We need more research, but CBD is proving to be a helpful, relatively nontoxic option for managing anxiety, insomnia, and chronic pain. CBD, or cannabidiol, is the second most prevalent active ingredient in cannabis (marijuana). Potential adverse drug events and drug–drug interactions with medical and consumer cannabidiol (CBD) use. Taylor L, Crockett J, Tayo B, Morrison G. A phase 1, open-label, parallel-group, single-dose trial of the pharmacokinetics and safety of cannabidiol (CBD) in subjects with mild to severe hepatic impairment. Cannabidiol (CBD) is a non-intoxicating phytocannabinoid from cannabis sativa that has demonstrated anti-inflammatory effects in several inflammatory conditions including arthritis. This alert warns consumers about the potential for adverse events due to insufficient labeling of products containing THC and CBD. In animals, high doses of CBD have caused negative effects on developing fetuses.4 The anxiolytic properties of CBD (cannabidiol) have been subject to thorough investigation in diverse animal and human research. Further research is essential, necessitating meticulous scrutiny of the study's framework, particularly in terms of dosage selection and administration methods . Notably, the research also revealed a dose-dependent reduction in the expression of glial fibrillary acidic protein . Subsequently, administering intraperitoneal injections of CBD (at doses of 2, 5, 10, or 20 mg/kg i.p.) resulted in enhanced cognitive performance. Despite extensive research into the biological effects of synthetic CBD derivatives, they have not been evaluated for their interaction with TRPV1, 5-HT1A and adenosine A2A receptors in the context of anti-inflammatory and antioxidant activity. Furthermore, hydrogenated CBD derivatives such as (+)-dihydrocannabidiol and (+)-tetrahydrocannabidiol have CB1 receptor affinity (Table 2) and show anti-inflammatory effects on the peritoneal cells of C57BL/6 mice and a macrophage cell line. Therefore, known or potential effects of naturally occurring CBD derivatives are presented. In addition, studies in Wistar rats have shown that CBD, by activating 5-HT1A receptors, can reduce physiological and behavioral responses to restrictive stress . Voxel-wise meta-analysis of fMRI studies in patients at clinical high risk for psychosis. Memory-rescuing effects of cannabidiol in an animal model of cognitive impairment relevant to neurodegenerative disorders. Effects of acute cannabidiol administration on anxiety and tremors induced by a Simulated Public Speaking Test in patients with Parkinson’s disease. Figure 1 is a PRISMA 2020 flow diagram showing how related studies included in the review were identified . A PRISMA flow diagram 2020 was used to show the study’s inclusion and exclusion of articles found in the databases used. Furthermore, other publications in the reference list and related studies were also examined to see if they were relevant and could be included in this review. 3. Arthritis-Related Pain CBD had no effect on disease activity at the end of treatment and at 2 weeks follow-up . The effect of oral administration of CBD (20 mg/day for 8 weeks) on disease activity assessed by the Crohn’s disease activity index was evaluated in a small group of patients with long-standing Crohn’s disease taking concomitant medications. Compared to placebo, CBD did not have a significant effect on the level of high-density lipoproteins, the primary endpoint for this study . In contrast, the other study, which included patients with schizophrenia having co-occurring CUD, did not report symptom changes with administration of a modest dose of oral and smoked THC; THC significantly increased serum THC and resulted in a trend toward tachycardia, as expected. The D'Souza study, which was carefully designed to assess symptoms, documented increased positive, negative, and general symptoms of psychosis, as well as impaired cognition when intravenous THC was given to patients with schizophrenia. The Boggs study did not clearly describe the randomization process and pharmaceutical company funding for some of these studies could contribute some potential for bias in the findings (Table 2). A notable point of study design heterogeneity is the inclusion or exclusion of CUD and/or cannabis use during the trial; both studies with positive findings did not omit participants with CUD. The different sample characteristics (age, presence of CUD, or recent use of cannabis), different CBD dose, treatment duration, outcome measures and timing of assessments could contribute to the heterogeneity of findings. Because CBD products aren’t regulated by the FDA in the way that drugs are, there is huge variation in quality and, quite possibly, safety. For example, there is no evidence to suggest that CBD is safe during pregnancy or breastfeeding, or for people who are immunocompromised. This may change as more studies are done, but for now, the jury is out. No current evidence exists on whether or not cannabis-based medicines including CBD prolong time to total arthroplasty following a diagnosis of osteoarthritis. The authors describe an increase in self-reported cannabis use from 1% to 11% following its legalization, attributable either to increased use, or increased self-reporting, given the lack of legal ramifications . In a study by Jennings et al. in 2019, 1,000 records of patients undergoing primary total joint arthroplasty (500 consecutive before and 500 consecutive after the legalization of the commercial sale of marijuana in Colorado) were analyzed. Within large database claims such as this, though, cannabis use was likely not the sole culprit for risks of complications, and additional studies have attempted to understand the influence of specific marijuana use on postoperative outcomes in joint arthroplasty. In 2011, Bergamaschi et al. reviewed the safety and side effects of CBD in both in vitro and in vivo studies and concluded that CBD is well tolerated in humans based on therapeutic case reports but recommended additional studies to better define observed side effects (Bergamaschi et al., 2011). This represents a significant data gap that requires large-scale randomized controlled clinical trials with validated objective sleep measures. On the other hand, intraperitoneal injection of relatively higher doses of CBD (20–40 mg/kg bw) increased slow-wave sleep time and decreased wakefulness in rats (Monti, 1977). Studies investigating the effect of CBD on sleep in animal models and human subjects have yielded mixed results, which could, at least in part, be attributable to the differential effect of CBD based on the administered dose (Babson et al., 2017; Bonaccorso et al., 2019). Our approach of recruiting respondents through email databases of non-vape CBD brands may explain why the sublingual administration route is much more frequent in our study than in the American survey.Nevertheless, CBD and morphine combination produced synergistic effects in reversing acetic acid-stimulated stretching behavior, but subadditive effects in the hot plate thermal nociceptive assay and the acetic acid-decreased operant responding for palatable food assay .Widespread efforts to reduce opioid medications for chronic pain (Dowell et al., 2016) markedly decreased the number of opioid prescriptions (Schieber et al., 2019) leaving older adults with unmet needs for treating their pain (Ritchie et al., 2020).Most studies reported outcomes differently and even in cases where the same outcome was reported it was measured differently.If you do run into any adverse symptoms, such as diarrhea, fatigue, or changes in appetite, discontinue use immediately.In spite of this strong evidence for an involvement of the endocannabinoid system inthe pathophysiology of depression, no clinical trials have been registered toevaluate the efficacy of medical cannabis/medicinal cannabinoids for the treatmentof major depression.The impact of neurological disorders can be substantial, affecting individuals physically, mentally, and emotionally. A complete medical history, including primary and secondary diagnoses, was collected at baseline visit. A waiver of consent