Table 1 - uploaded by Colin N Haile
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Stimulant-related disorders (SRD) continue to be an important public health problem for which there are presently no approved pharmacotherapies. Although behavioral interventions provide some benefit response varies. The development of novel and effective pharmacotherapies continues to be a research priority. Understanding neural mechanisms critica...
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Previous research has focused on developing theories of addiction that may explain behavior in cocaine- and methamphetamine-dependent individuals. The primary goal of this report was to compare and contrast the prevalence of self-reported measures of impulsivity, depression, lifetime stress and sensation-seeking in healthy controls versus individua...
Citations
... While there are risks inherent in any drug use, research has long suggested that cannabis has the potential to reduce illicit drug use related harms through substitution [5][6][7][8][9][10]. Intentional use of cannabis is associated with decreased use of other substances [11][12][13][14][15][16][17][18], from alcohol [19][20][21][22] to methamphetamine [23] to fentanyl [24], and in jurisdictions where cannabis is regulated, there is evidence of reductions in overdose deaths [25,26]. ...
Background
The United States (US) continues to experience unprecedented rates of overdose mortality and there is increased need to identify effective harm reduction practices. Research from Canada describes cannabis donation through harm reduction agencies as an adjunctive strategy to mitigate the negative consequences of more harmful drugs. This case study describes the operational logistics, feasibility, and potential benefits of a cannabis donation program that was operated through a harm reduction program in rural Michigan.
Case presentation
We applied a community driven research approach to gather information from harm reduction program staff about the implementation and evolution of cannabis donation efforts in Michigan. We also examined 20-months (September 2021 through May 2023) of administrative data from a cannabis company to compare the sale and donation of cannabis products. Ten cannabis-experienced harm reduction clients received cannabis donations, with clinical staff determining client interest and appropriateness, and providing weekly pick-up or delivery. To expand product availability and sustainability, we examined administrative data from a commercialcannabis company that volunteered to provide donations. This administrative data suggests that while flower products constitute most of the adult and medical sales, edible, oil, and topical products predominated donations. Further, cost analysis suggests that donations represent only 1% of total gross sales and account for much less than the expected yearly donation amount.
Conclusions
Research suggests there is potential to reduce alcohol and drug use related harms of more dangerous substances through substitution with cannabis. This case study is the first to document cannabis donation as a harm reduction practice in the US and suggests potential for sustainability dependent on state laws. Findings from this case study provide a starting point for inquiry into cannabis donation as a harm reduction strategy in the US; future research is needed to fully understand the individual-level outcomes, public health impacts, necessary legal regulations, and best practices for cannabis donation programs through harm reduction organizations.
... While there are risks inherent in any drug use, research has long suggested that cannabis has the potential to reduce illicit drug use related harms through substitution (7)(8)(9)(10)(11)(12). Intentional use of cannabis is associated with decreased use of other substances (13)(14)(15)(16)(17)(18)(19)(20), from alcohol (21)(22)(23)(24) to methamphetamine (25) to fentanyl (26), and in jurisdictions where cannabis is regulated, there is evidence of reductions in overdose deaths (27,28). ...
Background
The United States (US) continues to experience unprecedented rates of overdose mortality and there is increased need to identify effective harm reduction practices. Research from Canada describes cannabis donation through harm reduction agencies as an adjunctive strategy to mitigate the negative consequences of more harmful drugs. This case study describes the operational logistics, feasibility, and potential benefits of a cannabis donation program that was operated through a harm reduction program in rural Michigan.
Case presentation
We applied a community driven research approach to gather information from harm reduction program staff about the implementation and evolution of cannabis donation efforts in Michigan. We also examined 20-months (September 2021 through May 2023) of administrative data from a cannabis company to compare the sale and donation of cannabis products. Ten cannabis-experienced harm reduction clients received cannabis donations, with clinical staff determining client interest and appropriateness, and providing weekly pick-up or delivery. To expand product availability and sustainability, we examined administrative data from a retail cannabis company that volunteered to provide donations. This administrative data suggests that while flower products constitute most of the adult and medical sales, edible, oil, and topical products predominated donations. Further, cost analysis suggests that donations represent only 1% of total gross sales and account for much less than the expected yearly donation amount.
