gauge changes in providers’ and users’ behavior if they learn fentanyl was indeed responsible.

    The idea for checking drugs with strips came from a so-called safe injection site in Vancouver, Canada, researchers and advocates believe.

    The Hopkins-Brown study is probably the first to check the strips’ accuracy and adoptability, said the researchers, who partnered with the Bloomberg American Health Initiative’s public health solutions program.

    There are still barriers. This is an “off-label” use of the strips — one not approved by the U.S. Food and Drug Administration. To test a drug for fentanyl, a sample would be mixed with water and the strip would display two stripes for fentanyl and one stripe for none.

    Public health officials could be put in legal jeopardy if users rely on inaccurate results. They also could be handling illegal drugs that they help test.

    Researchers said the strips do appear reliable, outperforming electronic versions by accurately detecting even tiny amounts of the drug, according to the study, which has not yet been submitted for publication in a scientific journal.

    There also seemed to be interest when researchers asked hundreds of users about using strips. Few said they would abandon drugs with fentanyl, but three-quarters said they would change their behavior, such as using less initially.

    Another drawback is that the strips only detect fentanyl and three chemical variations, while law enforcement officials say illegal labs constantly churn out new formulations. Strips also can’t detect other dangerous substances.

    The researchers hope to spur some pilot projects in cities around the country to assess the strips’ usefulness.

    Tino Fuentes, a former heroin users turned advocate and consultant, believes they will become widely used. After he began buying strips about a year ago and handing them out in the New York area, he began getting calls from people requesting more.

    He said people tell him they are fearful of fentanyl, though he said a small number seek it for a stronger high. He does bring up treatment with those who are receptive but said for now most just want to avoid overdose.

    “This is not a solution to the problem and will not stop drug use, but what they will do is help change user patterns and keep people alive,” Fuentes said. “Overdoses are getting more frequent, so we need new thinking of ways to stop them. Anything to keep them alive.”

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Cocaine use disorder has been difficult to treat.Certainly motivational enhancement therapy works to a degree, but few pharmcotherapies have been productive. An article in the American Journal of Addiction in December 2017 demonstrated the use of Sertraline to help in cocaine use disorder. The net effect of the study showed that 200 mg a day given to patients with some depressive symptoms and two weeks of abstinence had a decreased relapse rate of almost TWISE.

Bashiri M et al. Moderators of response to sertraline versus placebo among recently abstinent, cocaine dependent patients: A retrospective analysis of two clinical trials. Am J Addict 2017 Dec; 26:807. (http://dx.doi.org/10.1111/ajad.12635)

Those most likely to benefit are OLDER people and alcoholics.

Higher risk of relapse with cocaine used disorder: Current alcoholics, older age, male, lower depressive ratings.

Abstract

AIMS:

Whether the selective serotonin re-uptake inhibitor sertraline at 200 mg/day delays relapse in recently abstinent cocaine-dependent individuals.

DESIGN:

The study involved a 12-week, double-blind, placebo-controlled clinical trial with 2-week residential stay followed by 10-week out-patient participation.

SETTING:

Veterans Affairs residential unit and out-patient treatment research program.

PARTICIPANTS:

Cocaine-dependent volunteers (n = 86) with depressive symptoms (Hamilton score > 15), but otherwise no major psychiatric or medical disorder or contraindication to sertraline.

MEASUREMENTS:

Participants were housed on a drug-free residential unit (weeks 1-2) and randomized to receive sertraline or placebo. Participants then participated on an out-patient basis during weeks 3-12 while continuing to receive study medication. Patients participated in a day substance abuse/day treatment program during weeks 1-3 and underwent weekly cognitive behavioral therapy during weeks 4-12. The primary outcome measure was thrice-weekly urine results and the secondary measure was Hamilton Depression scores.

FINDINGS:

Pre-hoc analyses were performed on those who participated beyond week 2. Generally, no group differences in retention or baseline characteristics occurred. Sertraline patients showed a trend towards longer time before their first cocaine-positive urine (‘lapse’, χ(2) = 3.67, P = 0.056), went significantly longer before having two consecutive urine samples positive for cocaine (‘relapse’, χ(2) = 4.03, P = 0.04) and showed significantly more days to lapse (26.1 ± 16.7 versus 13.2 ± 10.5; Z = 2.89, P = 0.004) and relapse (21.3 ± 10.8 versus 32.3 ± 14.9; Z = 2.25, P = 0.02). Depression scores decreased over time (F = 43.43, P < 0.0001), but did not differ between groups (F = 0.09, P = 0.77).