was required and approved by Advarra Ethics Committee, who also approved the study protocol, and by the provincial privacy commission (La commission d’accès à l’information du Quebec). Yet, RWE on CBD-rich products is scarce (Goodman et al. 2020; Shannon et al. 2019). The bottom line on cannabidiol A recent survey carried out by Wheeler et al. of 340 young adults, some of whom were CBD users, found the top reasons to be stress relief, relaxation, and sleep improvement.Duration of use of oral cannabis extract in a cohort of pediatric epilepsy patients.By emphasizing CBD's potential to improve patient well-being, this investigation presents a revised viewpoint on its suitability as a therapeutic intervention for neurological illnesses.However, in a Medicare database study by Roche et al. in 2018, patients with a history of drug abuse including cannabis (cannabis use disorder) were at a significantly increased risk for revision total knee arthroplasty than a matched cohort .Reports indicate that the cannabinoid content in products purchased online were only accurate in 26 of the 84 products tested (Bonn-Miller et al., 2017).Cannabis with CBD had a greater impact on the functional connectivity between these two regions relative to cannabis without CBD (Freeman et al., 2018).But bioavailability is not only essential to understanding the pharmacokinetics, but drug interactions are also important to comprehend, as medical CBD users are polypharmacy patients.What’s the most important thing cancer patients should know about CBD oil? In a recent open-label study involving patients with chronic pain and more than 2 years of opioid use, 53.2% of participants were able to reduce opioid medications, lessen their pain, and improve sleep quality after 8 weeks of consuming oral CBD hemp extract (Capano et al., 2020). Despite a lack of evidence supporting long-term opioid use for arthritic pain, a recent study evaluating prescribing practices found that 12.8% of patients were prescribed opioid medications for knee arthritis (Gwam et al., 2021). The magnitude of pain alleviation in our study participants, as measured by percentage reduction in pain or point difference, both surpass the clinically important differences reported in literature (2-point reduction or 30% reduction in pain, respectively) (Farrar et al., 2001, Salaffi et al., 2004). Given the evidence supporting CBD as a sustainable option for pain management, we believe it may be a potential alternative in treating patients with arthritis. It's worth emphasizing that there are more than 100 types of arthritis, and while pain is a cardinal feature of all of them, these conditions do not all act alike. Until recently, there's been little research and even less guidance for people (or their doctors) interested in CBD products that are now increasingly legal and widely promoted. After all, most types of arthritis are not cured by other treatments, and CBD is considered a less addictive option than opiates. The Arthritis Foundation conducted its own poll, and found that 29% reported current use of CBD (mostly in liquid or topical form), and nearly 80% of respondents were either using it, had used it in the past, or were considering it. Taking CBD combined with certain medications can cause higher or lower levels of these medications in the bloodstream, which may alter their effects. In the former open-label trial with eight participants, a dose of 600 mg/day was tested, and two out of five participants completed the 7-day inpatient treatment. Two open-label studies testing the effectiveness of two different concentrations of CBD (200 mg/day and 600–1200 mg/day) obtained positive outcomes with doses as low as 600 mg/day (Hallak et al., 2010; Pokorski et al., 2017). The dose range of 4.1 to 12.8 sprays/day was reported among nabiximols group. All three RCTs in this section provided evidence for the use of nabiximols for moderate to severe cannabis use disorder. The data supporting the findings of this study are available from the corresponding author upon request. There is some evidence, even though low quality, that supports anxiolytic effect of acute administration of oral CBD. RCTs are needed to confirm the effect of CBD on skin disorders, epilepsy and ADR following HPV vaccine. The studies identified that evaluated identical conditions, regrettably employed different endpoints or tools of assessment. Keep in mind, studies show that lower doses of THC/CBD were generally better tolerated than higher doses (Johnson et al., 2010; Portenoy et al., 2012). Discuss the risk for adverse drug effects, such as hepatotoxicity and the need to use lower doses due to accumulation and prolonged effect. Identify preconceived notions of cannabis products and explore expectations the patient may have about CBD and their condition (Highet et al., 2020). Also, clinical findings are currently limited to SAD, whereas preclinical evidence suggests CBD’s potential to treat multiple symptom domains relevant to GAD, PD, and, particularly, PTSD. Limited results in healthy subjects also support the efficacy of CBD in acutely enhancing fear extinction, suggesting potential for the treatment of PTSD, or for enhancing cognitive behavioral therapy. The fearful faces task activates the amygdala, and other medial temporal areas involved in emotion processing, and heightened amygdala response activation has been reported in anxiety disorders, including GAD and PTSD 113, 114. The study has limitations that must be considered when interpreting these results. Recently, the World Health Organization released a critical review on CBD and found it is generally well tolerated with a good safety profile and does not have abuse potential (Expert Committee on Drug Dependence, 2018). Cannabidiol could have unwanted side effects and/or interactions with other medications. Although CBD is available for purchase without consultation with a doctor, the authors recommend that patients discuss this with their doctor before use. One open-label trial suggested favorable evidence for the use of cannabinoids CBD and Δ9-THC for hyperactivity, self-injurious behaviors, and anxiety symptoms in patients with ASD with Grade B recommendation. Nabiximols and CBD were beneficial in cannabis-related disorders in almost all studies with Grade B recommendation, resulting in a decreased risk of withdrawal symptoms and dependence among participants. The evidence reviewed here favors CBD use for patients with schizophrenia and psychosis in Parkinson’s disease in four out of seven studies, except in treatment-resistant cases. Although fewer side effects were reported overall by patients in the studies reviewed here, the vulnerability to addiction to cannabinoids should not be ignored. Future studies designed to explore the comparative benefits of these treatments can shed further light on their clinical potential. Physical health risks (e.g., respiratory and cardiovascular, prematurity and restricted fetal growth, hyperemesis syndrome among others) have also been linked with repeated consumption of cannabis with a high THC content. Regular use of high THC products can produce addiction (cannabis use disorder or CUD). The legalization of cannabis for medical and recreational purposes has progressed internationally. Finally, the effectiveness of CBD in treating mental disorders such as schizophrenia, anxiety and depression remains inconclusive. While there have been a few human studies, the sample sizes have been small, the applied doses showed a large variability and control groups were often lacking. Another promising area of research is the use of CBD in the treatment of neurodegenerative disorders. However, CBD binds to several receptors and enzymes and, therefore, its mode of action remains elusive.CBD probably doesn’t help curb anxiety the way advertisements or anecdotal evidence claim.Bergamaschi et al. describe a chronic study, where a teenager with severe side effects of traditional antipsychotics was treated with up to 1500 mg/day of CBD for 4 weeks.The examination of treatment regimen has been seldom addressed in the literature and further development is required to inform