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Medicine · Research topic

Open research questions in Cannabis and Cannabinoid Research

1,058 gap statements mined from Cannabis and Cannabinoid Research papers in our 7.9M-paper local library, which holds 4,796 papers on the topic — drawn mostly from each paper's own stated research gap, future-work, challenge and limitation notes, and its abstract. The ones listed below are a selection still marked open; each names the study that raised it, with a DOI link where the paper has one.

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What the literature leaves open

One challenge is the limited understanding of the pharmacodynamic interactions among cannabinoids, terpenes, flavonoids, polyphenols, and other Cannabis-derived bioactive compounds. Another challenge is the lack of standardization among cannabis-derived products. The paper also identifies the need for more robust clinical evidence validating the entourage effect in AD patients.
Modulation of the Endocannabinoid System by Cannabis sativa Bioactives in Alzheimer’s Disease: Therapeutic and Nutritional Implications · 2026 · DOI
Most available clinical studies involve relatively small patient cohorts, short intervention periods, and heterogeneous outcome measures. Limited understanding of the pharmacodynamic interactions among cannabinoids, terpenes, flavonoids, polyphenols, and other Cannabis-derived bioactive compounds. Lack of standardization among cannabis-derived products.
Modulation of the Endocannabinoid System by Cannabis sativa Bioactives in Alzheimer’s Disease: Therapeutic and Nutritional Implications · 2026 · DOI
Lack of research investigating the effects of cannabis use disorder on clinical outcomes following ACDF surgery. Limited understanding of the impact of cannabis use disorder on healthcare utilization and opioid use. Need for further study on the potential modulatory effect of cannabis on pain perception.
Impact of cannabis use disorder on risk of surgical complications following anterior cervical discectomy and fusion · 2026 · DOI
Further studies are needed to examine the effects of heroin on CB1 receptor expression and function in humans. Further studies are needed to examine the effects of other opioids on CB1 receptor expression and function. Further studies are needed to examine the effects of CB1 receptor antagonism on heroin CPP in humans.
Heroin-induced neuroadaptations of CB1 receptors and their involvement in conditioned place preference · 2026 · DOI
The neuroadaptations of CB1 receptors following opioid exposure are not well understood. The involvement of CB1 receptors in opioid-driven behaviors, particularly heroin CPP, is less clear.
Heroin-induced neuroadaptations of CB1 receptors and their involvement in conditioned place preference · 2026 · DOI
One of the challenges is the complexity of the endocannabinoid system and its role in shaping the effects of stress and trauma. Another challenge is the need for precision cannabinoid therapeutics, particularly for PTSD and stress-related disorders. The paper also identifies the need to prioritize biological moderators, including sex, developmental stage, and individual ECS profiles.
EBPS2023 special issue: Stress, trauma and cannabinoids · 2026 · DOI
One challenge is the lack of understanding of the effects of perinatal THC exposure on goal-directed behavior and dopamine functioning. Another challenge is the difficulty in measuring dopamine functioning in the brain. The study also faces the challenge of controlling for potential confounding variables, such as maternal behavior and litter size.
Perinatal exposure to delta-9-tetrahydrocannabinol (THC) alters goal-directed behavior and dopamine functioning in wistar rats · 2026 · DOI
Future studies should examine the effects of perinatal THC exposure on other behavioral domains. Future studies should investigate the neural mechanisms underlying the effects of perinatal THC exposure on goal-directed behavior. Future studies should examine the effects of THC exposure on dopamine functioning in other brain regions.
Perinatal exposure to delta-9-tetrahydrocannabinol (THC) alters goal-directed behavior and dopamine functioning in wistar rats · 2026 · DOI
Future studies using inhibitors of eCB synthesis (e.g., the DAG lipase inhibitor DO34 and the NAPE-PLD inhibitor LEI-401) are needed to determine the impact of reduced eCBs during adolescence. Better understanding specific age windows in which eCBs influence behavior will require further investigation. Pretreatment with CB1 receptor antagonists will be needed to confirm that drug effects involve eCB signaling.
Differential effects of adolescent fatty acid amide hydrolase and monoacylglycerol lipase inhibition on adolescent and adult behaviors in male rats · 2026 · DOI
There is a gap in understanding how disrupted catabolism of endocannabinoids during adolescence affects adult behaviors. The study aims to fill this gap by investigating the effects of monoacylglycerol lipase and fatty acid amide hydrolase inhibition on adolescent and adult behaviors.
Differential effects of adolescent fatty acid amide hydrolase and monoacylglycerol lipase inhibition on adolescent and adult behaviors in male rats · 2026 · DOI
There is a lack of research on the long-term effects of adolescent THC exposure on cognitive functioning and anxiety in adulthood. The study aims to fill this gap by investigating the effects of THC exposure on male rats. Prior research has focused on the acute effects of THC exposure, rather than the long-term effects.
Long-term effects of adolescent THC exposure on anxiety-like behavior and cognitive function in male rats · 2026 · DOI
The research highlights the need to understand the dose-dependent effects of β-caryophyllene on cognitive function. The study notes the challenge of translating findings from animal models to human clinical applications.