Conclusions
Research suggests there is potential to reduce alcohol and drug use related harms of more dangerous substances through substitution with cannabis. This case study is the first to document cannabis donation as a harm reduction practice in the US and suggests potential for sustainability dependent on state laws. Findings from this case study provide a starting point for inquiry into cannabis donation as a harm reduction strategy in the US; future research is needed to fully understand the individual-level outcomes, public health impacts, necessary legal regulations, and best practices for cannabis donation programs through harm reduction organizations.
... While these efforts aim to mitigate harm and decrease mortality, there is a noted lack of robust evidence supporting the effectiveness and safety of the prescription of stimulants for individuals with stimulant use disorders. Despite decades of research, there are currently no approved medications for treating stimulant use disorder [12]. While a meta-analysis conducted by Tardelli et al. in 2020 yielded positive findings-stating that prescription amphetamines have a beneficial effect for promoting abstinence in individuals with cocaine use disorder [13]-most reviews and meta-analyses have consistently highlighted the low quality of evidence, high dropout rates, exclusion of common comorbidities, and potential adverse reactions and side effects from high-dose psychostimulant exposure [14][15][16][17][18]. ...
... While numerous reviews have explored the use of prescribed psychostimulants for stimulant use disorders, it is essential to note that only one meta-analysis conducted by Tardelli et al. (2020) reached a positive conclusion [13,26]. Most other reviews and meta-analyses have consistently highlighted the lack of evidence supporting pharmacological interventions for these disorders [12,14,27,28]. They have emphasized the low-grade quality of the evidence, high dropout rates potentially leading to bias, the absence of improvements in treatment retention, the exclusion of common comorbidities, and potential adverse reactions and side effects from high-dose psychostimulant exposure [14][15][16]. ...
Amidst the opioid epidemic, harm reduction-oriented approaches have gained traction, including interventions that focus on prescribing pharmaceutical-grade psychoactive substances, such as opioids, instead of illicit versions, intending to mitigate fatal overdose risks arising from the variability in potency and additives found in illicit drugs. Stimulants have increasingly been found in the victims of opioid overdoses, further prompting some to argue for the prescription of stimulant medications for individuals with stimulant use disorders. Yet, the evidence supporting this practice remains insufficient. In this communication, we critically examine the existing evidence, challenges, and cautions surrounding the treatment of stimulant use disorder.
... To address this question, we compared the effects of systemic administration of D 1 R, D 2 R, and AMPA-R antagonists on motivation for cocaine following ShA versus ExA self-administration. Based on findings in humans with a cocaine use disorder suggesting better efficacy for glutamate versus dopamine-based pharmacological treatments (Haile and Kosten 2013), we predicted that systemic administration of DA and glutamate receptor antagonists would mirror effects observed following sitespecific modulation in the NAc (i.e., greater effects of DA receptor antagonism in the ShA versus ExA group, and greater efficacy of AMPA-R antagonism in the ExA versus ShA group; Doyle et al. 2014;Ramôa et al. 2014). ...
Rationale
The development of addiction is accompanied by a shift in the mechanisms motivating cocaine use from nucleus accumbens (NAc) dopamine D1 receptor (D1R) signaling to glutamate AMPA-kainate receptor (AMPA-R) signaling.
Objective
Here, we determined whether similar shifts occur for NAc-D2R signaling and following systemic manipulation of D1R, D2R, and AMPA-R signaling.
Methods
Male rats were given short-access (20 infusions/day) or extended-access to cocaine (24 h/day, 96 infusions/day, 10 days). Motivation for cocaine was assessed following 14 days of abstinence using a progressive-ratio schedule. Once responding stabilized, the effects of NAc-D2R antagonism (eticlopride; 0–10.0 μg/side) and systemic D1R (SCH-23390; 0–1.0 mg/kg), D2R (eticlopride; 0–0.1 mg/kg), and AMPA-R (CNQX; 0–1.5 mg/kg) antagonism, and NAc-dopamine-R gene expression (Drd1/2/3) were examined.