guidelines for prescription and refinement of clinical practice.THC and CBD showed task-specific opposite effects during emotional processing (fronto-temporal), verbal memory (fronto-striatal), response inhibition (fronto-limbic-striatal), and auditory/visual processing (temporo-occipital).Three studies showed no significant improvement in reducing pain, and one had mixed findings in pain control.Additionally, the limited understanding of CBD's mechanisms of action and potential drug interactions necessitates further investigation .In a mouse chronic neuropathic pain model involving foramen rotundum inflammatory constriction trigeminal infraorbital nerve injury, CBD administered orally in a peanut butter vehicle alleviated mechanical allodynia within 1 h and remained significant through 6 h . Research of Cannabidiol Uses for Pain in the Older Adult GPR3 activation also modulates cocaine reinforcement (Tourino et al. 2012), suggesting it may play a role in risk for addiction disorders. Unlike the other 5HT receptors that couple to G-protein-coupled receptors, 5HT3A is a ligand-gated ion channel (Rodriguez Araujo et al. 2020). GPRs 3, 6, and 12 are also called cannabinoid-related orphan receptors, because of their reactivity to endogenous and exogenous cannabinoids (Laun et al. 2019). Cells within these tissues communicate through action potentials, chemical and electrical synapses, and gap junctions, all of which are mediated by the ion channels that control the membrane potential (Neher 1992). These ions regulate the cell membrane potential, which is critical in excitable tissues such as the brain, heart, and pancreas (Neher 1992). Preclinical studies show CBD has numerous cardiovascular benefits, including a reduced blood pressure (BP) response to stress. Pharmacokinetics of oral and intravenous cannabidiol and its antidepressant-like effects in chronic mild stress mouse model. Understanding the modulatory effects of cannabidiol on Alzheimer’s disease. The clinical symptoms of Parkinson’s disease. A phase I study to assess the effect of food on the single dose bioavailability of the THC/CBD oromucosal spray. GPR3, GPR6 and GPR12 are primarily responsible for neurite outgrowth, cell survival and proliferation but have also been implicated in neuropathic pain development . The data presented herein unravel what is known about CBD’s pharmacodynamics and analgesic effects to provide readers with current state-of-art knowledge regarding CBD’s action and future perspectives for research. Therefore, we review the basic research regarding the molecular mechanisms of CBD’s actions with particular focus on its analgesic potential. However, data regarding its mechanism of action and therapeutic potential are abundant and omnifarious. Individuals without psychiatric conditions were significantly more likely than those with to admit that CBD was effective in relieving their symptoms (71.7% vs. 57.8%, Table 3). Other reasons included curiosity, tiredness, depression, chronic and menstrual pain, skin problems, and neurodegenerative diseases. These data align with those of other research on the reasons for using CBD products (13, 21). There was no significant relationship between daily CBD dosage and cannabis use (see Table 4). Respondents who reported using psychotropic medication consumed a higher daily CBD dosage, as well as those who reported any prescribed medication use (see Table 3; Table 1A in Supplementary Materials). Some men may experience mild side effects such as stomach upset or headaches when first starting Nature Boost Gummies, but these side effects are usually temporary and diminish with continued use. When taken regularly, Nature Boost Gummies can help improve overall sexual health and performance by addressing the root causes of ED . Ginseng and maca root are adaptogens that can help reduce stress and anxiety, which are often contributing factors to ED . 2. The Effect of CBD on Parkinson's Disease The Y-axis is arbitrary “Study ID.” The size of each point represents the number of patients included in the study and gives an idea of the “weight” of each study. Notably, 6 out of 11 studies showed over 80% of the patients reporting improvement. The results of efficacy in the studied population suggest that treatment with CBD-based products significantly reduces seizure frequency, even for this otherwise treatment-resistant population. All studies used a heterogeneous population of epilepsy patients, and the segmentation in specific types of syndromes was eventually done afterwards (Figure 1). This study mainly aimed to provide the pharmacokinetics of CBD, as well as the safety and dosing information; however, they did report decreases from the baseline number of seizures. Furthermore, a decrease in the average duration of the seizure was reported in tonic-clonic, tonic, clonic, atonic, myoclonic, countable, and absence seizures; however, the placebo group also reported decreases (34%) in seizure duration as well (Guy et al., 2014; Devinsky et al., 2017). In addition to the proven efficacy, this research has shown an acceptable long-term safety profile and sustained reduction in seizures in long-term CBD treatments (Thiele et al., 2018). 43.9% of the treated patents reported improvement from baseline, which is contrasted to 21.8% reporting improvement in the placebo group. Administration had minimal effects on inflammatory pain but significantly reduced interleukin 1β (IL-1β), IL-10, interferon γ (IFN-γ) levels and increased IL-6 levels . A study with complete Freund’s adjuvant (CFA)-induced inflammatory pain in rodents revealed an important role for CBD and its modified derivatives in chronic pain attenuation . In several inflammatory-induced chronic pain models, cannabinoids, including CBD, may exert an analgesic and anti-inflammatory effects. Key risk factors include being male, of younger age and using high-potency cannabis . It is estimated that 22% of people who ever use cannabis meet criteria for CUD, increasing to 33% in those who use weekly or daily . Worldwide, 22 million people are estimated to meet criteria for CUD, similar in number to opioid use disorders (27 million people) . These targets were often not replicated throughout various models, suggesting the hypothesis of state-dependent effects of CBD. In vivo studies have revealed significant roles of various molecular targets in different models, namely, 5HT1a, CB1, CB2, TRPV1, α3 GlyRs, adenosine A1 and TRPA1. Due to its complex pharmacological profile, effects observed from CBD administration vary and might be state-dependent. However, it is unknown what effects will be caused by “CBD gummies” or “CBD water”, which are increasingly offered by manufactures to a wide audience. Cannabis craving and withdrawal also did not change with THC vs. placebo in these abstinent participants, but scores were also not reported. Only one region, within visual cortex, showed greater connectivity with the NAc in patients than controls. Twelve stable, treated, abstinent outpatients with schizophrenia and CUD were assessed, in contrast to the D'Souza trial, in which CUD was excluded. Two reports were published from a trial evaluating the effect of oral THC 15 mg or smoked THC from a 3.6% NIDA joint on symptoms, cognition and brain circuitry using fMRI (56, 57). The National Academies concluded that substantial evidence exists for the use of cannabis and cannabinoids to treat chronic pain while meta-analyses and systematic reviews of cannabis use, including prescription cannabinoids, have given mixed results for treating chronic pain 85–87. Evidence supports the use of cannabis in patient populations without CKD for treating several of these symptoms including chronic pain, nausea, and loss of appetite. State legalized consumption of cannabis is in conflict with federal law where it remains a Schedule I controlled substance without accepted medical use and a high potential for abuse. For example, chemovars with a higher concentration of THC are selectively produced for recreational use, because THC activation of CB1 mediates the psychotropic effects of cannabis, whereas medical cannabis generally has