Development and characterization of a novel conjugated methamphetamine vaccine.

BACKGROUND: Methamphetamine (METH) addiction is a major public health concern globally with limited management options. The development of a METH vaccine through hapten design has received significant attention as a promising platform for the potential treatment of METH addiction and overdose, however there is yet to be a successful candidate in human trials. RESEARCH DESIGN AND METHODS: In this study, we developed a novel conjugated METH vaccine using oxidized mannan (a polymannose) as an immunogenic carrier. A METH hapten was synthesized by using amphetamine and conjugated to mannan with a (Lysine-Glycine-Lysine-Glycine-lysine-Glycine-Lysine-Glycine-Lysine-Glycine) (KG)5 peptide linker. RESULTS: The reaction between amphetamine and (KG)5, oxidation of mannan, and conjugation of amphetamine-(KG)5 with oxidized mannan were confirmed by color tests, Fourier-transform infrared spectroscopy, gas and liquid chromatography mass spectrometry, thin-layer chromatography, and ultraviolet spectrophotometer. Additionally, the ability of the vaccine to generate antibodies was confirmed in C57BL/6 mice. CONCLUSIONS: The successful development and characterization of the METH-mannan conjugate vaccine, provides a potential therapeutic intervention to curb METH substance use disorders. Each step of vaccine development was characterized to aid in future research on these vaccines, and the immunogenicity shown in the animal models supports future evaluation of the approach. Future studies of the conjugated METH vaccine should evaluate the efficacy in animal models of acute and chronic METH to pave the way for human studies.

Using a fotonovela to battle crystal meth in South Africa.

This study evaluated the effects of a health-related fotonovela about crystal meth (S-methamphetamine hydrochloride) among "Colored" people (an ethnic label for people of mixed race) in the Western Cape province of South Africa. Crystal meth use is most common among Colored people in this province and it is considered a major social problem. The fotonovela was compared to a no-message control group and a traditional brochure in a randomized controlled trial (N = 303). The fotonovela outperformed the control condition for knowledge level and it outperformed the traditional brochure on intention toward starting conversations about crystal meth. Especially readers with relatively low levels of education clearly preferred the fotonovela over the traditional brochure.

Expression of miR-133a-5p and ROCK2 in Heart in Methamphetamine-Induced Rats and Intervention of Rhynchophylline.

INTRODUCTION: Rhynchophylline, as a traditional Chinese medicine, was used for the treatment of drug addiction. OBJECTIVE: To investigate miRNAs expression profile in the rat hearts of methamphetamine dependence and the intervention mechanisms of rhynchophylline. MATERIALS AND METHODS: This study detected the expression profile of miRNAs in the methamphetamine-induced rat hearts by microarray and verified the expression of miR-133a-5P and Rho-associated, coiled-coil containing protein kinase 2 (ROCK2) protein. RESULTS: After conditioned place preference training, methamphetamine significantly increased the time spent in the drug-paired compartment, while rhynchophylline and MK-801 could reduce the time. Cluster analysis results of miRNAs showed that compared with the control group, the expression of miR-133a-5p in methamphetamine-induced rat hearts was decreased significantly; rhynchophylline could significantly increase the expression of miR-133a-5p. The result was verified by real-time polymerase chain reaction. The results of target gene predictive software and related research showed that ROCK2 protein may be the target gene of miR-133a-5p. The immunohistochemistry results of heart tissues showed that the expression of ROCK2 protein was significantly upregulated in the methamphetamine group and downregulate in the rhynchophylline group; the difference between the MK-801 group and the methamphetamine group was not significant. The result of western blot was consistent with the immunohistochemistry. CONCLUSION: The active ingredient of Chinese herbal medicine rhynchophylline can effectively inhibit the formation of methamphetamine-dependent conditional place preference (CPP) effect in rats to some extent. MiR-133a-5p may participate in the cardioprotective effects of CPP rats by targeting ROCK2.

Cost effectiveness of text messages to reduce methamphetamine use and HIV sexual risk behaviors among men who have sex with men.