Results
Motivation for cocaine was markedly higher in the extended- versus short-access group confirming the development of an addiction-like phenotype in the extended-access group. NAc-infused eticlopride decreased motivation for cocaine in both the short- and extended-access groups although low doses (0.1–0.3 μg) were more effective in the short-access group and high doses (3–10 μg/side) tended to be more effective in the extended-access group. Systemic administration of eticlopride (0.1 mg/kg) was more effective in the extended-access group, and systemic administration of CNQX was effective in the extended- but not short-access group. NAc-Drd2 expression was decreased in both the short- and extended-access groups.
Conclusion
These findings indicate that in contrast to NAc-D1R, D2R remain critical for motivating cocaine use with the development of an addiction-like phenotype. These findings also indicate that shifts in the mechanisms motivating cocaine use impact the response to both site-specific and systemic pharmacological treatment.
... ,40 Moreover, moderator analyses by primary drug target showed variability in effect-size direction and magnitude with effects for cocaine and stimulant studies showing a range from moderate and negative35,41 to large and positive 57,58 effects. This variability may be due, in part, to the lack of FDA-approved pharmacotherapy for cocaine/stimulant use disorder.73 In other words, FDA approval in this case was potentially confounded with the primary drug target. ...
Importance
Substance use disorders (SUDs) represent a pressing public health concern. Combined behavioral and pharmacological interventions are considered best practices for addiction. Cognitive behavioral therapy (CBT) is a first-line intervention, yet the superiority of CBT compared with other behavioral treatments when combined with pharmacotherapy remains unclear. An understanding of the effects of combined CBT and pharmacotherapy will inform best-practice guidelines for treatment of SUD.
Objective
To conduct a meta-analysis of the published literature on combined CBT and pharmacotherapy for adult alcohol use disorder (AUD) or other SUDs.
Data Sources
PubMed, Cochrane Register, MEDLINE, PsychINFO, and Embase databases from January 1, 1990, through July 31, 2019, were searched. Keywords were specified in 3 categories: treatment type, outcome type, and study design. Collected data were analyzed through September 30, 2019.
Study Selection
Two independent raters reviewed abstracts and full-text articles. English language articles describing randomized clinical trials examining CBT in combination with pharmacotherapy for AUD and SUD were included.
Data Extraction and Synthesis
Inverse-variance weighted, random-effects estimates of effect size were pooled into 3 clinically informative subgroups: (1) CBT plus pharmacotherapy compared with usual care plus pharmacotherapy, (2) CBT plus pharmacotherapy compared with another specific therapy plus pharmacotherapy, and (3) CBT added to usual care and pharmacotherapy compared with usual care and pharmacotherapy alone. Sensitivity analyses included assessment of study quality, pooled effect size heterogeneity, publication bias, and primary substance moderator effects.
Main Outcomes and Measures
Substance use frequency and quantity outcomes after treatment and during follow-up were examined.
Results
The sample included 62 effect sizes from 30 unique randomized clinical trials that examined CBT in combination with some form of pharmacotherapy for AUD and SUD. The primary substances targeted in the clinical trial sample were alcohol (15 [50%]), followed by cocaine (7 [23%]) and opioids (6 [20%]). The mean (SD) age of the patient sample was 39 (6) years, with a mean (SD) of 28% (12%) female participants per study. The following pharmacotherapies were used: naltrexone hydrochloride and/or acamprosate calcium (26 of 62 effect sizes [42%]), methadone hydrochloride or combined buprenorphine hydrochloride and naltrexone (11 of 62 [18%]), disulfiram (5 of 62 [8%]), and another pharmacotherapy or mixture of pharmacotherapies (20 of 62 [32%]). Random-effects pooled estimates showed a benefit associated with combined CBT and pharmacotherapy over usual care (g range, 0.18-0.28; k = 9). However, CBT did not perform better than another specific therapy, and evidence for the addition of CBT as an add-on to combined usual care and pharmacotherapy was mixed. Moderator analysis showed variability in effect direction and magnitude by primary drug target.
Conclusions and Relevance
The present study supports the efficacy of combined CBT and pharmacotherapy compared with usual care and pharmacotherapy. Cognitive behavioral therapy did not perform better than another evidence-based modality (eg, motivational enhancement therapy, contingency management) in this context or as an add-on to combined usual care and pharmacotherapy. These findings suggest that best practices in addiction treatment should include pharmacotherapy plus CBT or another evidence-based therapy, rather than usual clinical management or nonspecific counseling services.