CONCLUSIONS:

Sertraline delays time to relapse relative to placebo in cocaine-dependent patients who initially achieve at least 2 weeks of abstinence.

No consistently effective pharmacotherapy exists for preventing relapse in cocaine use disorder. However, sertraline has shown promise in abstinent individuals with some depression symptoms. The current researchers pooled data from two similarly designed, 12-week, double-blind studies in Connecticut and Arkansas (N=126; median age, 39).

All participants were cocaine dependent, were randomized as inpatients to sertraline at 200 mg/day or placebo, and completed 2 weeks of residential treatment. Rates of current major depression were 74% in the Connecticut study and 50% in the Arkansas study. In both treatment groups, current alcohol dependence diagnosis, older age, male sex, lower depression ratings, and a negative urine screen at baseline predicted a higher risk for relapse. Overall, sertraline was associated with relapse prevention (relapse was defined as two sequential positive or missing urine cocaine results). The abstinence rate with sertraline was nearly double that of placebo (34% and 18%). Older age and current alcohol dependence predicted a stronger response to sertraline than placebo.

COMMENT

Studies of sertraline at lower doses and in outpatients and of other selective serotonin reuptake inhibitors have yielded disappointing results. Here, however, sertraline, dosed at 200 mg and given to participants with some depression symptoms and at least 2 weeks of abstinence, prevented relapse. Sertraline might work best to sustain rather than to initiate abstinence. This fairly low-risk intervention should be considered even if individuals don’t currently have major depression, similar to a significant portion of this sample. Older people and those with current alcohol dependence may be especially likely to benefit from sertraline, although these findings need replication.

 

cocaine treatments pipeline 2016

Cocaine treatment options:

In the seminal trial, cocaine-dependent subjects were randomly assigned to
receive D-amphetamine (15 or 30 mg/day; n = 26 and
28, respectively) or placebo (n = 40) for 25 weeks
(Grabowski et al., 2001). During the fifth week, the
D-amphetamine dose was doubled. Subjects maintained
on the higher D-amphetamine dosing regimen
(30/60 mg/day) used significantly less cocaine during
the trial than subjects maintained on either the lower
dosing regimen (15/30 mg/day) or placebo as determined
by benzoylecgonine-free urines. In the next study, dependent
cocaine injectors were assigned to placebo (n =
14) or 60 mg/day D-amphetamine (n = 16) for 14 weeks
(Shearer et al., 2003). In the D-amphetamine maintenance
group, the percent of cocaine-positive urines
decreased from 94% at baseline to 56% by the end of the
trial. In contrast, the percent of cocaine-positive urines
in the placebo maintenance group remained stable at
approximately 79% from the beginning to the end.

Methylphenidate:

In the more recent trial, 48 subjects were
randomly assigned to placebo or methylphenidate over
14 weeks (Levin et al., 2007). The methylphenidate dose
was titrated upward to a target dose of 60 mg/day.
Methylphenidate-treated individuals demonstrated a
significant decrease in the probability of providing a
cocaine-positive urine sample during the trial.

Desipramine:

Two studies meeting inclusion criteria for this review
evaluated desipramine for managing cocaine use disorder
(Gawin et al., 1989; Campbell et al., 2003). In the
first study, which lasted 6 weeks, cocaine-dependent
subjects were assigned to receive placebo (n = 24) or
2.5 mg/kg desipramine daily (Gawin et al., 1989).
Subjects who received desipramine were more likely
to achieve abstinence for longer periods, as verified by a
combined use indicator of a cocaine-negative urine
sample and self-report of no cocaine use, than subjects
assigned to receive placebo. In the more recent study,
cocaine-dependent subjects were maintained on placebo
(n = 50) or desipramine (n = 49) in an 8-week trial
(Campbell et al., 2003). The desipramine dose started at
50 mg/day and was titrated up to 200 mg/day. Groups
did not differ in their ability to sustain cocaine abstinence
or in proportion of cocaine-positive urine samples.  < Ambivalent