higher CBD levels than recreational chemovars, often even exceeding the THC content. Freeman et al. (2018) investigated the acute effects of inhaled cannabis with and without CBD, while they listened to classical music and scrambled sound, using the same sample of occasional cannabis users as described by Wall et al. (2019). Significant correlations between the subjective measures of feeling the drug’s effect and brain effects were only found after cannabis without CBD was administered. Seven fMRI studies investigated the acute effects of CBD in direct comparison to those induced by THC, during resting state or a cognitive task. During the sessions, ratings of anxiety (STAI), intoxication (AIS), psychotic symptoms (PANNS) and subjective feelings (VAMS) were obtained. Seven studies performed different cognitive tasks (i.e., go-no go, verbal learning, emotional processing, visual and auditory processing) using the same sample of 15 healthy volunteers (Borgwardt et al., 2008; Bhattacharyya et al., 2009; Fusar-Poli et al., 2009; Fusar-Poli et al., 2010; Winton-Brown et al., 2011; Bhattacharyya et al., 2012b; Bhattacharyya et al., 2015). CBD-rich treatment effectiveness on pain, anxiety, depression symptoms, and on overall wellbeing in 279 patients. Despite growing evidence and interest, no real-world data (RWD) studies have yet investigated patients’ reports of CBD impact on symptom control in the common expression of pain, anxiety, depression, and poor wellbeing. Within the limited results from randomized controlled trials, and lack of trust in product quality and known clinical guidelines and dosages, real-world evidence (RWE) from countries with robust regulatory frameworks may fill a critical need for patients and healthcare professionals. Activation of 5HT1A receptors mediates the anxiolytic effects of cannabidiol in a PTSD model. Long-term use of a cannabis-based treatment in spasticity and other symptoms in multiple sclerosis. Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naïve social phobia patients. Trembly B, Sherman M. Double-blind clinical study of cannabidiol as a secondary anticonvulsant. Zuardi, A. W., Shirakawa, I., Finkelfarb, E., and Karniol, I. G. Action of cannabidiol on the anxiety and other effects produced by delta 9-THC in normal subjects. For example, patients who use Epidiolex may experience diarrhea or other gastrointestinal issues. People who suffer from insomnia experience difficulty falling asleep or staying asleep at night. Currently, there is insufficient research to determine the effectiveness of CBD in treating other health conditions. So far, CBD’s effectiveness in the treatment of epilepsy is well-supported by research. But aside from Epidiolex, no CBD product has been approved by the FDA for any other medical purpose. Have any products using CBD-oil been approved by the FDA to treat anything? Have any CBD-oil derived products been approved by the U.S. There have been reports that cannabinoids like THC and CBD may be helpful for nausea and vomiting and anorexia, as well as neuropathy, anxiety, depression and insomnia. Nine of these 14 studies were conducted in animal models employing what is termed the forced swimming test, a testing paradigm widely used to assess antidepressant effects.Another study of 84 CBD products bought online showed that more than a quarter of the products contained less CBD than stated.You may see them referred to as “marijuana doctors” or “medical marijuana clinics.”It is unclear whether mortality is related to cannabis use, predisposing factors or combinations thereof.Although CBD demonstrates safety and a good side effect profile in many clinical trials , all of the therapeutic options for CBD discussed in this review are limited in a concentration-dependent manner.The clinical relevance of these interactions needs to be explored in future studies (Brown & Winterstein, 2019).Cannabidiol (CBD) has gained significant attention in recent years for its potential therapeutic effects in various neurological disorders. Chronic treatment with CBD also diminished infarct size and cardiac leukocyte infiltration in rat model of ischemia and reperfusion. In conclusion, the studies conducted so far do not reveal hypotensive action of CBD in hypertension, although this compound exhibit antioxidative properties in this disease. However, hemodynamic effects in pithed and vagotomised SHR (increase in SBP and HR and decrease in DBP) were comparable to controls . Similarly to the SHR, the vasodilatory effect of CBD in isolated pulmonary arteries was reduced in patients with hypertension . These opposite effects may result from different pathogenesis and changes in the endocannabinoid system in employed hypertension models . Overall, through presenting data from 16 completed clinical trials involving CBD-based drugs, we intend to inform clinicians about the current status of CBD-based drugs and guide future clinical trial designs for cannabinoid medications to have objective measurements of success, as well as detrimental side effects. This low-abuse and addiction potential formulation is generally well tolerated in most patients, and has a proven long-term safety profile (Schoedel et al., 2018; Laux et al., 2019). Food and Drug Administration (FDA) for two conditions, which rescheduled this formulation to a Schedule III drug, a low abuse potential classification, which allows its use in clinical trials (Drug Scheduling, n.d). Most patients were also taking psychiatric medications and receiving other mental health services, such as counseling, which limits the ability to make any causal links to CBD treatment. Likewise, the clinical population in this case series is skewed younger than typical for our clinic, and future studies could explore the possible selection bias inherent in this treatment option. These results must be interpreted cautiously because this was a naturalistic study, all patients were receiving open-label treatment, and there was no comparison group. Four patients declined CBD treatment because of religious or ethical concerns about the relation to cannabis. The reported half-life of CBD in humans depends on the study (different doses, routes of administration) and may vary from about one hour to five days 58,67. However, it seems that this conversion does not occur in vivo in humans, as evidenced by the absence of THC in the blood of patients who took even very high doses of CBD orally. Multiple studies have shown that CBD has many effects independent of direct or indirect interaction with CB1/CB2 receptors. Cannabidiol (CBD) is a non-intoxicating and generally well-tolerated constituent of cannabis which exhibits potential beneficial properties in a wide range of diseases, including cardiovascular disorders. Administration of CBD to healthy volunteers or animals usually does not markedly affect hemodynamic parameters. This article provides an overview of the scientific work on cannabinoids, CBD, and hemp oil and the distinction between marijuana, hemp, and the different components of CBD and hemp oil products. In June 2018, the first CBD-based drug, Epidiolex, was approved by the US Food and Drug Administration for treatment of rare, severe epilepsy, further putting the spotlight on CBD and hemp oils. Cannabidiol (CBD) oils are low tetrahydrocannabinol products derived from Cannabis sativa that have become very popular over the past few years. RC provides legal advice to companies that manufacture and/or distribute products that contain CBD. Because the FDA currently does not regulate CBD, there are no specific recommended doses. Not much research has looked specifically at CBD and fertility, and most studies have been in animals, not people. If you are taking other medications, CBD can impact their efficacy, and your doctor may need to reevaluate the dose you are taking. CBD can potentially interact with other medications, such as antiepileptic drugs, antidepressants, and opioid analgesics. One trial suggested an increased risk of liver injury among people using other epilepsy drugs (valproate and clobazam), but a later study did not. In addition, CBD activates other vanilloid receptors