... Among these interventions, the instrumental use of cannabis among people who use drugs (PWUD) continues to be explored as a prospective harm reduction strategy to reduce or eliminate the use of more harmful drugs. Several studies have pointed to the potential for cannabis to reduce the harms of illicit drug use through lowering the frequency or outright substitution of other toxic substances (Ciccarone, 2011;Corsi, Davis, Kral, Bluthenthal & Booth, 2015;Haile & Kosten, 2013;Lau et al., 2015;Lucas, 2017;Reiman, 2009; (Lucas et al., 2016) (Lucas et al., 2013)). Much of the literature has drawn on medical cannabis patients' self-report data (Corroon, Mischley & Sexton, 2017;Lucas, 2017;Reiman, Welty & Solomon, 2017) and has demonstrated that cannabis is associated with self-reported decreases in the use of prescription opioid analgesics (see also Boehnke, Litinas & Clauw, 2016;Lucas & Walsh, 2017). ...
The ongoing overdose crisis in the United States and Canada has highlighted the urgent need for innovative interventions to reduce drug-related harms. This, in turn, has led to increased interest in the potential of cannabis as a harm reduction strategy. While Canada has recently legalized cannabis, meaningful barriers to accessing legal cannabis remain for people who use drugs (PWUD) from marginalized communities. In the Downtown Eastside of Vancouver, Canada, innovative, grassroots cannabis distribution programs that dispense cannabis and cannabis products from unregulated sources to PWUD for free have recently emerged. In this study, we draw upon 23 in-depth qualitative interviews and ethnographic fieldwork with PWUD who access these programs. We found that these distribution programs play an important function in bridging access to cannabis for PWUD in a structurally disadvantaged neighborhood and do so by implementing few restrictions on who can access, providing a variety of cannabis products that would otherwise be inaccessible, and distributing cannabis at no cost. In addition, many people reported the program spaces provided an avenue to socialize and connect. Most of our participants reported that legal cannabis was inaccessible both through the legal medical and non-medical systems. Considering Canadian governments have made important regulatory changes in regards to cannabis, understanding emerging patterns and the structural barriers to accessing legal cannabis will be critical to maximizing the potential uses of cannabis as a harm reduction tool and ensuring equitable access to structurally disadvantaged populations. Examining the impact of cannabis use on PWUD and ensuring these groups have access to cannabis is an important component in determining whether cannabis deregulation reduces drug-related harms.
... [21] b) N Acetyl cysteine [22] c) Gabapentin [23] Although antagonism of CB1 receptors is beneficial in acute cannabis intoxication but such drugs were withdrawn from the market because of psychiatric adverse effects such as suicidality and anxiety. [24,25] Methamphetamines [26] No drugs approved till date [27,28] b) Mirtazapine (found efficacious) [29] c) Bupropion (useful for less severe SUD) [30] Study showed beneficial effect of naltrexone in methamphetamine use disorder [31,32] Cocaine [33,34] No FDA approved drugs ...
... After three decades of pre-clinical research and clinical trials of promising medications, no pharmacotherapy exists for the treatment of for stimulant use disorder (Haile and Kosten 2013). Trials of disulfiram, doxazosin, modafinil, topiramate, buproprion, modafinil, naltrexone, and methylphenidate have proven disappointing. ...
Growing recognition of the biological underpinnings of substance use disorders (SUDs) has led to increased acceptance of pharmacotherapy-based treatments for general populations and, more recently, for individuals under criminal justice supervision, including those in correctional settings. This paper focuses on pharmacotherapies that have been approved by the United States Food and Drug Administration (FDA) for treatment of alcohol use disorder and opioid use disorder. For alcohol use disorder, these medications are disulfiram, naltrexone, and acamprosate; for opioid use disorder, these are methadone, buprenorphine, and naltrexone. Promising pharmacotherapies for stimulant use disorder are also briefly summarized. The paper concludes with three “lessons learned,” specifically: (1) treatment and policy should reflect the fact that substance misuse and addiction is a medical disorder, (2) interventions for SUDs should be integrated into primary care, and (3) reductions in substance use among pharmacotherapy-treated patients do not necessarily lead to concomitant reductions in crime (nor should this be the primary rationale for providing such treatment).
