Jul 2026· Current Neuropharmacology· Vol 24· 0 citations
Medicine
TL;DR
Evidence is provided regarding the impact of trace amine-associated receptor 1 (TAAR1) agonists on rodent models of substance use disorders (SUDs) and a lack of studies examining the effects of TAAR1 agonists in female subjects to strengthen evidence for TAAR1 agonists as potential therapeutic agents for cocaine-use disorder.
Abstract
This narrative review provides evidence regarding the impact of trace amine-associated receptor 1 (TAAR1) agonists on rodent models of substance use disorders (SUDs). We delineated the fundamental aspects of the pharmacodynamics and pharmacokinetics of TAAR1 agonists and collected in vivo studies that investigated TAAR1 activation in behavioral sensitization, conditioned behaviors, or self-administration models. TAAR1 agonists have demonstrated efficacy in suppressing addiction-relevant behaviors associated with cocaine. Their effectiveness is largely consistent across intrinsic activity levels, routes of administration, and experimental protocols. TAAR1 agonists also show certain preliminary promise as amphetamine psychostimulants, nicotine, alcohol, and opioids, but the number of studies remains very small. The reported effects occurred at doses that did not impair natural reward behavior. Moreover, the findings for alcohol use disorder demonstrated efficacy in both male and female subjects. Conversely, opioid studies have presented mixed results, highlighting the need for further investigation. There is a lack of studies examining the effects of TAAR1 agonists in female subjects, which is crucial for understanding potential sex differences in treatment responses. The limited number of research groups working on this topic raises concerns regarding bias and reproducibility. Future research should address these gaps, expand investigations to diverse populations, and replicate findings across laboratories to strengthen evidence for TAAR1 agonists as potential therapeutic agents for cocaine-use disorder.
Trace amines (TAs) are endogenous biogenic amines present at low concentrations in the brain and were historically considered byproducts of monoamine metabolism. The discovery of trace amine-associated receptors (TAARs), a family of G protein-coupled receptors, has redefined their physiological and pharmacological relevance. TAAR1 regulates dopaminergic, serotonergic, and glutamatergic signaling and is increasingly implicated in neuropsychiatric disorders. Preclinical studies show that TAAR1 agonists normalize dopaminergic function and improve cognitive deficits in schizophrenia models. Early clinical evidence suggests potential antipsychotic efficacy with a favorable extrapyramidal and metabolic safety profile. However, the failure of subsequent phase III trials to meet their primary efficacy endpoints highlights the need to identify responsive patient subgroups, optimize trial design, and clarify the clinical settings in which TAAR1 agonism may provide the greatest therapeutic benefit. In depression, TAAR1 activation produces antidepressant-like effects in preclinical models, whereas findings in anxiety are variable and context-dependent. TAAR1 may also modulate reward-driven feeding and metabolic parameters. Mechanistically, TAAR1 agonists differ in their effects on dopamine transporter function and monoaminergic neuron activity, indicating that their pharmacological effects are compound-specific rather than class-wide. These properties distinguish TAAR1-targeting compounds from classical D2 receptor antagonists and may underlie their clinical profile. Further translational studies are required to confirm their efficacy across symptom domains and establish long-term clinical benefit.
Overall, the existing findings support TAAR1 as a therapeutic target for treatment of substance use disorders, however, translating these findings into effective human pharmacotherapies requires navigating ligand-specific effects and pharmacokinetic demands and defining the role of human TAAR1 genetic diversity in therapeutic response.
Samantha M. Rios, Shkelzen Shabani, T. J. Phillips· Handbook of Experimental Pha...· 0 citations
Alcohol use disorder (AUD) is a prevalent condition associated with significant morbidity and mortality rates. Existing pharmacological and psychosocial treatments offer limited long-term effectiveness. At present, there is a critical need for novel AUD treatments. The endogenous cannabinoid system (ECS) may offer some therapeutic promise for AUD, given that it appears to play a role in alcohol use motivation, while alcohol alters ECS function. Since craving and withdrawal are key AUD symptoms and represent important treatment targets, the role of the ECS in mediating craving and withdrawal should be fully explored. Exploitation of the ECS may have potential as a treatment target for AUD.
This review synthesizes results from preclinical investigations into the impact of cannabinoid (CB) receptor modulation on measures of craving and withdrawal since the discovery of the CB1 receptor.
Researchers identified studies published between 1988 and 2026 involving direct CB receptor modulation, measuring outcomes pertaining to craving or withdrawal, and containing a control group were included in qualitative synthesis. Studies focused on alcohol consumption were not analyzed unless craving or withdrawal-related outcomes were reported. Risk of bias was examined using the SYRCLE tool for preclinical studies.
Thirty-nine studies met inclusion criteria, all preclinical. Overall, CB1 activation generally increases craving-related behaviors, while antagonism tends to attenuate craving and some withdrawal-related outcomes, although dose-dependent effects were also reported. CB2 may mediate reinforcing effects of alcohol, but direction of effects is inconsistent. Evidence regarding withdrawal is limited and inconsistent.
Preclinical evidence suggests that cannabinoid receptor modulation influences alcohol craving and withdrawal-related behaviors. Integration of these behavioral findings with the broader ECS literature suggests that CB1-mediated reward and motivational processes, and CB2-mediated neuroimmune signaling may represent important mechanisms underlying these phenotypes. Greater methodological standardization and clinical investigation are needed to confirm these mechanisms and determine their translational potential for AUD treatment.
