Open research questions in Cannabis and Cannabinoid Research

What the literature leaves open

• Potential for combination therapies, precision medicine, and overcoming resistance In the management of metabolic disorders, especially obesity and related disorders, novel CB1 receptor blockers offer a bright future. Combination medicine, precision medicine and overcoming resistance are important areas of Journal of Pharmaceutical Research. Vol. 25, No. 2, April-June 2026:102 Jain, et al.: Peripherally selective CB1 receptor antagonists- a promising therapeutic strategy for metabolic disorders interest, and these areas will be the focus of future development.

  Peripherally Selective CB1 Receptor Antagonists: A Promising Therapeutic Strategy for Metabolic Disorders · 2026 · DOI

• While preclinical studies consistently suggest anxiolytic and antidepressant‐like effects of CBD, clinical evidence remains inconsistent and fails to establish robust therapeutic efficacy.

  Psychiatric effects of cannabidiol, cannabinol, and tetrahydrocannabinol: A narrative review of clinical evidence and risk profiles · 2026 · DOI

• A ratio-based framework offers a parsimonious explanation for contradictory findings in the literature, and aligns ECS 74 Journal of Pre-Clinical and Clinical Research 2026, Vol 20, No 2 David A.

  Ratio-based cannabinoid signalling – limitations of absolute endocannabinoid levels in predicting clinical states · 2026 · DOI

• While this study yields valuable insights, several limitations must be acknowledged to interpret the findings appropriately. First, the sample was drawn from university students in three major cities in Türkiye and was not randomly selected. We used a combination of convenience and snowball sampling for the survey, and then purposively sampled high-risk individuals for interviews. As such, our sample may not be fully representative of all Turkish university students. Those who volunteered for a study on cannabis likely include a higher proportion of frequent users and students open about their use. Students who abstain or who use but fear disclosure might be underrepresented. This sampling bias means the prevalence estimates and even the strength of associations observed might not generalize to more hidden users or to other regions (e.g., more conservative rural areas or different universities). Relatedly, because the qualitative phase deliberately focused on students with elevated cannabis problems or psychological distress, the themes identified may emphasize the more problematic end of the spectrum. Caution is needed in extending conclusions to casual or infrequent cannabis users—our study was exploratory and intentionally targeted those experiencing issues, to maximize informational richness, but that comes at the cost of generality. Second, the study relied on self-report measures for both the survey (questionnaires) and the interviews. Self-report is inherently vulnerable to certain biases. Notably, substance use can be underreported due to social desirability or fear of repercussions—a concern particularly salient in the Turkish context where cannabis is illegal and stigmatized. We assured participants of confidentiality, but some may still have minimized their use or related problems.

  Psychological distress, distress tolerance, and cannabis-related problems among university students in Türkiye: a mixed-methods study · 2026 · DOI

• Future research should adopt longitudinal designs to clarify the temporal and potentially bidirectional relationships between psychological distress and cannabis use. Experience sampling methods may further elucidate moment-to-moment associations between affect and use behavior. Expanding the range of examined variables—such as coping motives, personality traits, and social context—would provide a more comprehensive understanding of risk and protective factors. Additionally, intervention-focused studies targeting emotion regulation and distress tolerance are warranted to evaluate strategies for reducing maladaptive coping through substance use. Future research should also explore potential gender differences in cannabis use, coping motives, and psychological outcomes.

  Psychological distress, distress tolerance, and cannabis-related problems among university students in Türkiye: a mixed-methods study · 2026 · DOI

• BackgroundPsychotic-like experiences (PLEs) index early risk for psychotic disorders and are consistently associated with childhood trauma, yet underlying biological mechanisms remain poorly understood.

  Developmental Associations Linking Childhood Trauma and Early Cannabis Use to Adolescent DNA Methylation and Psychotic-Like Experiences · 2026 · DOI

• Conclusions Current evidence is inconclusive as to whether THC-containing cannabis products might have a positive effect in IBD, given heterogenous findings and mostly low-to-moderate evidence quality.