Methamphetamine use is highly prevalent among gay, bisexual, and other men who have sex with men (MSM) in the United States and has been associated with condomless anal intercourse (CAI), a common route of HIV infection. Text messaging is a very low-cost method of delivery for intervention content. This paper presents a cost-effectiveness analysis of a randomized controlled trial testing three nested methods of text message delivery designed to reduce methamphetamine use and HIV sexual risk behaviors among MSM (Project Tech Support2). From March 2014 to January 2016, 286 non-treatment seeking methamphetamine-using MSM were randomized into one of three study arms: 1) Interactive text message conversations with Peer Health Educators, plus five daily automated, unidirectional theory-based messages, plus a weekly self-monitoring text message assessment (TXT-PHE; n = 94); or, 2) Five daily automated, unidirectional theory-based messages plus a weekly self-monitoring text message assessment (TXT-Auto; n = 99); or, 3) The weekly self-monitoring text message assessment only (AO; n = 93). Methamphetamine use at nine months post-enrollment was lower than at baseline in all three arms. The addition of Peer Health Educators and/or theory-based text messages did not produce cost-effective reductions in methamphetamine use over the weekly AO text messages. However, both intervention arms outperformed the AO arm in reducing HIV risk behaviors, but the TXT-Auto arm dominated the TXT-PHE arm in achieving greater reductions in days of methamphetamine use and CAI at lower cost. The TXT-Auto arm achieved greater reductions in CAI than the attentional control at a cost in the base case of ~$37.50 per episode of CAI reduced per month. Sensitivity analyses showed that results were robust to a number of changes in assumptions. Interventions seeking to reduce methamphetamine use among non-treatment-seeking MSM may seek to add minimal attentional control-style text messages to their routines querying about recent methamphetamine use and/or high-risk sex. Interventions seeking to additionally reduce HIV sexual risk behaviors among non-treatment-seeking MSM, specifically engagement in CAI, may seek to additionally apply theory-based text messages.

Interventions to Reduce Drug Use Among Methamphetamine Users at Risk for HIV.

PURPOSE OF REVIEW: This paper reports on the results of a study comparing two behavioral treatments for methamphetamine users. The outcome was the effectiveness of the interventions in reducing meth use. The interventions were contingency management (CM) and contingency management plus strengths-based case management (CM/SBCM). RECENT FINDINGS: CM/SBCM was found to be associated with attending more sessions for people who reported being in a couple. Also, participants who earned more money in the first part of the study were more likely to have more clean urinalysis in the second part of the study. Latent class analysis identified a class of participants who were in a couple, without sexual abuse history, and less meth use at baseline. This class tended to have more clean urinalysis in the CM/SBCM intervention. These results indicate that incentive-based interventions with case management may be useful for helping meth users reduce their drug use.

"Gave me a line of ice and I got hooked": Exploring narratives of initiating methamphetamine use.

OBJECTIVE: This study explores factors associated with methamphetamine initiation based on the narratives from an online support group for methamphetamine users. METHODS: We conducted a qualitative study of 202 first-person narratives submitted to an anonymous, online support group for methamphetamine users. The narratives were analyzed in the Dedoose qualitative software using Charmaz's adaptations to Glaserian grounded theory methodology. RESULTS: Ten factors for initiating methamphetamine use emerged from our analysis and corresponded to three constructs from the Theory of Planned Behavior: attitude (needing energy to work, wishing to escape pain, wanting to have fun, and desiring a thinner body), subjective norms (ubiquity of methamphetamine use, yearning for closer relationships, and wanting to fit in), and perceived behavioral control (believing addiction is inevitable, feeling forced to fit in, and having no real control). Many participants described initiating methamphetamine use because they believed it would help them meet personal goals or needs. Other participants began using it out of curiosity, to develop relationships, and/or because of the drug's ubiquity in their social environments. Some users described how their perceived lack of control left them with limited ability to resist trying the drug. CONCLUSIONS: Results from this study may aid public health researchers and interventionists seeking theoretically informed methamphetamine prevention programs.

Low-frequency repetitive transcranial magnetic stimulation inhibits the development of methamphetamine-induced conditioned place preference.

The abuse of amphetamine-type stimulants (ATS) has become a global public health issue in recent years, these new-type drugs can cause addiction and serious cognitive impairment. However, there are no effective methods for the prevention and treatment of ATS addiction at present. Repetitive transcranial magnetic stimulation (rTMS) is a painless and non-invasive new therapeutic approach that has been used for the treatment of depression and other neuropsychiatric disorders, but whether it can be used to treat drug addiction is unclear. In the present study, we investigated the possible effects of rTMS on methamphetamine(METH)-induced conditioned place preference (CPP). High-frequency (10 Hz) and low-frequency stimulation patterns (1 Hz) were applied to test the effect of rTMS on METH-induced CPP. The results showed that low-frequency but not high-frequency rTMS could block METH-CPP, accompanied with a downregulation of gamma-aminobutyric acid type B receptor subunit 1 (GABABR1) expression in rat dorsolateral striatum. These results suggested that low-frequency rTMS could effectively inhibit the development of METH addiction and shed light on the rTMS as a potential approach for the prevention of drug addiction.