β-caryophyllene, a CB2-selective phytocannabinoid, differentially modulates attention and inhibitory control in low- and high-performing young and aged mice · 2026 · DOI
Further studies are needed to investigate the therapeutic effects of CBD in humans. The effects of CBD on other types of pain and comorbidities should be investigated. The mechanisms by which CBD exerts its therapeutic effects should be further elucidated. The potential for CBD to be used in combination with other therapies should be investigated.
Cannabidiol in the anterior insular cortex attenuates chronic neuropathic pain and comorbid anxiety- and depression-like behaviors: involvement of CB1 and 5-HT1A receptor signaling · 2026 · DOI
There is an urgent need for more effective and better-tolerated therapeutic strategies for neuropathic pain. Current pharmacological treatments have limitations, including partial pain relief and adverse effects.
Cannabidiol in the anterior insular cortex attenuates chronic neuropathic pain and comorbid anxiety- and depression-like behaviors: involvement of CB1 and 5-HT1A receptor signaling · 2026 · DOI
Differentiating between acute impairment and the 'morning after' presence of cannabinoids in biological markers is a challenge. The residual effects of cannabis use on cognitive and psychomotor performance are not well understood.
The use of THC cutoff levels in blood and oral fluid for detecting impairment in frequent cannabis users who smoked cannabis the “evening before” · 2026 · DOI
More work is needed to better understand interactions between sex and dose in determining acute pharmacological effects of cannabis. The human evidence for sex differences in the effects of cannabis is more equivocal than animal evidence. There is a need to examine sex differences in the acute effects of smoked cannabis, particularly at higher potencies of Δ 9 -tetrahydrocannabinol (THC).
Investigating sex differences in the acute effects of smoked cannabis: a potency-ranging, controlled administration, human laboratory experiment · 2026 · DOI
Further studies could investigate the relationship between substance abuse and comorbidities, - Research could focus on the development of more effective treatment strategies for substance-related…
Patterns of Detecting Substances of Abuse in a Large Series of Patients in Spain During 2021–2025 · 2026 · DOI
Counts of ≤ 10 are platform-suppressed, - Incomplete observation of records, - Limited to patients with adequate potential…
Association of cannabis use disorder with clinical outcomes following lumbar spinal fusion: a propensity-matched cohort study · 2026 · DOI
Investigate the effects of CUD on long-term outcomes after lumbar spinal fusion, - Examine the relationship between CUD and other postoperative…
Association of cannabis use disorder with clinical outcomes following lumbar spinal fusion: a propensity-matched cohort study · 2026 · DOI
Investigating the role of 2-AG as a biomarker of stress vulnerability or resilience, - examining the effects of precision cannabinoid therapeutics on PTSD and stress-related disorders, - considering genetic biomarkers and polymorphisms affecting ECS…
EBPS2023 special issue: Stress, trauma and cannabinoids · 2026 · DOI
The study only examined male Sprague-Dawley rats, - The study used a specific dose of THC (5 mg/kg/day), - The study had a limited sample size…
Long-term effects of adolescent THC exposure on anxiety-like behavior and cognitive function in male rats · 2026 · DOI
The study only examined the effects of acute BCP administration, - The study used a limited number of doses ('0, 25, 50, or 100 mg/kg'), - The study only used male and female C57BL/6J mice, - The study did not examine the long-term effects of BCP…
β-caryophyllene, a CB2-selective phytocannabinoid, differentially modulates attention and inhibitory control in low- and high-performing young and aged mice · 2026 · DOI
Small sample size, - Limited to a specific population of healthy adults who used cannabis 1-5 days/week, - Study was conducted in a controlled laboratory…
Investigating sex differences in the acute effects of smoked cannabis: a potency-ranging, controlled administration, human laboratory experiment · 2026 · DOI
Small sample size of 22 participants, - Limited to non-treatment seeking individuals diagnosed with AUD, - No significant main treatment effects…
Cannabidiol and neural correlates of threat anticipation in alcohol use disorder · 2026 · DOI
Investigate the neural effects of CBD on neurobiological, cognitive, and psychological processes involved in threat anticipation in larger samples, - Examine the effects of CBD on direct responses to salient stimuli rather than anticipatory…
Cannabidiol and neural correlates of threat anticipation in alcohol use disorder · 2026 · DOI

Most-cited papers in Cannabis and Cannabinoid Research

Isolation and Structure of a Brain Constituent That Binds to the Cannabinoid Receptor · Science · 1992 · 4,582 citations
Molecular characterization of a peripheral receptor for cannabinoids · Nature · 1993 · 4,138 citations
Structure of a cannabinoid receptor and functional expression of the cloned cDNA · Nature · 1990 · 4,069 citations
Unresponsiveness to Cannabinoids and Reduced Addictive Effects of Opiates in CB 1 Receptor Knockout Mice · Science · 1999 · 3,425 citations
Adverse Health Effects of Marijuana Use · New England Journal of Medicine · 2014 · 2,129 citations
Cannabinoids for Medical Use · JAMA · 2015 · 1,962 citations
Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review · The Lancet · 2007 · 1,728 citations
Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study · The Lancet · 2005 · 1,221 citations
The Endocannabinoid System and the Brain · Annual Review of Psychology · 2012 · 911 citations
An improved brief measure of cannabis misuse: The Cannabis Use Disorders Identification Test-Revised (CUDIT-R)☆ · Drug and Alcohol Dependence · 2010 · 848 citations

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