Medicinal cannabis in the management of anxiety disorders: A systematic review

Posted on May 27, 2025 by David

“Background: With rising anxiety disorder diagnoses, many individuals are seeking alternatives to standard pharmacotherapies, like medicinal cannabis. This systematic review focuses exclusively on anxiety-related disorders and examines a wide range of cannabis-based preparations and interventions.

Method: We searched MEDLINE, EMBASE, CINAHL, and PsycInfo (October-December 2023) for peer-reviewed empirical studies, excluding case series, case studies, and review papers. Inclusion criteria were studies on adults (18+ years) diagnosed with anxiety-related disorders, examining the efficacy or effectiveness of medicinal cannabis. Studies on recreational cannabis or cannabis-use-disorder were excluded. The MASTER and QualSyst tools were used to assess bias.

Results: Fifty-seven studies met the inclusion criteria: 40 % cohort (n = 23), 30 % randomised controlled trials (n = 17), 18 % cross-sectional (n = 10), 12 % qualitative or other designs (n = 7). The MASTER scale revealed a high risk of bias, with a mean score of 62.9 (out of 100) due to inadequate reporting. Among the 13 highest-quality studies, 70 % (n = 9) reported a positive improvement for disorders including generalised anxiety disorder (GAD), social anxiety disorder (SAD), and post-traumatic stress disorder (PTSD). 30 % (n = 4) reported a negative result for conditions like obsessive-compulsive disorder, trichotillomania, test anxiety and SAD. Over 90 % of all studies, including lower quality studies, reported positive outcomes for CBD and THC-based cannabis. However, 53 % (n = 30) either omitted, or included self-reported data on either form and/or dosage.

Conclusion: Medicinal cannabis demonstrates potential in reducing anxiety symptoms, but the long-term benefits and overall impact on quality of life remain unclear. Further high-quality, longitudinal research with standardised dosing is needed.”

https://pubmed.ncbi.nlm.nih.gov/40413923/

“Across a range of anxiety-related disorders, most high-quality studies found that medicinal cannabis reduced anxiety symptoms in individuals with GAD, PTSD and SAD.”

https://www.sciencedirect.com/science/article/pii/S0165178125002008?via%3Dihub

Low-dose cannabidiol treatment prevents chronic stress-induced phenotypes and is associated with multiple synaptic changes across various brain regions

Posted on May 24, 2025 by David

“Major Depressive Disorder (MDD) is a heterogeneous and debilitating mood disorder often associated with stress. Although current treatments are available, they remain ineffective for approximately 30% of affected individuals and are frequently accompanied by undesirable side effects.

Cannabidiol (CBD) has emerged as a potential and safe therapeutic option for alleviating depressive symptoms; however, the underlying molecular mechanisms through which this compound exerts its beneficial effects are not yet fully understood.

In this study, we demonstrate that a very low dose of CBD (1 mg/kg) can partially reverse some sequelae induced by chronic stress, a well-established mouse model used to simulate depressive-like symptoms. Using mass spectrometry to analyze different brain regions, we observed several improvements following CBD treatment, particularly in the medial prefrontal cortex (mPFC), across multiple neurotransmission systems (including glutamatergic and serotonergic pathways). Microstructural experiments, utilizing double-labeling of F-Actin and VGlut1-positive clusters, revealed a complete restoration of mature synapses in the mPFC of mice treated with CBD.

In conclusion, our findings indicate that a very low dose of CBD is effective in counteracting the adverse effects of chronic stress, possibly through the synaptic remodeling of excitatory synapses in the mPFC.”

https://pubmed.ncbi.nlm.nih.gov/40409535/

“We show that a very low dose of CBD is enough to correct emotional sequelae in a mouse model of chronic stress.”

https://www.sciencedirect.com/science/article/pii/S0028390825002321?via%3Dihub

Daily Impact of Medical Cannabis on Anxiety and Sleep Quality in Older Adults

Posted on May 19, 2025 by David

“Objective: Older adults represent the fastest growing demographic of cannabis users, and they endorse cannabis use for a variety of reasons including modulation of chronic pain, mental health symptoms, and sleep concerns. However, current evidence leaves questions of efficacy unanswered among these groups. Goals of the present study were to examine the hypothesis that medical cannabis (MC) use will, at the daily level, predict lower pain, depression, anxiety, and improved sleep.