such as TRPV2 and the potential ankarin protein 1 receptor subtype (TRPA1), while antagonizing the TRP-8 receptor (TRPM8) . In addition, CBD treatment has recently been shown to exhibit an unusual protective effect by transporting proteins including multidrug-1 resistance protein and cytosol transferases, such as S-glutathione-M1 transferase, prior to modification by lipid peroxidation products. These reactions reduce the level of reactive lipid peroxidation products, while increasing the formation of adducts with proteins that promote cell signaling disorders, thus stimulating metabolic modifications that can lead to cellular dysfunction and apoptosis 47,48. With growing acceptance of both medical and recreational cannabis and cannabinoids, further research is required to determine the efficacy, safety, and acceptability of medical and recreational cannabis use among people with CKD and ESRD. Consistent with recommendations regarding the use of tobacco and other smoked substances among patients with CKD and ESRD, smoked cannabis should be avoided among people with cardiovascular or pulmonary disease. It is hypothesized that CBD may act preferentially to reduce seizure spread (Jones et al., 2012), but the exact mechanism underlying the anti-convulsant effects of CBD has not yet been elucidated. CBD has been shown to exert anti-convulsant effects in various animal models of epileptic seizures (Jones et al., 2012; Klein et al., 2017; Costa et al., 2022). A large proportion of epileptic patients suffer from drug-resistant seizures that further increase the rate of cognitive impairment as well as psychiatric and physical disability. Again, the lack of a control group and the low sample size make it impossible to draw any conclusions from this study, as acknowledged by the authors. Grade C recommendation exists for insomnia, anxiety, bipolar disorder, posttraumatic stress disorder, and Tourette syndrome. These levels of evidence help in grading the recommendations, including Grade A (strong), Grade B (moderate), Grade C (weak), and Grade D (weakest). Ethical approval was not required since this research investigated non-sensitive information using completely anonymous survey procedures when the participants are not defined as “vulnerable” and participation will not induce undue psychological stress or anxiety (UCL REC n.d.). The datasets used and analysed during the current study are available from the corresponding author on reasonable request. CH is funded by a University College Hospital National Institute of Health Research (NIHR) Biomedical Research Centre bridging fellowship. However, in the context of receptor activation, few studies elucidate the differential impact of CBD from the major metabolites, including 7-OH CBD, CBD-glucuronide, and 10-OH-7-COOH-CBD (Ujváry and Hanuš 2016). Oral consumption of CBD products requires the CBD to undergo first pass metabolism in the liver, which causes a tenfold reduction in available CBD to be metabolized before entering the circulatory system (Franco et al. 2020). Vaping products tend to be more concentrated than smoking products, leading to higher blood stream CBD levels (Lucas et al. 2018). Increased anandamide levels and improvements in the symptoms of psychosis were reported in another 4-week-long RCT comparing the efficacy of CBD to amisulpride for the treatment of schizophrenia (Leweke et al., 2012). Four of the included studies did not report any adverse effects of CBD among patients with psychosis. Of the seven studies, level 2 evidence was found in three RCTs, level 3 evidence in two clinical trial, and level 4 evidence in one case report and one case series (OCEBM, 2019). No studies of substance use disorders other than cannabis use were identified. The respective treatment was maintained for three additional weeks. Oral doses of 150–400 mg/day CBD (in the last week) were administered. They hopefully will shed light on the inconsistencies observerd in animal studies. Clinical chronic (lasting longer than a couple of weeks) studies in humans are crucial here but were mostly still lacking at the time of writing this review. In the case of clobazam this led to sedation, and its levels were subsequently lowered in the course of the study. In a 4-week open trial, CBD was tested on Parkinson's patients with psychotic symptoms. These results are supported by another study described in the review by Grotenhermen et al.63 In this study, 33 children were treated with a daily dose of 5 mg/kg CBD, which was increased every week by 5 mg/kg increments, up to a maximum level of 25 mg/kg. The CBD interaction with isozymes CYP3A4 and CYP2C19 caused increased clobazam bioavailability, making it possible to reduce the dose of the antiepileptic drug, which in turn reduced its side effects.62 One can often argue that what the studies call “chronic” CBD administration only differs to acute treatment, because of repeated administration of CBD. Moreover, the only acute study that also measured CBD effect on appetite was the study we described above, comparing different cannabis strains. The possibility that larger effects may be observed for patients in the early phases of the disease had been suggested 28, 45. CBD had positive effect on psychotic symptoms especially in acutely psychotic patients , while it had small or no effect on chronic schizophrenia patients who had been treated with anti-psychotics. In the present review, two principal outcomes were considered for schizophrenia patients, psychotic symptoms and cognitive functioning. Food and Drug Administration (FDA); this product is approved for the treatment of rare pediatric seizure disorders. The collective market for cannabis/hemp-based CBD products (including retail, dispensary, and pharmaceutical sales) is expected to exceed $20 billion in the U.S. by 2024 (BDS Analytics). Hemp-derived CBD products have become ubiquitous because they are no longer considered controlled substances, meaning they are widely available in jurisdictions in which cannabis remains illegal. It acts by receptor-dependent mechanisms CB1 (greater affinity than CB2) and CB2, which modulate pain, spasticity, sedation, appetite, and mood, in addition to being a bronchodilator, neuroprotector, antioxidant, and anti-inflammatory. Although cannabis is considered a monospecies (Cannabis sativa L.), there are different subspecies and varieties. In addition, the therapeutic properties of this species have been described in Hindu, Assyrian, Greek, and Roman texts, with clear indications for treating pain, inflammation, or lack of appetite. The hemp plant, also known as cannabis or botanically as Cannabis sativa L. Other clinical trials investigating the effects of CBD on HD symptoms included THC-containing medicines, such as nabilone or Sativex (Curtis et al., 2009; López-Sendón Moreno et al., 2016). To the best of our knowledge, there is only one clinical trial available that investigated the effects of CBD administration in patients suffering from HD. As such, there is a high need for placebo-controlled clinical studies evaluating the effect of isolated CBD supplements to clarify the role and the underlying mechanisms of CBD in chronic pain management. Furthermore, the applied doses ranged from 40 to 300 mg/d and were reported inconsistently and incompletely by patients, which further added complexity to the interpretation of these results. The Impact of THC and CBD in Schizophrenia: A Systematic Review In our survey, sleep was the second-highest-ranking reason for CBD use. They found it significantly lowered feelings of anxiety, accompanying changes in limbic areas, in subjects with social anxiety disorder (SAD) (Crippa et al. 2011). Crippa et al. administered an oral dose of 400 mg CBD or placebo, in a double-blind procedure. It's common to see placebo effects ranging from 15 to 25% in well-conducted epilepsy studies (24, 25), but a recent clinical study surprisingly showed a placebo effect as high as 40% (32). Important to say, not every study reported all the clinical parameters (e.g., % of responders, side effects, quality of life endpoints, etc.), therefore, the analysis might be skewed in