  Effectiveness of THC-containing cannabis for inflammatory bowel disease: a systematic review · 2026 · DOI

• Although regular CU beginning in adolescence is expected to blunt dopamine-related neurophysiology, this hypothesis has not been tested in adolescents due to methodological limitations.

  The role of subcortical brain tissue iron as an indicator of dopamine neurophysiology in adolescent cannabis use · 2026 · DOI

• Structural alterations in the orbitofrontal cortex (OFC) and medial prefrontal/anterior cingulate cortex (mPFC/ACC) have been linked to cannabis use, though findings remain inconsistent in directionality.

  High-resolution Orbitofrontal Cortex Morphometry and Cannabis Use Disorder Severity in High-risk Emerging Adults: A Preliminary Study · 2026 · DOI

• While studies of current and new MC users have informed the field, research on the pre-initiation phase—identifying factors associated with intention to start MC—is scarce.

  Baseline factors associated with intention to initiate medical cannabis among older adults with chronic pain in a prospective cohort · 2026 · DOI

• A key strength of this study was the longitudinal design, which addressed a gap in the literature by qualitatively examining quality of life experiences among people with anxiety over a period of 12 months after treatment commencement.

  Beyond symptom change: a qualitative descriptive study of reported quality of life experiences among adults prescribed medicinal cannabis for anxiety disorders · 2026 · DOI

• Future research could examine QoL outcomes across broader demographic, cultural, and clinical contexts and explore how experiences evolve over longer periods of medicinal can- nabis treatment. Further work is also needed to develop and validate approaches to assessing driving impairment follow- ing prescribed medicinal cannabis treatment to support road safety and inform policy.

  Beyond symptom change: a qualitative descriptive study of reported quality of life experiences among adults prescribed medicinal cannabis for anxiety disorders · 2026 · DOI

• requires comprehensive CB1 and CB2 play vital roles in many physiological processes important for human health, survival, and recovery. Because their overall structures are highly similar, it is often difficult to design ligands that bind selectively to one receptor without affecting the other. Most cannabinoid ligands reported so far show only moderate selectivity, differing by a few-fold in potency between CB1 and CB2. Resolving these subtle selectivity differences structural insight into both receptors. However, the current structurally available data poses limitations. Since CB1 was discovered earlier, most available three-dimensional structures represent CB1-bound complexes, while CB2 structures remain relatively few. This imbalance may bias comparative analyses and restrict conclusions about CB2-specific interactions. Expanding the CB2 structural repertoire and investigating receptor behavior within membrane environments may reveal conformations that favor selective ligand binding.

  Structural insights into cannabinoid receptors CB1 and CB2: determinants of ligand selectivity · 2026 · DOI

• Advancing the scientific basis for the claims and hypotheses developed here will require prospective, controlled, and biomarker-anchored research. The following directions represent priorities identified by this analysis: • Longitudinal biomarker plasma measuring studies cannabinoid levels, cortisol trajectories, rate variability, and inflammatory markers (e.g., IL-6, TNF-α, CRP) across extended periods heart • Pharmacokinetic modeling of and CBD accumulation clearance dynamics in highfrequency, multi-route users, with particular attention to the temporal persistence of effects physiological relative subjective effects to • Trauma-informed clinical trials examining CBD’s role in autonomic regulation and stress-response attenuation, with designs that exclude confounding by concurrent THC exposure correctional • Ethical observational studies and within custodial environments examining the physiological consequences of cannabinoid deprivation acute stress conditions under of • Policy analyses examining the current adequacy classification cannabinoid frameworks emergency in medicine, detention health, and public health contexts From a regulatory perspective, consider should agencies classification revising frameworks reflect pharmacological specificity, clinical that ensuring guidelines and institutional protocols in current evidence rather than legacy stigma. Specifically, the distinction between CBD and intoxicating cannabinoids should grounded are to IJMJ-V4-N1-2026-P- 64 Kathleen Eberhardt [2026]. International Journal of Medical Justice, IJMJ, Volume 4, Issue 1: January-June 2026 [E-ISSN: 2583-7958] International ISSN [CIEPS]: 3006-208X[Print] 3006-2098[Online] greatest of the peeranticustodial be codified in clinical triage protocols, health standards, and drug testing interpretation guidelines.