Method: A final sample of 106 MC users were recruited nationwide (ages 55-74, 66.67% female, 82.86% white). A fully within-subject multilevel structural equation model was conducted with use patterns and symptomology broken into four temporal epochs. MC use, operationalized as subjective intoxication (Epoch 1), averaged across the day was used to predict subsequent pain, anxiety, and depression levels (Epoch 2), which were then used to predict sleep that night (Epoch 3), then subsequent pain, anxiety, and depression the following day (Epoch 4) prior to initiation of MC use.Results: Subjective intoxication predicted lower post-use pain, anxiety, and depression. Subjective intoxication is related to lower anxiety and better sleep the following night.

Conclusions: These findings provide evidence of momentary improvements in pain, anxiety, depression, and indirect benefits for sleep quality. In combination with other findings, the results advance our understanding of the efficacy and limitations of MC among older adults. Findings are limited by MC measurement and sample homogeneity (primarily White, non-Hispanic female). Future research should seek to further measurement of use and corresponding effects and examine expectancy effects in aging clinical populations.”

https://pubmed.ncbi.nlm.nih.gov/40372396/

https://www.tandfonline.com/doi/full/10.1080/00332747.2025.2484827

Cannabinoids: Adaptogens or Not?

Posted on May 8, 2025 by David

“Since ancient times, humanity has been exploring natural substances with the aim of increasing stress resistance, enhancing biochemical homeostasis, and treating different diseases. In this way, the objective of the present review is to compare the biological effects of cannabinoids (CNBs) with adaptogens, this exploration allows us to consider the controversy if they can be classified together considering the effects on the body.

First, the work revises different features of adaptogens such as their chemical structure, ligand-receptors properties, and homeostasis-stress capabilities. Also, this review includes an overview of preclinical and clinical studies of the effect of adaptogens considering a broad spectrum of adverse biological, chemical, and physical factors.

Then, the work does a review of the CNBs effects on the body including the principal uses for the treatment of several diseases as neurodegenerative disorders, arthritis, cancer, cardiovascular affections, diabetes, anxiety, chronic pain, among others. In addition, the different characteristics of the specific endocannabinoid system are described explaining the wide CNBs body effects.

Finally, this review presents a comparative analysis between CNBs and adaptogens properties, expecting to contribute to understanding if CNBs can be classified as adaptogens.”

https://pubmed.ncbi.nlm.nih.gov/40332769/

https://www.liebertpub.com/doi/10.1089/can.2024.0108

“Adaptogens are herbs and plant-based substances believed to help the body manage stress and restore balance after stressful situations”

“Adaptogens are active ingredients in certain plants and mushrooms that may impact how your body deals with stress, anxiety and fatigue.”

Improvements in health-related quality of life are maintained long-term in patients prescribed medicinal cannabis in Australia: The QUEST Initiative 12-month follow-up observational study

Posted on April 3, 2025 by David

“Aims: Since 2016, more than one million new patients with chronic health conditions have been prescribed medicinal cannabis in Australia. We aimed to assess overall health-related quality of life (HRQL), pain, fatigue, sleep, anxiety, depression, and motor function in a large real-world sample of patients prescribed medicinal cannabis. We previously found all patient-reported outcomes improved in the first 3-months and hypothesised that improvements would be maintained to 12-months.

Methods: The QUEST Initiative, a multicentre prospective study, recruited adult patients with any chronic health condition newly prescribed medicinal cannabis oil between November 2020 and December 2021. Participants identified by 114 clinicians across Australia completed validated questionnaires at baseline, then 2-weeks titration, and 1-,2-,3-,5-,7-,9- and 12-months follow-up.