some way that it's impossible to account for. Pooled together, the data from 11 studies provide strong evidence in support of the therapeutic value of high-CBD treatments, at least as far as this population of 670 patients is regarded. The present meta-analysis study confirms the anecdotal evidence that CBD treatment improves seizure control in patients with treatment-resistant epilepsy. One hundred sixty-five of 387 (42.6%) endorsed using CBD for self-perceived anxiety. Depression, PTSD, fibromyalgia, ADHD, headache, asthma, THC counteract effects, and restless legs did not vary by sex or age. Overall, 42.5% of respondents said they were using CBD for some sleep issue, either to improve sleep or for self-perceived insomnia. Those using CBD for self-perceived anxiety had lower odds of using CBD in the evening (aOR 0.56, 95% CI 0.14–0.45, p ≤ 0.001). In a study by Malfait et al. in 2000, DBA/1 mice underwent a collagen-induced arthritis (CIA) by immunization with type II collagen (CII) in complete Freund’s adjuvant (CFA) . CBD is a marijuana constituent that has pharmacologic benefits without the additive psychotropic effect of Δ9-tetrahydrocannabinol (THC), another major cannabis ingredient. Additionally, a number of CBD products currently available as supplements with different methods of administration, and it is important to remember that these products are non-pharmaceuticals. Based on available literature relying on retrospective data and case reports, it is challenging to propose a recommendation for CBD use in perioperative pain management. However, there is a lack of high-quality, novel research investigating the use of CBD in human musculoskeletal diseases aside from anecdotal accounts and retrospective reviews, perhaps due to legal ramifications limiting the enrollment of patients. Also in human clinical trials, the potential of CBD as a therapeutic agent for drug-resistant seizures has recently been investigated. Another study assessed the longitudinal impact of CBD on EEG measures in subjects with treatment-resistant epilepsy (Grayson et al., 2021). EEG recordings were mainly used to document the effects of CBD on patients with seizures. Evidence for the effects of CBD on EEG activity in healthy individuals is currently lacking. Additionally, CBD's anti-inflammatory and antioxidant properties may have neuroprotective effects, potentially slowing the progression of neurodegenerative disorders like Alzheimer's disease . It may also have anxiolytic properties, making it a potential option for individuals with anxiety disorders . Research on the use of CBD in neurological disorders is still emerging, but there is growing evidence to suggest that CBD may have beneficial effects in various conditions . Additionally, neurological disorders can have a significant impact on mental health, leading to depression, anxiety, and social isolation. Some common neurological disorders include epilepsy, multiple sclerosis, Parkinson's disease, Alzheimer's disease, neuropathic pain, and anxiety disorders. Epidemiological studies of various neuropsychiatric disorders indicate that a higher CBD content in chronically consumed cannabis may protect against adverse effects of THC, including psychotic symptoms, drug cravings, memory loss, and hippocampal gray matter loss 115–118 (reviewed in ). Overall, preclinical evidence supports systemic CBD as an acute treatment of GAD, SAD, PD, OCD, and PTSD, and suggests that CBD has the advantage of not producing anxiogenic effects at higher dose, as distinct from other agents that enhance CB1R activation. We found that existing preclinical evidence strongly supports CBD as a treatment for generalized anxiety disorder, panic disorder, social anxiety disorder, obsessive–compulsive disorder, and post-traumatic stress disorder when administered acutely; however, few studies have investigated chronic CBD dosing. Most patients (71%) reported no adverse effects, while 6% reported a cough or throat irritation and 5% feared arrest even though medical cannabis is legal in Hawai‘i. However, approximately 17% reported exceeding 100 mg daily, and approximately 10% were uncertain about their CBD dosage.Combination of the two often improved upon the deleterious and psychoactive effects of THC-only administration (Ueberall et al., 2019).Future studies are warranted to properly understand the underlying mechanisms by which CBD improves symptoms of depression and to determine effective dose regimens.For example, in asystematic review, Walsh et al16identified several cross- sectional investigations in which there was clear evidencefor an improvement of mood through medical cannabis.The endocannabinoid system encompasses a growing list of receptors that are bound by the endogenous cannabinoids, or endocannabinoids, 2-arachidonoyl glycerol (2-AG) (Sugiura et al. 1995) and arachidonoyl ethanolamide, or anandamide (AEA) (Felder et al. 1993).However, emphasis was placed on studies providing mechanistic insights, robust methodologies, or clinical relevance to ensure reliability in the synthesis.In situations that differ from those described above, the study was considered at unclear rick of bias.FTC’s principal interest lies in ensuring that advertising claims for consumer products are truthful, accurate, not misleading, and adequately substantiated.Furthermore, psychotic symptoms were reduced in PD patients receiving a flexible dose of CBD (starting at 150 mg/d) for 4 weeks (Zuardi et al., 2009). Furthermore, most of the currently available studies were focused on the toxicity of CBD when administered orally. Moreover, interactions between CBD and other drugs have been suggested based on elevated transaminase levels (indicator of liver injury) in patients taking the antiepileptic drug valproate, concomitantly with Epidiolex® (Gaston et al., 2017). In addition, it has been shown that food can greatly influence CBD bioavailability as evidenced by plasma concentrations of CBD increasing by 4–5-fold when CBD was taken with high-fat meals (Taylor et al., 2018). Clearly the answer to this question is very much dependent on the amount of CBD contained in the products as well as how many and the amounts of these products a typical consumer uses over time. Although CBD-containing consumer products are considered relatively safe by the public, are they risk free? Noteworthy, the original description of the physiology of allosteric modulation of these receptors was performed by the main author of the current paper (41). Another interesting aspect of cannabinoid pharmacology is that CBD tends to block some of adverse events of THC, like anxiety and paranoia (38). The interpretation of higher potency of CBD in combination with other minor compounds is in line with previous reports of synergistic effects between cannabinoid and even non-cannabinoid compounds (34). This might suggest a big impact of the belief in the current “fashionable” therapy using cannabinoids on reported therapeutic responses. Synthetic cannabinoids bind to cannabinoid receptors but may affect the brain in unpredictable ways compared to THC (Centers for Disease Control, 2021). CB1 receptors are found in the brain and peripherally (e.g., intestines, liver, adipose, immune cells), whereas CB2 receptors are in the spleen, tonsils, and immune cells (Mastinu et al., 2020). These endocannabinoids bind to cannabinoid receptors (CB1 and CB2) in various parts of the body. Relatively recently, multidirectional biological effects have been demonstrated in various preclinical models, including the antioxidant and anti-inflammatory effects of cannabidiol 14,73. The derivatives with potential antioxidant and anti-inflammatory effects include, but are not limited to, (+)-CBD derivatives, dihydrocannabidiol and tetrahydrocannabidiol derivatives, and (+)-dihydro-7-hydroxy-CBD . CBD has also been suggested as a therapeutic compound for the treatment of painful diabetic neuropathy due to its ability to activate 5-HT1A receptors . Fasinu et al. created a table with an overview of clinical studies currently underway, registered in Clinical Trials. The high CBD concentration led to a significant decrease in