Amantadine

Three prospective trials have tested the efficacy of
amantadine for treating patients with cocaine use
disorder (Kampman et al., 1996, 2006; Shoptaw et al.,
2002). Three prospective trials have tested the efficacy of
amantadine for treating patients with cocaine use
disorder (Kampman et al., 1996, 2006; Shoptaw et al.,
2002). In the earliest study, cocaine-dependent subjects
were assigned to placebo (n = 30) or 300 mg/day
amantadine (n = 31) for 4 weeks (Kampman et al., 1996).
The proportion of urine samples indicating cocaine use
was not significantly different across groups, with 57.5%
of samples being positive in the placebo group and 49.6%
of samples being positive in the amantadine group when
counting missing samples as positive. In the next study,
cocaine-dependent subjects were assigned to receive
placebo (n = 35) or 200 mg/day amantadine (n = 34) for
18 weeks (Shoptaw et al., 2002). Amantadine maintenance
increased the probability that subjects would
provide a cocaine-negative urine sample, with statistically
significant differences observed at a priori comparison
time points (i.e., weeks 8 and 16). In the most recent
study, 199 cocaine-dependent subjects with severe
withdrawal symptoms were assigned to receive placebo,
300 mg/day amantadine, 100 mg/day propranolol
or combined amantadine and propranol for 10 weeks
(Kampman et al., 2006). There was no difference between
the amantadine-treated and the placebo-treated groups
on cocaine use outcomes. Taken together, the results are
equivocal. Differences in the subjects’ severity of cocaine
use may have played a role in the discrepancy.

The only human
laboratory study of D-amphetamine reported results
similar to those of rodent and nonhuman primate laboratory
studies and several clinical trials that all support the
effectiveness of chronic D-amphetamine to decrease cocaine
use. Although three animal studies did not show
that reductions in self-administration were selective for
cocaine (versus food) self-administration, all three of
those studies examined acute D-amphetamine treatment,
whereas all studies that showed positive results
involved chronic D-amphetamine administration. Thus
it is clear that the predictive validity of these animal
models, at least with respect to D-amphetamine, is
critically dependent on chronic treatment with the
putative medication.
Data with methylphenidate that may appear equivocal
at first glance are reconciled when the ADHD
status of subjects is considered. Results were negative
in rats (Hiranita et al., 2009), rhesus monkeys (Czotyet al., 2013), and a clinical trial in subjects without
comorbid ADHD (Grabowski et al., 1997). When tested
in an ADHD population, however, more encouraging
results were found in the only human laboratory study
(Collins et al., 2006) and one of two clinical trials (Levin
et al., 2007). The effects of modafinil were positive in the
one preclinical study in monkeys and one study in
humans. Four of the six reviewed clinical trials reported
negative results, although in some cases positive results
were found in subsets of the subjects based on sex or
history of alcohol dependence. Likewise, negative results
were found with the norepinephrine uptake
blocker desipramine in laboratory studies in nonhuman
primates and humans and in one of two clinical trials
(Campbell et al., 2003). However, positive results were
seen with lower doses of desipramine in the other
clinical trial (Gawin et al., 1989). Finally, negative
results with amantadine were reported in monkey and
human laboratory studies as well as two of three clinical
trials.
Taken together, results with D-amphetamine (when
administered chronically) and amantadine are clearly
consistent across settings; negative results with
desipramine have been found in all but one study and
apparent discrepancies with methylphenidate can
largely be explained when ADHD status is taken into
consideration. Only modafinil resulted in clearly discordant
conclusions across settings. However, as noted
above, recent data suggest that the effectiveness in
clinical trials may require the absence of lifetime
alcohol dependence: if true, this would bring clinical
trial results more in line with the only nonhuman
primate study conducted to date (Newman et al.,
2010). Moreover, investigators have enumerated other
reasons for the discordance across clinical trials that
may affect translation.

Conclusions regarding the promise of
baclofen as a putative pharmacotherapy for treating
cocaine use disorder are similar across animal, human
laboratory, and clinical studies in that all three settings
have produced mixed results. Acute baclofen treatment
in rodents produced positive results (i.e., a selective
decrease in cocaine versus food self-administration)
only in the laboratory that used food pellets as a
reinforcer but not in two others where liquid food
was used. Baclofen did not selectively decrease cocaine self-administration in monkeys. Thus we concluded
mixed findings as 5 of 8 studies showed that baclofen
reduced cocaine self-administration (Table 2) similar to
studies in the other two settings. The two human
laboratory studies produced opposite results and the
results of clinical trials were also mixed, perhaps based
on the extent of cocaine use of the subjects. In addition,
because of the relatively short duration of action of
baclofen and documented side effects (e.g., Brebner
et al., 2002; Bowery, 2006), it is tempting to speculate
that experimental parameters, such as dose, duration of
treatment, and drug pretreatment times (in acute
experiments), may contribute to the discordant results
obtained with baclofen. The tiagabine results are more
clearly concordant, showing no differential effects on
cocaine taking observed as a function of tiagabine
treatment across nonhuman primate and human laboratory
and clinical trial research (Lile et al., 2004b;
Weerts et al., 2005; Winhusen et al., 2005, 2007).