Mindfulness-based relapse prevention combined with virtual reality cue exposure for methamphetamine use disorder: Study protocol for a randomized controlled trial.

BACKGROUND: Mindfulness-based relapse prevention (MBRP) is a method that combines cognitive behavioral relapse prevention with mindfulness practice. Research suggests that MBRP can effectively reduce withdrawal/craving in people with substance use disorder (SUD). An important part of MBRP is to practice mindfulness meditation to cope with high-risk situations for relapse, such as stimuli and situations associated with drug taking. Virtual reality cue exposure (VRCE) may be a complementary approach to MBRP as it allows for controlled and graded presentations of various high-risk situations with distal and proximal drug cues. The aim of the study is to investigate the effects of MBRP combined with VRCE, in comparison to MBRP alone or treatment as usual, on craving and emotional responses in people with methamphetamine use disorders. METHOD/DESIGN: The study is a parallel randomized controlled study including 180 participants with methamphetamine use disorder. Three parallel groups will receive 8 weeks of MBRP combined with VRCE, MBRP alone, or treatment as usual, respectively. Craving, virtual cue reactivity, anxiety, depression, emotion regulation, mindfulness and drug-related attention bias will be assessed at pre-treatment, post-treatment, and 3 and 6 months of follow-up. DISCUSSION: This innovative study aims at investigating the effects of MBRP combined with VRCE in people with SUD. The combined intervention may have important clinical implications for relapse prevention due to its ease of application and high cost-effectiveness. This study may also stimulate research on the neuronal and psychological mechanisms of MBRP in substance use disorder. TRIAL REGISTRATION NUMBER: ChiCTR-INR-17013041.

Transcranial DC stimulation modifies functional connectivity of large-scale brain networks in abstinent methamphetamine users.

Background: Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation tool suited to alter cortical excitability and activity via the application of weak direct electrical currents. An increasing number of studies in the addiction literature suggests that tDCS modulates subjective self-reported craving through stimulation of dorsolateral prefrontal cortex (DLPFC). The major goal of this study was to explore effects of bilateral DLPFC stimulation on resting state networks (RSNs) in association with drug craving modulation. We targeted three large-scale RSNs; the default mode network (DMN), the executive control network (ECN), and the salience network (SN). Methods: Fifteen males were recruited after signing written informed consent. We conducted a double-blinded sham-controlled crossover study. Twenty-minute "real" and "sham" tDCS (2 mA) were applied over the DLPFC on two separate days in random order. Each subject received both stimulation conditions with a 1-week washout period. The anode and cathode electrodes were located over the right and left DLPFC, respectively. Resting state fMRI was acquired before and after real and sham stimulation. Subjective craving was assessed before and after each fMRI scan. The RSNs were identified using seed-based analysis and were compared using a generalized linear model. Results: Subjective craving decreased significantly after real tDCS compared to sham stimulation (p = .03). Moreover, the analysis shows significant modulation of DMN, ECN, and SN after real tDCS compared to sham stimulation. Additionally, alteration of subjective craving score was correlated with modified activation of the three networks. Discussion: Given the observed alteration of the targeted functional brain networks in methamphetamine users, new potentials are highlighted for tDCS as a network intervention strategy and rsfMRI as a suitable monitoring method for these interventions.

Kalaban: Young drug users' engagements with law enforcement in the Philippines.

BACKGROUND: A violent 'war on drugs' continues to be waged in the Philippines, even as the use of drugs - particular methamphetamine - continues to rise. Furnishing contextual background to the current situation, this paper explores how long-running law enforcement approaches in the Philippines might be viewed by those in their receiving end by presenting findings of an ethnography among marginalized young men. METHODS: Semi-structured interviews and focus group discussions were conducted among 20 young men throughout a 12-month period of participant-observation from December 2011 to September 2013. FINDINGS: Young people make use of various 'tactics' to keep using drugs and evade law enforcement, even as drug use itself is a tactic in their everyday lives. A sense of hypocrisy and injustice, borne of their own experiences, informs their view of law enforcers, whom they call kalaban (enemy). They feel they are being unfairly targeted, but in their view, this danger is just part of the perils of their everyday lives. CONCLUSION: Young men's resort to various tactics speaks of an agency that is often ignored in public discourses. Their 'lay assessments of risks' and experience-based perceptions of law enforcement raises questions about the efficacy of fear-based anti-drug campaigns. Overall, the study offers an ethnographic argument against the punitive methods being employed by the Philippines, and for measures that reframe the relationship between police and young drug users - from hostility to trust.

Could Modafinil Prevent Psychostimulant Addiction? An Experimental Study in Rats.