The protocol was pre-registered through Prospero (registration CRD42022309872) on 5/31/22.
Meggan L. Archey Drennan, Eleftherios M. Hetelekides, H. Karoly· Journal of Cannabis Research· 0 citations
OBJECTIVE
Cannabis policy, public perception, and consumption patterns have undergone enormous shifts, yet the scientific understanding of these changes has lagged. Our objective is to describe how human behavioral pharmacology studies provide a rigorous framework for modelling Cannabis Use Disorder (CUD) and for informing the development of treatment approaches.
METHODS
This narrative review synthesizes insights from over 25 years of human laboratory research, highlighting how behavioral pharmacology, e.g., dose, placebo control, behavioral specificity, inform the development of evidence-based therapies and targeting the behavioral drivers of CUD.
RESULTS
Key takeaways: (1) Cannabis potency is not Δ9-tetrahydrocannabinol dose. Participants adjust inhalation patterns as a function of cannabis strength. (2) Placebo responding is robust even among experienced cannabis smokers; placebo-controlled studies are limited by regulatory barriers but are essential to distinguish pharmacological effects from expectancy. (3) How medications alter CUD-relevant behaviors (reinforcement, misuse-related ratings) and non-specific behaviors (e.g., sedation) portend clinical efficacy and tolerability and vary as a function of participant phenotype.
CONCLUSIONS
Rigorous, placebo-controlled human laboratory studies of the behavioral effects of cannabis are essential to informing a quickly evolving field complicated by the complexity of cannabis as a plant with a myriad of active constituents, regulatory hurdles, and industry narrative.
Alcohol use disorder (AUD) is highly prevalent, yet current pharmacotherapies remain underutilized and demonstrate only modest efficacy. Cannabidiol (CBD) has emerged as a potential therapeutic option for numerous psychiatric conditions, including AUD. Three reviews published in 2019 examined the effects of CBD on alcohol-related outcomes, but conclusions were limited by the scarcity of clinical trials at that time. The clinical research and published literature have since expanded substantially, warranting an updated synthesis of the evidence. In this narrative review, we evaluate the current state of research on CBD as a pharmacotherapy for AUD. Despite strong preclinical evidence for CBD isolate reducing alcohol consumption, clinical trials have yielded largely null findings. Effects on alcohol craving and reward are inconsistent across human and preclinical studies. Initial evidence from observational studies suggests plant-derived CBD formulations including small amounts of THC and other cannabinoids may reduce alcohol consumption and craving, which warrants further investigation in a randomized, controlled trial. There is also growing preclinical evidence that CBD reduces symptoms of alcohol withdrawal and attenuates alcohol-induced liver disease and neurodegeneration; however, clinical evidence is limited in these domains. Several methodological considerations may account for these mixed findings. CBD has poor oral bioavailability, suggesting that alternative formulations and routes of administration may improve ecological validity and therapeutic potential. Future clinical trials should prioritize transparent reporting of cannabinoid content, including THC, as well as measurement of plasma CBD levels. Additionally, incorporating biobehavioral phenotyping approaches may help identify subgroups most likely to benefit from CBD. Overall, preclinical evidence supporting CBD as a treatment for AUD remains strong, while emerging human data are mixed. More rigorous and methodologically refined clinical trials are needed to clarify the potential therapeutic applications of CBD for AUD.
Background/Objectives: Methylphenidate is one of the most widely prescribed psychostimulants for attention-deficit/hyperactivity disorder, with increasing global use. Its pharmacological action on dopaminergic pathways raises concerns regarding its addictive potential. This systematic review aims to synthesize current evidence on the addictive properties of methylphenidate, including misuse, abuse, tolerance, craving, and withdrawal symptoms. Methods: This systematic review was conducted in accordance with PRISMA guidelines and registered in the PROSPERO database under registration number CRD420261303803. Literature searches were performed in PubMed, Web of Science, and Google Scholar without time restrictions. Studies assessing behavioral, subjective, or neurobiological indicators of methylphenidate addiction were included. Eligible designs comprised randomized controlled trials, observational studies, neuroimaging studies, case reports, and relevant preclinical models. Study quality was assessed using the EPHPP tool. A total of 35 studies were included in the qualitative synthesis. Results: The evidence demonstrated that methylphenidate produced measurable reinforcing effects and subjective drug liking, which were found to be closely related to craving and to depend on dose, pharmacokinetics, and route of administration. Rapid increases in brain dopamine levels, particularly following non-oral or high-dose administration, were associated with higher abuse potential. Misuse was observed to be more common among individuals without ADHD and was often motivated by cognitive enhancement rather than euphoria. In contrast, appropriately monitored therapeutic use was associated with a low observed risk of substance use disorders. Pharmacodynamic tolerance was identified in a subset of patients, whereas a classical withdrawal syndrome was not consistently observed and was generally limited to symptom recurrence. Conclusions: Methylphenidate exhibits measurable addictive potential. However, its clinical significance is context-dependent. Under therapeutic conditions, the risk of addiction is low, whereas it increases substantially with non-medical use, high doses, and alternative routes of administration. These findings support careful patient selection, preference for extended-release formulations, and monitoring of misuse risk.
Unknown authors· Pharmaceuticals· 0 citations
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