Buspar

Two clinical trials evaluated the efficacy of buspirone
for treating cocaine use disorder (Moeller et al., 2001;
Winhusen et al., 2014). In the earlier study, cocainedependent
subjects were randomized to receive placebo
(n = 18) or 45 mg/day buspirone (n = 17) for 12 weeks
(Moeller et al., 2001). The two groups did not differ in
percent of cocaine negative urines nor did they differ in
semiquantitative levels of cocaine metabolites in urine
samples. In the second study, which lasted 16 weeks
and was designed to evaluate the ability of buspirone to
prevent cocaine relapse, subjects were first admitted to
an inpatient treatment unit to achieve cocaine abstinence.
While on the unit, subjects were randomized to
receive placebo (n = 27) or 60 mg/day buspirone (n = 35;
Winhusen et al., 2014). There were no differences
between the groups assigned to receive placebo or
buspirone in their ability to maintain cocaine abstinence
after discharge from the inpatient unit or in the
number days using cocaine after discharge from the
inpatient unit.

 

Buprenorphine

In the first study, 30 cocaine- and opioid-dependent
subjects received ascending daily doses of buprenorphine
(2, 4, 8, 12, and 16 mg, doses varied across
individual subjects) for 21 days at each dose (Schottenfeld
et al., 1993). The buprenorphine dose was then tapered.
During the taper, the proportion of cocaine-positive
urines was lower than during the dose escalation period,
with similar effects across doses. In the next study,
116 opioid-dependent cocaine abusers were randomly
assigned to receive 4 or 12 mg/day buprenorphine or 20
or 65 mg/day methadone for 24 weeks (Schottenfeld
et al., 1997). None of the treatment groups differed in
rates of cocaine use. The third study evaluated 2, 8, or
16 mg/day buprenorphine or 16 mg buprenorphine
every other day in 200 cocaine and opioid-dependent
subjects (Montoya et al., 2004). Urine toxicology
testing revealed significantly reduced benzoylecgonine
concentrations in the subjects randomized to 8 or 16 mg
buprenorphine daily. The 16 mg/day buprenorphine
group also displayed significant reductions in the
number of cocaine-positive urines during withdrawal
from opioid maintenance. The most recent trial
compared maintenance on 12–16 mg buprenorphine
to maintenance on 65–85 mg methadone in 162
individuals assigned to contingency management or
performance feedback using a 2  2 factorial design
over 24 weeks (Schottenfeld et al., 2005). Subjects
assigned to methadone, regardless of behavioral
therapy platform, were significantly more likely to
provide cocaine-negative urines and achieved longer
consecutive periods of abstinence from cocaine than
their buprenorphine-treated counterparts.

 

Levamisole in Cocaine – adulterants that can kill! Suboxone in Fairfax 703-844-0184

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The Truth About Britain’s ‘Flesh-Eating’ Cocaine    << Link to article in paper

Levamisole, a common cutting agent in cocaine, made the news recently for its apparent skin-destroying properties—but there’s a lot more to the substance than that!

cocaine and levisamole Article Link

Clinicians may be less cognizant of the
problems caused by some of the adulterants added
to cocaine. Recent recognition of levamisole-induced
agranulocytosis, vasculitis, and other complications,
from contaminated cocaine, dictate that
physicians be aware of these potential problems. The New Mexico Department of Health found evidence of levamisole, an antihelminthic agent, in drug paraphernalia of cocaine users.  Levamisole was also detected using gas chromatography/mass
spectrometry (GC/MS) in a postmortem
blood specimen from a cocaine user who died of
Serratia marcescens sepsis secondary to agranulocytosis. (https://emergency.cdc.gov/epix/index.asp CDC epidemic exchange)

Levamisole is a synthetic imidazothiazole derivative
used for its immunomodulatory properties. Since
the 1970s, it has been used for treatment of rheumatoid arthritis as a disease-modifying antirheumatic
drug. In 1990, the United States Food
and Drug Administration approved it for use with
5-fluorouracil for colon cancer treatment. However,
levamisole was subsequently withdrawn from the
United States and Canadian markets in 2000 and
2003, respectively, because of reports of agranulocytosis.