Results: Of 2744 consenting participants who completed baseline assessments, 2353 also completed at least one follow-up questionnaire and were included in analyses, with completion rates declining to 778/2353 (38%) at 12-months. Ages ranged between 18-97 years (mean 50.4y; SD = 15.4), 62.8% were female. Chronic conditions commonly treated included musculoskeletal pain (n = 896/2353; 38.1%), neuropathic pain (n = 547/2353; 23.2%), insomnia (n = 546/2353; 23.2%), anxiety (n = 520/2353; 22.1%), and mixed depressive and anxiety disorder (n = 263/2353; 11.2%). Clinically meaningful improvements were observed in HRQL: EQ-5D-5L index (d = 0.52) and QLQ-C30 summary scores (d = 0.91), PROMIS fatigue (d = 0.51) and sleep disturbance (d = 0.76). Participants diagnosed with chronic pain experienced clinically meaningful improvement in scores on QLQ-C30 pain (d = 0.5), PROMIS pain intensity (d = 0.76), and PROMIS pain interference (d = 0.76). There was significant improvement in DASS anxiety (d = 0.69) and DASS depression (d = 0.65) for those with anxiety or depressive conditions, but no motor function improvements observed for participants with movement disorders. All observed improvements were statistically significant.

Conclusions: Statistically significant and clinically meaningful improvements in overall HRQL, fatigue, and sleep disturbance were maintained over 12-months in patients prescribed medical cannabis for chronic health conditions. Anxiety, depression, insomnia, and pain also improved over time for those with corresponding health conditions.”

https://pubmed.ncbi.nlm.nih.gov/40173146/

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0320756

Cannabidiol alters psychophysiological, craving and anxiety responses in an alcohol cue reactivity task: A cross-over randomized controlled trial

Posted on February 2, 2025 by David

“Background: Preclinical studies have demonstrated that cannabidiol (CBD) reduces alcohol-seeking behaviors and may have potential for managing alcohol use disorder (AUD). In this study, we examined the effects of CBD versus placebo on (i) psychophysiological, craving and anxiety responses to alcohol and appetitive cues; (ii) tolerability measures including cognitive functioning.

Methods: Twenty-two non-treatment-seeking individuals with AUD (DSM-5) participated in a cross-over, double-blind, randomized trial, receiving either 800 mg of CBD or matched placebo over 3 days. A laboratory alcohol cue reactivity task with appetitive control (juice) and alcohol exposures, and subsequent recovery periods to examine regulation of cue-elicited responses after cue-offset (recovery) was completed, with psychophysiological indices of autonomic nervous system activity (skin conductance, high-frequency heart rate variability [HF-HRV]) and self-reported measures (alcohol craving and anxiety). Self-reported scales of sedation and neuropsychological executive function tasks were also completed.

Results: CBD sessions were significantly associated with elevated parasympathetic nervous system (PNS) activity across the task, as indicated by increased HF-HRV. Reductions in self-reported anxiety during cue exposure stages compared to placebo sessions were also evidenced. Reductions in self-reported alcohol craving after cue exposure were seen during CBD sessions only. There were no significant differences between CBD and placebo on executive functioning performance.

Conclusions: In a short-term regimen, CBD appears to modulate PNS activity, reduce cue-elicited anxiety during cue exposure and reduce alcohol craving after cue exposure while not significantly impairing cognition. Large, parallel clinical trials with longer term regimens are now needed to determine the therapeutic potential of CBD in the management of AUD.”

https://pubmed.ncbi.nlm.nih.gov/39891614/

https://onlinelibrary.wiley.com/doi/10.1111/acer.15514

Bridging the gap: The endocannabinoid system as a functional fulcrum for benzodiazepines in a novel frontier of anxiety pharmacotherapy

Posted on January 29, 2025 by David

“While benzodiazepines have been a mainstay of the pharmacotherapy of anxiety disorders, their short-term efficacy and risk of abuse have driven the exploration of alternative treatment approaches.