Addiction is a serious health problem which leads to general social impairment. The period of adolescence plays a significant role in drug abuse liability. Psychostimulants, such as modafinil (MOD), are majorly used by teenagers seeking improvements in cognition, which contributes to its indiscriminate use. This study aimed to investigate the influence of MOD (64 mg/kg by gavage, once a day) treatment during adolescence [post-natal day (PND) 28-42] on amphetamine (AMPH, 4 mg/kg i.p.)-conditioned place preference (CPP) in early adulthood (PND 60). Our findings showed that AMPH increased CPP for the drug and anxiety-like behaviours; on the other hand, AMPH decreased the number of crossings and recognition index. In addition, AMPH decreased catalase activity and increased reactive species, malondialdehyde and carbonyl protein levels in the hippocampus. AMPH also increased pro-brain derived neurotrophic factor (BDNF), tyrosine kinase receptor B, dopamine transporter, D1R and decreased BDNF and D2R immunoreactivity. Contrarily, animals pre-exposed to MOD showed reduced AMPH-CPP, no locomotor impairment, less anxiety-like behaviours and no memory deficits. In addition, MOD showed antioxidant activity by preventing AMPH-induced oxidative damage in the hippocampus. Moreover, molecular analysis showed that MOD was able to modulate the hippocampal dopaminergic system, thus preventing AMPH-induced impairments. Animals that received MOD during adolescence showed reduced AMPH-CPP in early adulthood. These unexpected behavioural effects of MOD on CPP could be due to its hippocampal dopaminergic system modulation, mainly by its action on D1R, which is closely linked to drug addiction. Nevertheless, further studies are necessary.

['Ecstasy-light' - not as light as its name suggests: toxic effects of 4-fluoroamphetamine]. / 'Ecstasy-light': niet zo onschuldig als het lijkt.

BACKGROUND: The use of 4-fluoroamphetamine (4-FA) has shown a marked increase, especially because users perceive its effects to be relatively mild. 4-FA is also known as ecstacy-light, but is probably not as light as its name suggests. From April 2017 its use has therefore been forbidden in the Netherlands. CASE DESCRIPTION: In a short time, we saw three patients at our emergency department who had signs of a severe intoxication with 4-FA. A 21-year-old male developed a tonic-clonic seizure, bruxism, mydriasis, and rhabdomyolysis. A 19-year-old female was confused and was longing for death. A 22-year-old male needed to be admitted to intensive care to be intubated, sedated and cooled due to tachycardia, hypertension and hyperthermia. CONCLUSION: Because of its relatively mild effects, 4-FA is gaining in popularity in the Netherlands. However, the use of this designer drug can lead to severe problems such as severe confusion, hyperthermia and tonic-clonic seizures.

Effective active vaccination against methamphetamine in female rats.

BACKGROUND: Immunotherapies directed against methamphetamine (MA) abuse have shown success in rodent models, however only a limited number of studies have investigated active vaccination in female mice and none in female rats. It is critical to determine if potential immunotherapeutic strategies generalize across sex, particularly for drugs that may produce significant sex-differences on behavioral or physiological endpoints. METHODS: Female Wistar rats were initially vaccinated with keyhole-limpet hemocyanin (KLH) or an anti-methamphetamine-KLH conjugate (MH6-KLH) three times over five weeks and implanted with radiotelemetry devices to assess locomotor activity and body temperature responses to MA. Rats were first exposed to MA via vapor inhalation (100mg/mL in propylene glycol) and then by injection (0.25-1.0mg/kg, i.p.) and vapor after a final vaccine boost. RESULTS: The MH6-KLH vaccine generated an increase in antibody titers across the initial 6-week, 3 immunization protocol and a restoration of titer after a week 14 booster. Locomotor stimulation induced by 0.25mg/kg MA, i.p, in the KLH group was prevented in the MH6-KLH group. MH6-KLH animals also exhibited an attenuated locomotor stimulation produced by 0.5mg/kg MA, i.p. No group differences in locomotion induced by vapor inhalation of MA were observed and body temperature was not differentially affected by MA across the groups, most likely because vapor inhalation of MA that produced similar locomotor stimulation resulted in ∼10-fold higher plasma MA levels. CONCLUSIONS: This study confirms the efficacy of the MH6-KLH vaccine in attenuating the effects of MA in female rats.

Extended-Release Injectable Naltrexone (XR-NTX) With Intensive Psychosocial Therapy for Amphetamine-Dependent Persons Seeking Treatment: A Placebo-Controlled Trial.