Patients with levamisole toxicity typically present
with cutaneous manifestations consisting of large,
painful hemorrhagic bullae and/or necrosis. The
face is commonly affected, especially the bilateral
helixes and cheeks. Similar bullae
can present elsewhere on the body, with case reports
documenting involvement of the abdomen, chest,
lower back, buttocks, and legs. Retiform purpura
with or without bullae may also be prominent.

Laboratory findings include leukopenia, neutropenia,
agranulocytosis, positive antinuclear antibody
titers, positive anti-proteinase 3 titers, and positive
perinuclear or cytoplasmic staining patterns for
antineutrophil cytoplasmic antibodies. Absolute
neutrophil counts ranging from 0 to 3000 have been
reported, and these patients are at high risk of infection.
Bone marrow biopsies from such patients
have shown markedly decreased production of all
cell lines. When positive, antinuclear antibody is
often mildly or moderately elevated, most commonly
in a speckled pattern. Anti– double-stranded
DNA and lupus anticoagulant findings are also inconsistently
positive. Complement studies typically yield
normal results, although mildly decreased levels of C4
and/or C3 have been reported.

Symptoms:

  • Generalized malaise
  •  fatigue
  • arthralgias
  • Pulmonary hemorrhage
  • renal failure
  • seizures
  • Skin necrosis
  • (hemorrhagic) bullae
  • retiform purpura
  • Leukopenia
  • neutropenia
  • agranulocytosis
  • hyponatremia
  • Positive results for ANA
  • PR3
  • ANCAs,
  • dsDNA
  • lupus anticoagulant
  • antihuman elastase antibody
  • Urine toxicology studies positive for cocaine; occasionally positive for levamisole
  • Detection of levamisole in urine with GC/MS

Levamisole-contaminated cocaine a hairy affair BMJ CAse article

Cocaine use is widespread and all clinicians should
be aware of the diverse symptoms the drug can
bring about. In the last decade, levamisolecontaminated
cocaine was recognised as a cause
of antineutrophil cytoplasmic antibody (ANCA)-
associated vasculitis. The condition has a versatile
character and can present with symptoms involving
almost any organ system. Our patient suffered from
ulcerating skin lesions, as well as from several other
symptoms. Over the course of her illness, she suffered
diverse complications, most importantly
glomerulonephritis and ileal intussusception. The
latter has not been reported previously in
ANCA-associated vasculitis. Diagnostic uncertainty
remained when the patient persistently denied substance
abuse. Definitive proof was obtained by
testing the patient’s hair for toxins, an uncommonly
used technique that holds promise for wider
application. ANCA-autoantibodies can also be an
important diagnostic aid. The proper therapeutic
strategy is still disputed, but immunosuppressive
therapy can be indicated in case of severe organ
involvement.

▸ Levamisole-contaminated cocaine can cause antineutrophil
cytoplasmic antibody (ANCA)-associated vasculitis, often
presenting with skin lesions, arthralgia, neutropenia or nasal
midline destructive disease.
▸ Human neutrophil elastase-ANCA is indicative of
cocaine-induced disease, as well as simultaneous presence
of myeloperoxidase-ANCA and proteinase 3-ANCA.
▸ Hair testing for toxins can provide definitive proof of cocaine
and levamisole exposure.
▸ Cocaine abstinence is key, although immunosuppressive
therapy can be indicated in case of severe organ
involvement such as glomerulonephritis.
▸ Ileal intussusception can occur and is likely due to intestinal
involvement.

Cocaine metabolites are
detectable in urine for 2–4 days after consumption. The plasma
elimination half-life of levamisole is 3–6 h and only about 3%
of levamisole is excreted unchanged in urine. When diagnostic
uncertainty remains, toxicological screening of hair should be
considered. This has the ability to retrospectively confirm exposure
to cocaine, levamisole and other substances of abuse such as
amphetamines.