The endocannabinoid (eCB) system has emerged as a key modulator of anxiety-related processes, with evidence suggesting dynamic interactions between the eCB system and the GABAergic system, the primary target of benzodiazepines.

According to the existing literature, the activation of the cannabinoid receptors has been shown to exert anxiolytic effects, while their blockade or genetic deletion results in heightened anxiety-like responses. Moreover, studies have provided evidence of interactions between the eCB system and benzodiazepines in anxiety modulation. For instance, the attenuation of benzodiazepine-induced anxiolysis by cannabinoid receptor antagonism or genetic variations in the eCB system components in animal studies, have been associated with variations in benzodiazepine response and susceptibility to anxiety disorders.

The combined use of cannabinoid-based medications, such as cannabinoid receptor agonists and benzodiazepine co-administration, has shown promise in augmenting anxiolytic effects and reducing benzodiazepine dosage requirements.

This article aims to comprehensively review and discuss the current evidence on the involvement of the eCB system as a key modulator of benzodiazepine-related anxiolytic effects, and further, the possible mechanisms by which the region-specific eCB system-GABAergic connectivity modulates the neuro-endocrine/behavioral stress response, providing an inclusive understanding of the complex interplay between the eCB system and benzodiazepines in the context of anxiety regulation, to inform future research and clinical practice.”

https://pubmed.ncbi.nlm.nih.gov/39862927/

https://www.sciencedirect.com/science/article/abs/pii/S0163725825000117?via%3Dihub

Cannabidiol abrogates cue-induced anxiety associated with normalization of mitochondria-specific transcripts and linoleic acid in the nucleus accumbens shell

Posted on January 16, 2025 by David

“Anxiety disorders are one of the top contributors to psychiatric burden worldwide. Recent years have seen a dramatic rise in the potential anxiolytic properties ascribed to cannabidiol (CBD), a non-intoxicating constituent of the Cannabis Sativa plant.

This has led to several clinical trials underway to examine the therapeutic potential of CBD for anxiety disorders. Yet, CBD’s anxiolytic effects are mixed with some studies reporting little to no impact on trait anxiety but significant reductions in pathological anxiety with suggestions that CBD’s effect may relate to triggered or cue-induced behavior.

Here, we studied the effects of CBD on cued and non-cued behaviors and related neurobiological underpinnings. To investigate the effect of CBD on cue-induced anxiety, male rats underwent a fear conditioning protocol (odor associated with shock) followed by assessments of avoidance behavior. CBD (10 mg/kg) was administered 1 h prior to anxiety assessments. To understand molecular mechanisms associated with behavior, we investigated the transcriptome and lipid profile of the nucleus accumbens shell (NAcSh), a structure implicated in cue-mediated behaviors and aversion.

Administration of CBD significantly reduced avoidance behavior, but only in animals repeatedly exposed to a shock-paired cue. CBD did not affect behavior in animals exposed to neutral cue or encoding of the cue behavioral response. RNA sequencing revealed substantial impact of the shock-paired cue in control animals, recruiting mechanisms ranging from cytoskeletal dynamics to mitochondria dysfunction. The shock-paired cue also resulted in elevated linoleic acid in vehicle animals which correlated with anxiety-like behavior. CBD either reversed or normalized these cue-induced molecular phenotypes. CBD also recruited lipid networks which correlated with transcripts involved in synaptic plasticity, signaling, and epigenetic mechanisms.