OBJECTIVE: Explore the efficacy of extended-release injectable naltrexone (XR-NTX) for preventing relapse to amphetamine use. METHOD: Clinical trial of 100 amphetamine-dependent, treatment-seeking patients who were randomized to 6 monthly 380 mg doses of XR-NTX or matching placebo before entering intensive outpatient after varying lengths of inpatient treatment in Reykjavik, Iceland. Weekly urine drug tests, retention, and standardized instruments assessed efficacy. RESULTS: Of 169 approached, 100 were randomized. Although amphetamine dependence was the main reason for seeking treatment, three-quarters or more of participants had 1 or more other substance dependencies. Of 51 randomized to XR-NTX, 20 received 4 or more injections; of 49 assigned to placebo, 26 received 4 or more injections. Of the planned 2400 weekly urine drug tests, 1247 were collected (52%); 4% of these were positive for amphetamine, 8% for benzodiazepine, 7% for marijuana, 1% for cocaine, and 1% for opioid. XR-NTX had no effect on amphetamine-positive tests, retention, or other outcomes. Those providing half or more of their tests attended more weeks of treatment than those providing less than half of their tests (m = 10.76 vs 3.31; t (92) = 5.91, P < 0.0001), and 92 participants provided at least 1 test. CONCLUSIONS: Adding XR-NTX to the usual combination of inpatient and intensive outpatient treatment did not reduce amphetamine use. The low prevalence of substance use among collected urine samples, and the association between collected samples and weeks in treatment, was consistent with other studies showing that staying in treatment is associated with better outcomes.

Behavioral flexibility predicts increased ability to resist excessive methamphetamine self-administration.

Drug addiction is often associated with cognitive deficits and behavioral inflexibility that may contribute to the development and maintenance of addictive behaviors by reducing addicts' ability to control their behavior toward the drug. In this study, we investigated the relationships between pre-drug levels of behavioral flexibility and the risk to develop uncontrolled methamphetamine (METH) self-administration. First, we measured individual performance in an inter-dimensional set-shifting procedure in which animals have to switch between an external visual rule and an internal side rule in order to obtain food pellets. Then we allowed rats to self-administer METH for twenty long 14-hour sessions, and we investigated the relationships between behavioral flexibility and measures of control over drug intake. Rats rapidly acquired to self-administer high levels of METH which resulted in moderate weight loss. After several sessions of self-administration, whereas some rats progressively increased their METH intake, other rats showed very long voluntary pauses between drug injections and showed no escalation in METH self-administration. Interestingly, we found that behavioral flexibility is correlated with METH self-administration and that more flexible rats take less METH and do not escalate drug taking. These results suggest that traits of behavioral flexibility may protect against the development of excessive and dysregulated drug taking. Conversely, the inability to adapt behavioral responses as a function of the environmental contingencies may contribute to the risks to develop addiction to METH.

The changing landscape of drug abuse What's new? What can we do?

Every corner of the country is touched by drug abuse and addiction--Minnesota is no exception. Drug-induced deaths have tripled since 1990 and now outnumber fatalities from motor vehicle accidents. Deaths from opioid overdoes in particular have skyrocketed; they now outnumber cocaine and methamphetamine overdoes deaths, combined.

Peer-engagement and its role in reducing the risky behavior among crack and methamphetamine smokers of the Downtown Eastside community of Vancouver, Canada.

BACKGROUND: The role of peers (former or current drug users) in reducing risky behavior within methamphetamine and crack smokers has not been well described or researched. The current study not only explores the role of peers in reducing risk factors for morbidity within the illicit drug smoking population in the Downtown Eastside (DTES) community of Vancouver but it also investigates the changes in the nature of drug use after the closure of an unsanctioned smoking facility. METHODS: The data pertain to qualitative interviews with 10 peers and 10 illicit drug smokers. The semi-structured interviews were conducted through community-based research, and the digital transcripts were analyzed via NVivo 10 software. RESULTS: The results indicate that peers (former and current drug users who are employed as educators) are instrumental in transferring risk reduction knowledge within crack and methamphetamine smokers. For example, these peers have been able to teach users about the risk of sharing pipes, using brillo, and using public drug. Furthermore, the Vancouver Area Network of Drug Users provides employment for crack and methamphetamine users in Vancouver who tend to have scarce sources of employment. However, since the closure of the unsanctioned inhalation facility, there has been significantly more public drug use and pipe sharing in the vicinity of the facility, placing drug smokers at significant risk of arrest, violence, and blood-borne infections. CONCLUSIONS: The current study recommends expanding the harm reduction peer network for people who smoke illicit drugs in the DTES community of Vancouver who have historically been underserved.