CBD: References with PubMed Abstract Summaries

[1] Alexander C, Jeon J, Nickerson K, Hassler S, Vasefi M. CBD and the 5-HT1A receptor: A medicinal and pharmacological review. Biochem Pharmacol. 2025 Mar;233:116742. doi:10.1016/j.bcp.2025.116742. PMID: 39778776. [PubMed]

PubMed abstract — summary

This review examines the pharmacodynamic relationship between cannabidiol (CBD) and the serotonin 5-HT1A receptor. CBD interacts with multiple molecular targets, including 5-HT1A, TRPV1 and cannabinoid receptors, but the precise nature and clinical significance of its interaction with 5-HT1A remain under investigation. The authors review evidence linking this pathway to several neurotherapeutic effects, including anxiolytic and antidepressant actions, and emphasise that the interaction appears to depend on dose. They also propose mechanisms by which CBD may desensitise 5-HT1A signalling. Homologous desensitisation is proposed to involve GRK2 and beta-arrestin recruitment with receptor internalisation, whereas heterologous desensitisation may result from increased intracellular calcium or activation of protein kinases through other receptor systems.

[2] Bergamaschi MM, Queiroz RHC, Chagas MHN, de Oliveira DCG, De Martinis BS, Kapczinski F, et al. Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naïve social phobia patients. Neuropsychopharmacology. 2011 May;36(6):1219-1226. doi:10.1038/npp.2011.6. PMID: 21307846. [PubMed]

PubMed abstract — summary

This preliminary double-blind randomised study evaluated a single 600 mg dose of CBD in 24 treatment-naive patients with social anxiety disorder undergoing a simulated public-speaking test; 12 received CBD and 12 placebo, while 12 healthy controls completed the test without medication. Subjective anxiety, negative self-evaluation and physiological responses were assessed repeatedly during the procedure. Pretreatment with CBD significantly reduced anxiety, cognitive impairment and discomfort during speech performance and also reduced anticipatory alertness. Patients receiving placebo showed higher anxiety, impairment, discomfort and alertness than healthy controls. Measures of negative self-statements also worsened in the placebo group but were largely attenuated with CBD. Overall, the CBD-treated group responded more similarly to healthy controls than did the placebo group.

[3] Elmes MW, Kaczocha M, Berger WT, Leung KN, Ralph BP, Wang L, et al. Fatty acid-binding proteins (FABPs) are intracellular carriers for Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). J Biol Chem. 2015 Apr 3;290(14):8711-8721. doi:10.1074/jbc.M114.618447. PMID: 25666611. [PubMed]

PubMed abstract — summary

The study investigated how the highly lipophilic cannabinoids THC and CBD are transported within cells and how this may influence endocannabinoid clearance. Fatty acid-binding proteins (FABPs), which transport anandamide (AEA) intracellularly toward its catabolic enzyme FAAH, were identified as targets of both THC and CBD. Computational analyses and ligand-displacement experiments showed binding of these cannabinoids to several human FABPs. Functional studies demonstrated that THC and CBD can inhibit cellular uptake and catabolism of AEA by competing for FABPs. Importantly, CBD did not directly inhibit human FAAH enzymatic activity, in contrast to observations with rodent FAAH. The authors therefore propose that competition for FABPs can help explain the increased circulating AEA reported after cannabinoid exposure and may contribute to modulation of endocannabinoid tone by CBD.

[4] Leweke FM, Piomelli D, Pahlisch F, Muhl D, Gerth CW, Hoyer C, et al. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry. 2012 Mar 20;2(3):e94. doi:10.1038/tp.2012.15. PMID: 22832859. [PubMed]

PubMed abstract — summary

This translational study explored whether enhancement of anandamide signalling might contribute to the clinical effects of CBD. In a double-blind randomised trial in acute schizophrenia, CBD was compared with amisulpride. Both treatments produced significant clinical improvement, while CBD showed a more favourable side-effect profile. Treatment with CBD was accompanied by a significant increase in serum anandamide concentrations, and the magnitude of this increase was significantly associated with clinical improvement. The findings were interpreted in the context of earlier observations linking higher cerebrospinal-fluid anandamide concentrations with fewer psychotic symptoms. The authors conclude that reduced deactivation of anandamide, and the resulting enhancement of endocannabinoid signalling, may contribute to the antipsychotic mechanism of CBD.