... Cocaine abuse persists as a major public health problem for which no pharmacotherapy has proven to be sufficiently effective (Haile and Kosten, 2013;Czoty et al., in press). The success of methadone and nicotine replacement therapies in the treatment of opiate and nicotine addiction, respectively, has encouraged efforts to develop an indirect dopamine agonist medication to treat stimulant abuse (Grabowski et al., 2004a;Herin et al., 2010). ...
Chronic treatment with the monoamine releaser d-amphetamine has been consistently shown to decrease cocaine self-administration in laboratory studies and clinical trials. However, the abuse potential of d-amphetamine is an obstacle to widespread clinical use. Approaches are needed that exploit the efficacy of the agonist approach but avoid the abuse potential associated with dopamine releasers. The present study assessed the effectiveness of chronic oral administration of phendimetrazine (PDM), a pro-drug for the monoamine releaser phenmetrazine, to decrease cocaine self-administration in four rhesus monkeys. Each day, monkeys pressed a lever to receive food pellets under a 50-response fixed-ratio schedule of reinforcement and self-administered cocaine (0.005-0.56 mg/kg per injection, i.v.) under a progressive-ratio (PR) schedule in the evening. After completing a cocaine self-administration dose-response curve, sessions were suspended and PDM was administered (1.0-9.0 mg/kg, p.o., b.i.d.). Cocaine self-administration was assessed using the PR schedule once every 7 days while food-maintained responding was studied daily. When a persistent decrease in self-administration was observed, the cocaine dose-effect curve was re-determined. Daily PDM treatment decreased cocaine self-administration by 30-90% across monkeys for at least 4 weeks. In two monkeys, effects were completely selective for cocaine. Tolerance developed to initial decreases in food-maintained the third monkey, and in the fourth fluctuations were observed that were lower in magnitude than effects on cocaine self-administration. Cocaine dose-effect curves were shifted down and/or rightward in three monkeys. These data provide further support for the use of agonist medications for cocaine abuse, and indicate that the promising effects of d-amphetamine extend to a more clinically viable pharmacotherapy.
... Methamphetamine (MA) use disorder is a serious worldwide health problem for which there is no approved pharmacotherapy. 1 Medication development for substance use disorders (SUDs) has typically focused on agents that target receptors and/or neurotransmitter systems affected by MA. 2 Decades of research. However, has unfortunately yielded no viable treatment for MA use disorder. ...
... Note that levels were comparable at 8 and 12 weeks in mice used in the place conditioning study to mice used in the MA brain study. This statement is supported by a lack of statistical significance between groups (F (2,20) ¼ .012; p ¼ .988). ...
Background and objectives:
We previously reported that an anti-methamphetamine (MA) vaccine attenuated drug-conditioned effects in mice, but it used a carrier protein and adjuvant not available for clinical use. Here we produced a vaccine with the same hapten (succinyl-methamphetamine, SMA) but attached to tetanus toxoid (SMA-TT) and adsorbed to aluminum hydroxide, components approved for use in humans. We then assessed the vaccine's ability to generate anti-MA antibodies, alter acquisition and reinstatement of MA place conditioning, and prevent MA brain penetration.
Methods:
Mice were administered SMA-TT at weeks 0 and 3 and non-vaccinated mice received saline. Anti-MA antibody concentrations were determined at 8 and 12 weeks. Place conditioning began during week 9 in which vaccinated and non-vaccinated mice were divided into groups and conditioned with .5, or 2.0 mg/kg MA. Following acquisition training, mice were extinguished and then a reinstatement test was performed in which mice were administered their original training dose of MA. Separate groups of non-vaccinated and vaccinated mice were administered .5 and 2.0 mg/kg MA and brain MA levels determined.
Results and conclusions:
Anti-MA antibody levels were elevated at week 8 and remained so through week 12. The SMA-TT vaccine attenuated acquisition and reinstatement of MA place conditioning. Significantly greater proportions of vaccinated mice during acquisition and reinstatement tests showed conditioned place aversion. Moreover, MA brain levels were decreased in vaccinated mice following administration of both doses of MA.
Scientific significance:
Results support further development of anti-MA vaccines using components approved for use in humans. (Am J Addict 2015;XX:XX--XX).