polyps and a return to near-normal levels of phosphorylated Akt (elevation caused by the carcinogen).42 No adverse effects were mentioned in the described study.43 The authors assumed that the observed antitumor effects were mediated via TRPM8 together with ROS release and p53 activation.41 It has to be pointed out though, that xenograft studies only have limited predictive validity to results with humans. Consequently, CBD could be an alternative to other MMP1 inhibitors such as marimastat and prinomastat, which have shown disappointing clinical results due to these drugs' adverse muscoskeletal effects.37,38 The typical side effects of traditional anticancer medication, emesis, and collateral toxicity were not described in these studies. The categorical data of a total of 670 patients were analyzed by Fischer test. The systematic search took place in February/2017 and updated in December/2017 using the keywords “epilepsy” or “Dravet” or “Lennox-Gastaut” or “CDKL5” combined with “Cannabis,” “cannabinoid,” “cannabidiol,” or “CBD” resulting in 199 papers. Can simple exercises like stretching and walking have a noticeable impact on my health? CBD oil and other CBD products aren’t well regulated. If you would like to start using CBD products, it’s best to first talk to your doctor. This information may be useful for healthcare providers working with these patient populations to develop targeted interventions to address these symptoms and provide evidence-based education about CBD, including potential drug interactions. This study on CBD-rich products demonstrates the potential of RWE for the advancement of medical cannabis research and practice guidelines, especially in a world where CBD use is exponentially increasing but scientific data are limited. In such patients, CBD treatments may have been targeted to other clinical symptoms not assessed in the current study. Also, clinical findings are currently limited to SAD, whereas preclinical evidence suggests CBD’s potential to treat multiple symptom domains relevant to GAD, PD, and, particularly, PTSD.It can also show up on a drug test or lead to severe consequences legally or medically.All of their products are non-GMO, completely organic, and free from preservatives, additives, or fillers that you often find in lower-grade CBD oils.Patients in the studies by Fisher et al. and Whitfield-Gabrieli et al. either smoked a single dose of 3.6% THC cigarettes or ingested 15 mg oral THC on one occasion.At least, two systematic reviews have been published on safety and side effects of CBD.Trying over-the-counter products without more stringent regulation carries more risk than reward. Approximately 70% of the participants perceived CBD products as effective, while individuals without psychiatric conditions reported higher perceived effectiveness than those with psychiatric conditions. Moreover, our results suggest that individuals with psychiatric conditions and those using psychotropic medication were more likely to use CBD products to relieve stress and anxiety (medium size effect). Cannabis non-users were significantly more likely than cannabis users to experience CBD side effects (16.3% vs. 6.1%), as shown in Figure 2C (Table 4). Of the total sample, 11.2% reported experiencing side effects related to CBD product usage, with more detailed information shown in Figure 2A. Given the paucity of data in this area, clinical observations can be quite useful to advance the knowledge base and to offer questions for further investigation. CBD has demonstrated preliminary efficacy for a range of physical and mental health care problems. Practitioners in ancient China targeted malaria, menstrual symptoms, gout, and constipation. The most abundant cannabinoid, tetrahydrocannabinol (THC), is well known for its psychoactive properties, whereas cannabidiol (CBD) is the second-most abundant and is nonpsychoactive. In this chart review, CBD was well tolerated in all but 3 patients. There was no firm evidence to support CBD to treat bipolar mania (one case report) or nabiximols (one RCT) to treat ADHD. Nabiximols was found to be effective in reducing the frequency and severity of tics and improving the quality of life in patients with Tourette syndrome according to case reports. The effect on cannabis-related craving was pronounced, with an additive benefit from the use of psychotherapeutic options such as MET or CBT. There is a Grade B recommendation this diagnosis based on the levels of evidence. This review article provides evidence for CBD and CBD-containing nabiximols are two different pharmacological agents. Known as cannabinoids, CBD and delta-9-tetrahydrocannabinol (THC) are different chemicals found in cannabis. Today, you can find CBD oil in capsules, oil bases for vaporizers, tinctures, food items, and beauty products such as bath bombs or lotions. It is a natural substance found in cannabis (also known as marijuana) and hemp plants. There is clear evidence supporting the utility of CBD to treat epilepsy. The CBD product industry has experienced tremendous growth, in part, because CBD is widely touted as an effective therapeutic for myriad health conditions. Indeed, in non-medicated acute schizophrenic patients, AEA cerebrospinal fluid concentrations showed a negative correlation with psychotic symptoms (Giuffrida et al., 2004). Although effective, these treatments are often accompanied by severe side effects including deficits in motor control (Strange, 2001). Regarding the effect of CBD on sleep disorders in PD, some discrepancies are present in the existing results. Acute CBD supplementation (300 mg) was shown to reduce perceived feelings of anxiety and tremor amplitude in PD patients who underwent the simulated public speaking test (de Faria et al., 2020). When CBD was added to their treatments, patients showed improvements in total UPDRS score (Zuardi et al., 2009). A review of 25 studies found that some cannabis products offer modest relief for chronic pain.Demographic characteristics of 279 medical cannabis patients, by symptom groupSample sizes ranged from 15 (63) to 28 (58) in the single dose laboratory studies, and 36 to 88 in the longitudinal clinical trials (59, 61, 62).Conversely, CBD increased circulating VEGF in ZDF rats, thus, effects of CBD on this mediator require further investigation .THC, the major psychoactive component of cannabis, is known to cause tachycardia and orthostatic hypotension in humans (20), a hemodynamic response similar to that observed to CBD in the present study.We found that existing preclinical evidence strongly supports CBD as a treatment for generalized anxiety disorder, panic disorder, social anxiety disorder, obsessive–compulsive disorder, and post-traumatic stress disorder when administered acutely; however, few studies have investigated chronic CBD dosing.In spite of the limitations, numerous anecdotal findings testify to the therapeutic effects of CBD, including anticonvulsant, antipsychotic, anxiolytic, neuroprotective and sleep-promoting effects, which are further supported by research . Pelvic floor exercises: Help for incontinence, sexual health, and more In cancer anorexia cachexia syndrome patients’ cannabinoid treatment did not significantly improve appetite, oral intake, or anorexia-related quality of life . As an adjuvant treatment, they showed higher antiemetic effects than placebo or conventional anti-emetics . Nabiximols are only recommended if other treatments are ineffective, and a 4-week trial produces at least a 20% reduction in spasticity-related symptoms . There are biologically plausible reasons for the use of CBD in anxiety. Self-perceived anxiety was the top-ranked reason for the use of CBD with 42.6% reporting they take CBD for this reason. With more than 12.8 million working days lost because of work-related stress, anxiety, or depression in the UK (Hse 2019), the relationship between CBD and stress is an area of interest for further research. Yet, no studies are looking directly at how CBD affects perceived stress levels. 