The type of ANCA antibodies can be an aid
to the diagnosis and distinguish the entity from idiopathic autoimmune
ANCA-associated vasculitis. Indicative for cocaine–
levamisole-induced vasculitis is the presence of both
MPO-ANCA and PR3-ANCA simultaneously. Furthermore,
cocaine abusers are often positive for HNE-ANCA, which in
these patients is indicative of cocaine-induced nasal midline
destructive disease. (Tervaert JWC, Damoiseaux J. Antineutrophil cytoplasmic autoantibodies: how are they detected and what is their use for diagnosis, classification and follow-up? Clin Rev Allergy Immunol 2012;43:211–19.)

Levamisole has, over the last decade, become a major cutting agent in the world’s cocaine supplies. Depending on where you live, between 40 to 90 percent of cocaine contains the drug. The British government says around 80 percent of seized cocaine shipments in 2014 contained levamisole. In Spain, a 2012 study found the drug in 57 percent of cocaine, and in Denmark in the same year it was in 90 percent of samples. In Holland, the figure is 60 percent, and in the US the DEA puts it at 73 percent.

While the substance might be found frequently, that doesn’t mean cocaine is packed with the stuff. Cocaine purity research carried out by Lana Brockbals at drug identification firm TICTAC, seen exclusively by VICE, found that out of 106 samples of cocaine from an unnamed British festival last year, 83 contained traces of the de-wormer. However, the average concentration of levamisole in each wrap was just over 5 percent, with most samples containing between 1.5 and 5 percent of levamisole.

ANCA-positive vasculitis induced by levamisole-adulterated cocaine and nephrotic syndrome The kidney as an unusual target

But it turns out it may not just be about dose; Dr. Hoffman told me the evidence points to some people having a genetic vulnerability to the toxic effects of the drug. “The literature suggests that some patients have a unique genetic predisposition that increases their risk of toxicity,” he said. “There is always some consideration for dose, but it is a combination of dose plus susceptibility that sets the risk. Luckily for cocaine users, the known responsible genetic abnormality is very uncommon.”

The gene in question, HLA-B27, is present in about eight percent of caucasians, four percent of North Africans, two to nine percent of Chinese and 0.1 to 0.5 percent of Japanese. Oddly, in Lapland in northern Finland, a quarter of people have the gene.

The authors of the report, “Dynamics of chemical use in the production of cocaine in the Andean Region,” say there are a number of reasons why levamisole has become the number one cut. It’s easy to mix with cocaine, has a similar “fish scale” appearance to high quality cocaine flake and gives the impression of having a greater volume than it actually possesses. It also gives a false positive in street tests for cocaine, so bulk buyers are not able to spot the cocaine has been cut, and is relatively cheap and easily available in bulk from cities across the Andean countries. According to an expert working for the UNODC in Colombia, the drug is regularly purchased at $50 per kilo in Bogota, Cali, and Medellin, compared to $2,300 for a kilo of cocaine.

But the game changer—an asset of levamisole of which cartel chemists will be fully aware—is its ability to potentiate the action of cocaine in the body. A metabolite of levamisole called aminorex has amphetamine-like properties, and a growing body of research is beginning to suggest what the Colombian chemists may have known all along: Cocaine mixed with levamisole creates an additional high when it’s snorted.

Conducted by PRELAC (Prevention of the Diversion of Chemical Precursor Substances of Drugs in the Latin America and the Caribbean Countries), the study reveals Colombian firms were the first to start using levamisole a decade ago. Now it’s also used by cartels in Peru and Bolivia as the “cut” of preference for bulking out cocaine before it’s exported. In cocaine, levamisole is usually mixed with two other chemicals, such as diltiazem, phenacetin, hydroxyzine, and caffeine. For the US and European markets, cocaine is cut 20 percent. If it’s going to other countries in South America, such as Brazil, it can be cut to as much as 50 percent.

Greece’s infamous new drug, sisa, is basically meth and filler ingredients like battery acid, engine oil, shampoo, and cooking salt. The majority of its users are poor, often homeless, city dwellers reeling from the psychological and physical impacts of a country in the grip of economic collapse.

A homemade drug called Krokodil is gaining popularity in Siberia and its effects on users are horrific. Krokodil is Russian for Crocodile, because of the way addicts’ skin begins to get turn scaly, dry and eventually rot right off their bodies. Even most heroin users are frightened by Krokodil and want nothing to do with this terrifying drug.

I threw in the above links just for fun!

 

 

 

 

 

 

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