These results suggest that CBD may specifically alleviate salient, conditioned anxiety and normalize related biological mechanisms in the NAcSh which may guide therapeutic interventions for anxiety disorders.”

https://pubmed.ncbi.nlm.nih.gov/39815058/

https://www.nature.com/articles/s41380-024-02881-2

An Unexpected Activity of a Minor Cannabinoid: Cannabicyclol (CBL) Is a Potent Positive Allosteric Modulator of Serotonin 5-HT1A Receptor

Posted on January 16, 2025 by David

“Cannabicyclol ((±)-CBL), a minor phytocannabinoid, is largely unexplored, with its biological activity previously undocumented. We studied its conversion from cannabichromene (CBC) using various acidic catalysts. Montmorillonite (K30) in chloroform at room temperature had the highest yield (60%) with minimal byproducts. Key reaction conditions, such as solvent, temperature, and time, significantly impacted the yield. The structure of (±)-CBL was confirmed via X-ray crystallography. Stability studies showed that (±)-CBL and its MCT oil dilution remain stable at 25-40 °C for three months. Radioligand binding assays revealed high affinity of CBL for the 5-HT_1A receptor but weak interaction with CB₁ and CB₂ receptors. At 10 μM and 1 μM, (±)-CBL inhibited [³H]-8-hydroxy-DPAT binding to 5-HT_1A by 75% and 20%, respectively. Functional assays showed that (±)-CBL acts as a weak agonist at high concentrations but a potent positive allosteric modulator of serotonin-induced activation at low concentrations. At 4 μM, (±)-CBL increased serotonin-induced β-arrestin recruitment from 20% to 80%. This unique modulatory profile highlights the potential of (±)-CBL in drug discovery targeting serotonin receptors.”

https://pubmed.ncbi.nlm.nih.gov/39811943/

https://pubs.acs.org/doi/10.1021/acs.jnatprod.4c00977

“Positive allosteric modulators of the 5-HT1A receptor can help relieve anxiety and depression.”

CBD and the 5-HT1A receptor: A medicinal and pharmacological review

Posted on January 9, 2025 by David

“Cannabidiol (CBD), a phytocannabinoid, has emerged as a promising candidate for addressing a wide array of symptoms.

It has the ability to bind multiple proteins and receptors, including 5-HT1AR, transient receptor potential vanilloid 1 (TRPV1), and cannabinoid receptors. However, CBD’s pharmacodynamic interaction with 5-HT1AR and its medicinal outcomes are still debated.

This review explores recent literature to elucidate these questions, highlighting the neurotherapeutic outcomes of this pharmacodynamic interaction and proposing a signaling pathway underlying the mechanism by which CBD desensitizes 5-HT1AR signaling.

A comprehensive survey of the literature underscores CBD’s multifaceted neurotherapeutic effects, encompassing antidepressant, anxiolytic, neuroprotective, antipsychotic, antiemetic, anti-allodynic, anti-epileptic, anti-degenerative, and addiction-treating properties, attributable in part to its interactions with 5-HT1AR.

Furthermore, evidence suggests that the pharmacodynamic interaction between CBD and 5-HT1AR is contingent upon dosage. Moreover, we propose that CBD can induce desensitization of 5-HT1AR via both homologous and heterologous mechanisms. Homologous desensitization involves the recruitment of G protein-coupled receptor kinase 2 (GRK2) and β-arrestin, leading to receptor endocytosis. In contrast, heterologous desensitization is mediated by an elevated intracellular calcium level or activation of protein kinases, such as c-Jun N-terminal kinase (JNK), through the activity of other receptors.”

https://pubmed.ncbi.nlm.nih.gov/39778776/

“Cannabis was one of the first inhaled drugs utilized by humans, with evidence of use for gout, rheumatism, and malaria dating to 2737 BCE”

“The concurrent literature revealed that CBD produces several therapeutic effects through its complex pharmacodynamic interactions with 5-HT1AR. Therapeutic applications of CBD, including its anxiolytic, antidepressant, antipsychotic, anti-degenerative, neuroprotective, anti-epileptic, and anti-addictive properties were mediated, at least in part, by its binding to 5-HT1AR.”

https://www.sciencedirect.com/science/article/abs/pii/S0006295225000048?via%3Dihub

www.thctotalhealthcare.com

Category Archives: Anxiety