[5] Murillo-Rodriguez E, Blanco-Centurion C, Sanchez C, Piomelli D, Shiromani PJ. Anandamide enhances extracellular levels of adenosine and induces sleep: an in vivo microdialysis study. Sleep. 2003 Dec 15;26(8):943-947. doi:10.1093/sleep/26.8.943. PMID: 14746372. [PubMed]

PubMed abstract — summary

This animal study examined whether adenosine contributes to the sleep-promoting actions of the endocannabinoid anandamide. Male rats underwent basal-forebrain microdialysis and continuous sleep recording after systemic administration of anandamide, vehicle, the CB1 antagonist SR141716A, or the antagonist plus anandamide. Anandamide increased extracellular adenosine relative to vehicle, with maximal levels observed during the third hour after administration. Slow-wave sleep also increased significantly during that period. Both the rise in adenosine and the increase in sleep were prevented by CB1-receptor blockade. The authors therefore concluded that anandamide raises basal-forebrain adenosine and promotes sleep through a mechanism that depends on CB1-receptor signalling.

[6] Dunwiddie TV, Masino SA. The role and regulation of adenosine in the central nervous system. Annu Rev Neurosci. 2001;24:31-55. doi:10.1146/annurev.neuro.24.1.31. PMID: 11283304. [PubMed]

PubMed abstract — summary

This review describes adenosine as a widespread neuromodulator with predominantly inhibitory effects on neuronal activity. Basal extracellular adenosine tonically activates adenosine receptors in brain tissue, with inhibitory actions involving both A1 and A2A receptor systems. Blocking this tonic adenosinergic influence helps explain the excitatory effects of antagonists such as caffeine. The review discusses the physiological and pharmacological evidence that has led to broader hypotheses concerning adenosine in the central nervous system. Functions considered include regulation of sleep and arousal, neuroprotection, control of seizure susceptibility, locomotor effects, analgesia and mediation of some effects associated with ethanol and chronic drug exposure.

[7] Fusar-Poli P, Crippa JA, Bhattacharyya S, Borgwardt SJ, Allen P, Martin-Santos R, et al. Distinct effects of Δ9-tetrahydrocannabinol and cannabidiol on neural activation during emotional processing. Arch Gen Psychiatry. 2009 Jan;66(1):95-105. doi:10.1001/archgenpsychiatry.2008.519. PMID: 19124693. [PubMed]

PubMed abstract — summary

Fifteen healthy men participated in a double-blind, randomised, placebo-controlled functional MRI study comparing 10 mg delta-9-THC, 600 mg CBD and placebo during processing of faces designed to elicit different levels of anxiety. THC increased anxiety and several psychoactive effects, whereas CBD showed a trend toward reduced anxiety. During presentation of intensely fearful faces, CBD reduced fluctuations in skin conductance and attenuated blood-oxygen-level-dependent responses in the amygdala and anterior and posterior cingulate cortex. Reductions in amygdala and anterior cingulate activation were associated with reduced autonomic reactivity. The authors concluded that CBD and THC produce distinct neural and physiological responses, and that modulation of limbic and paralimbic regions by CBD may contribute to reduced autonomic arousal and subjective anxiety.

[8] Narayan AJ, Downey LA, Rose S, Di Natale L, Hayley AC. Cannabidiol for moderate-severe insomnia: a randomized controlled pilot trial of 150 mg of nightly dosing. J Clin Sleep Med. 2024 May 1;20(5):753-763. doi:10.5664/jcsm.10998. PMID: 38174873. [PubMed]

PubMed abstract — summary

This pilot randomised, placebo-controlled trial assessed 150 mg of nightly CBD as a sleep aid in 30 adults with primary insomnia. After a placebo run-in week, participants received CBD or placebo for two weeks, taken sublingually one hour before bedtime. Sleep was evaluated using wrist actigraphy, sleep diaries and weekly laboratory assessments, together with measures of insomnia severity, anxiety and well-being. Most sleep outcomes did not differ between CBD and placebo, including insomnia severity, self-reported sleep-onset latency, subjective sleep efficiency and wake after sleep onset. CBD was associated with higher well-being scores and, after two weeks, better objective sleep efficiency. The authors concluded that 150 mg nightly CBD was broadly similar to placebo for most sleep outcomes and that larger controlled studies across doses and treatment durations are needed.