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
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.
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
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 Psychiatryvolume22, pages76–81 (2017) |
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
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.
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.
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.:
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.
► 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.
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.
Positive results for ANA
antihuman elastase antibody
Urine toxicology studies positive for cocaine; occasionally positive for levamisole
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
▸ 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
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.
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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