  Physiological Context During Arrest and Custody: A Personal Recollection of Cannabinoid Exposure and Acute Stress · 2026 · DOI

• empirical research. cannabidiol, Keywords: system, endocannabinoid physiological resilience, trauma physiology, HPA axis, custodial health, autoethnography, opioid toxicity…

  Physiological Context During Arrest and Custody: A Personal Recollection of Cannabinoid Exposure and Acute Stress · 2026 · DOI

• This analysis is subject to several important constraints. First, observational foundation is autoethnographic, which — while methodologically legitimate for health research — does not permit causal inference (Ellis et al., 2011). No biomarker data (e.g., plasma CBD levels, cortisol concentrations, or inflammatory respiratory were collected contemporaneously or quantify retrospectively cannabinoid presence, autonomic temporal function, relationship CBD exposure and the acute event.

  Physiological Context During Arrest and Custody: A Personal Recollection of Cannabinoid Exposure and Acute Stress · 2026 · DOI

• The CBDP dose and co-administration ratio were selected based on prior CBD studies rather than being optimized for CBDP, representing a standardized condition within an established range rather than an optimized exposure.

  Cannabidiphorol (CBDP) acts as a negative allosteric modulator at two distinct sites of cannabinoid receptor 1 · 2026 · DOI

• Given the pharmacokinetic properties of CBDP remain undefined, this study was not designed to characterize formal dose–response or time-course relationships.

  Cannabidiphorol (CBDP) acts as a negative allosteric modulator at two distinct sites of cannabinoid receptor 1 · 2026 · DOI

• Previous studies of HIV and cannabis use have focused largely on heavy, such as daily, use. Study of mild/moderate use was necessary to discover different patterns for YWH, including examination of a range of cannabis use frequency which is critical for understanding population-specific impacts on cognitive functioning.

  Cannabis use frequency may differentially impact cognitive performance in young adults with and without HIV · 2026 · DOI

• In this review, we summarized some of the most relevant labeled probes that enabled the study of CB1R as part of the ECS. The available probes, both radio- and fluorescently labeled, have demonstrated great utility for CB1R in vitro and in vivo visualization, orthosteric, and allosteric target-engagement studies, diagnostic biomarker investigations, as well as pharmacological and pharmacokinetic studies. Still, for both, radio- and fluorescently labeled probes, research gaps remain. No CB1R radiolabeled probe has reached clinical practice as a diagnostic, despite examples of successful clinical translation and the advancements that have been made in the field in recent years. In the case of fluorescent CB1R probes, existing probes in part suffer from limited distribution and broader application in cross-validation studies. Tailored probe design, comprehensive pharmacological profiling, and applying high-quality probe validation principles will improve the reliability, accessibility, and applicability of both probe types. Despite the elaborate design and development, once thoroughly optimized for CB1R affinity and selectivity, physiochemistry, and on-target functional potency, labeled probes can serve as high-quality tools in ECS drug discovery research. When compared to genetic or immunological approaches, the complementarity and non-invasiveness of labeled chemical tool compounds have the potential to provide new insights and significantly extend our knowledge of CB1R’s molecular, pharmacological, and biological function. In addition, academic-industrial networks and partnerships can pave the way for synergistic, streamlined development and data sharing of CB1R probes, with mutual benefits of both basic and clinical research, combining capacities and expertise across disciplines such as medicinal chemistry, chemical biology, and translational drug discovery. AdvAnces in chemicAl Biology: insights from efmc-iscB 2025 CHIMIA 2026, 80, No.

  Unlocking the Multifaceted Role of CB1R in the Endocannabinoid System with Labeled Chemical Probes · 2026 · DOI

• While there are a few known CYP450 enzymes that are induced by THC and CBD, the induction of CYP450 enzymes is an understudied area of research and lacks clinical data.

  Effects of cannabidiol and Δ ⁹ -tetrahydrocannabinol on cytochrome P450 enzymes: a systematic review · 2024 · DOI

• Objective: A critical question regarding the public health impacts of cannabis legalization is its impact on alcohol consumption and alcohol-related harm, but little is known about whether changing cannabis policies are occurring in liberal or restrictive alcohol policy environments, which likely affect public health impacts.

  Relationships Between Alcohol and Cannabis Policies in U.S. States, 1999–2019 · 2023 · DOI

• Conclusions: Authors recommend additional research on mechanisms of change and motivational enhancement therapy, behavioral activation, and family-based skills interventions matched to YAP motivations for use/cessation.

  Scoping Review of Cannabis-Reduction Psychosocial Interventions and Reasons for Use among Young Adults with Psychosis · 2023 · DOI

• Cannabinoid-based medicines (CBM) have some benefits that inhibit BPSD and cause minimal adverse effects (AEs), yet limited research has been considered with this population.

  Examining the use of cannabidiol and delta‐9‐tetrahydrocannabinol‐based medicine among individuals diagnosed with dementia living within residential aged care facilities: Results of a double‐blind randomised crossover trial · 2023 · DOI

• The reversibility of neurologic deficits after cannabis use is noted at 7 and 28 days, but longer-term longitudinal follow-up data beyond 28 days is needed to establish sustained recovery patterns.

  Cannabis-Induced Psychosis in a Young Man With Traumatic Brain Injury · 2022 · DOI

Most-cited papers in Cannabis and Cannabinoid Research

• Adverse Health Effects of Marijuana Use · New England Journal of Medicine · 2014 · 2,129 citations
• Neuropsychological Performance in Long-term Cannabis Users · Archives of General Psychiatry · 2001 · 503 citations
• The association between cannabis use and depression: a systematic review and meta-analysis of longitudinal studies · Psychological Medicine · 2013 · 501 citations
• Blockade of Effects of Smoked Marijuana by the CB1-Selective Cannabinoid Receptor Antagonist SR141716 · Archives of General Psychiatry · 2001 · 396 citations
• Cannabis use disorders in the USA: prevalence, correlates and co-morbidity · Psychological Medicine · 2006 · 354 citations
• The time course and significance of cannabis withdrawal. · Journal of Abnormal Psychology · 2003 · 346 citations
• Medical Marijuana Laws, Traffic Fatalities, and Alcohol Consumption · The Journal of Law and Economics · 2013 · 326 citations
• What is the prevalence and risk of cannabis use disorders among people who use cannabis? a systematic review and meta-analysis · Addictive Behaviors · 2020 · 311 citations
• Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review · Drug Metabolism Reviews · 2013 · 290 citations
• Adverse effects of medical cannabinoids: a systematic review · Canadian Medical Association Journal · 2008 · 282 citations

Most recent work

• Prevalence and Correlates of Symptoms of Cannabinoid Hyperemesis Syndrome in the United States · medRxiv · 2026
• Cannabidiphorol (CBDP) acts as a negative allosteric modulator at two distinct sites of cannabinoid receptor 1 · Communications Chemistry · 2026
• Phytochemical screening and multi-analytical characterization of Cannabis sativa, cultivated in Mt Kenya region, Kenya · Plant Biosystems · 2026
• A retrospective analysis of voluntary adverse event reports to the TGA with higher THC medicinal cannabis products · Australian & New Zealand Journal of Psychiatry · 2026
• Genetic architecture of phenological, morphological, and phytochemical traits in Cannabis landraces. · The Plant Genome · 2026
• Acetaminophen alters endogenous lipid signaling and attenuates pathological pain through a mechanism requiring diacylglycerol lipase, monoacylglycerol lipase and cannabinoid CB1 receptors in mice · bioRxiv · 2026
• Links between Cannabinoid Hyperemesis Syndrome symptoms and drug use, mental health problems, antisocial behavior, and personality in a national survey of adults in the United States · medRxiv · 2026
• Change and Antecedents of Cannabis Consumption After the Legalization of Recreational Cannabis in Germany · Journal of Drug Education · 2026
• Relationships between cannabis use and mental disorders: assessing the coherence of evidence from studies with different methodologies · The Lancet Psychiatry · 2026
• Unlocking the Multifaceted Role of CB1R in the Endocannabinoid System with Labeled Chemical Probes · CHIMIA International Journal for Chemistry · 2026

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