37.5% of respondents reported using CBD for perceived stress, with 92.2% reporting reduced stress levels, making it the third-highest ranking reason for CBD use amongst our sample. Is it OK to consume CBD every day? Moreover, there was no significant difference in medical supervision and sublingual CBD use, by smoking, and vaping. There were no significant differences in diagnosed psychiatric disorders and sublingual CBD use, by smoking, or vaping. The most common route of CBD administration reported by participants was sublingual (73.41%), followed by smoking (37.45%), and vaping (19.1%), with more detailed analyses conducted. Males tended to use CBD products for a longer duration than females. Furthermore, the role of adenosine receptors in the anti-inflammatory and anti-nociceptive effects of CBD is worth further study as CBD is a potent inhibitor of adenosine reuptake; therefore, adenosine receptors might be the node of CBD’s action. Acute CBD treatment may not be sufficient to combat the cause of the pain and provide an effect lasting up to several hours (depending on the disease model, dose and route of administration). Patients suffering from chronic pain are often forced to take medications continuously for many years; it is not possible to test the effects of CBD on healthy people for such a long time 123,124. The referenced studies indicate a positive influence of CBD in treatment for various diseases in both pre-clinical and clinical trials. However, five of 16 patients reported a two-point or greater reduction in pain . The receptors and channels mediate many components of action potential propagation, including the influx of sodium ions during depolarization and the efflux of potassium during repolarization and hyperpolarization. These receptors, including the 5HT1A, 5HT3A, TRP channels, D2 dopamine receptors, KV7.2, KV7.3, NaV1.1–1.7, and L-type and T-type calcium channels, may have synergistic or oppositional effects upon CBD binding. The agonism of 5HT1A receptors hyperpolarizes the neuron, leading to a decrease in action potential propagation (Sprouse and Aghajanian 1986). CBD consumption may mediate neuronal function by agonizing or antagonizing multiple ion channels that maintain neuronal membrane potential, including potassium channels, sodium channels, and serotonin receptors, as well as G-protein-coupled receptors. In a rat model of myofascial pain (induced by nerve growth factor intramuscular injection), intramuscular injection of CBD or cannabinol (CBN) decreased mechanical sensitization and increased the mechanical threshold of masseter muscle mechanoreceptors . Individual studies indicate a potential beneficial role for CBD in various disease animal models. The effect was enhanced by TNFα pretreatment, which may suggest that CBD preferentially targets pro-inflammatory (activated) synovial fibroblasts, suggesting potential anti-arthritic activity . In a rat complete Freund’s adjuvant-induced monoarthritic knee joint model, transdermal CBD gel applied for 4 days dose-dependently reduced joint swelling, limb posture scores, synovial membrane thickening and animals’ pain. Administration of CBDA prior to carrageenan produced dose-dependent anti-hyperalgesia and anti-inflammatory effects. The research was funded by TheDrug.Store who had no role in any aspect of the study, including the design, data analysis, or manuscript preparation. JM initiated the study and drafted out the study design and the online survey together with CH. Further research is needed into whether CBD can efficiently and safely help treat these symptoms. Healthy controls scored better on both encoding and recall of the task compared to patients (after CBD or placebo). During the scanning procedure all participants performed a verbal learning task, the same used in previously described studies (Bhattacharyya et al., 2009; Bhattacharyya et al., 2010; Bhattacharyya et al., 2018). THC and CBD showed task-specific opposite effects during emotional processing (fronto-temporal), verbal memory (fronto-striatal), response inhibition (fronto-limbic-striatal), and auditory/visual processing (temporo-occipital). Due to their pharmacological properties, cannabis or cannabinoids are used for medical purposes (Table 1) 79, 80. Risk of death due to cannabis toxicity is very low, but there is a link between cannabis use at high doses and lethal motor vehicle collisions, cardiac pathophysiology and possibly suicide 17, 77, 78. These cyclical episodes occur with prolonged, high-dose cannabis use and are alleviated by hot baths and showers and abstinence from cannabis . While Epidiolex has a concentration of 100 mg/ml and a maximum recommended dose of 20 mg/kg/day, some studies examined drastically deviated from that recommendation (GW Biosciences, 2018). While the study designs are inconsistent, the drug and dosage being examined also varies significantly between studies. The physical and psychological measurements such as those in Dr. Leehey's study could act as a model study design for future clinical trials of Epidiolex to ensure safety and efficacy of new CBD-containing drug formulations. For example, Dr. Leehey's study evaluated more parameters and collected more comprehensive patient data than the more positive-focused outcomes observed in the GW Pharmaceutical funded studies, as well as using different exclusion criteria. The sample size describes the number of patients that have completed the clinical trial currently. Hepatic enzymes were also measured daily, but no effect was reported.56 A randomized, double-blind, crossover, placebo-controlled trial was conducted in 16 healthy nonanxious subjects using a within-subject design. In addition, no effects on peripheral cardiovascular measures such as heart rate and blood pressure were measured.54 This holds especially true for the extrapyramidal motor side effects elicited by classical antipsychotic medication.1 “CBD given postextinction (active after consolidation phase) enhanced consolidation of extinction learning as assessed by shock expectancy.” Apart from the extinction-enhancing effects of CBD in human aversive conditioned memory, CBD showed a trend toward some protection against reinstatement of contextual memory. Increasing numbers of older adults are using cannabis over recent years. They should also check with their doctors about potential interactions between CBD and any prescriptions or supplements they take. Whenever possible, people who use CBD products should check the certificate of analysis (which summarizes independent tests of potency and contaminant levels) before buying these products. While CBD is generally safe and doesn’t have next-day effects, it can interact with certain medications. Small benefits occurred with oral synthetic products higher in THC and plant-derived THC/CBD sprays. As our understanding of CBD and its effects on the brain continues to grow, it has the potential to become a valuable tool in the management of neurological conditions . In conclusion, CBD holds significant promise as a potential therapeutic option for various neurological disorders . In terms of safety, CBD is generally well-tolerated, with mild side effects such as fatigue, diarrhoea, and changes in appetite reported in some individuals . Despite this, the World Health Organization classifies CBD as having no potential for abuse and several oral cannabinoid-based pharmaceuticals are U.S. Physicians remain poorly educated with respect to cannabis and the endocannabinoid system 39,40▪. The two primary endocannabinoids are anandamide/N-arachidonoylethanolamine and 2-arachidonoylglycerol, which are the natural ligands for the cannabinoid receptors. Plant breeding has created numerous genetically unique Cannabis chemovars, enhancing certain desired effects. The prevalence of cannabis use more than doubled between 2001 and 2013 in the United States particularly among people over the age of 50 and even more so among those over 65 years 2▪,3,4▪,5▪. This bias limits the generalizability of results but is common across international medical cannabis regimens and should not discount the observed results. The current context of medical cannabis access, including social stigma, high cost, and lack of universal insurance coverage can increase the patient selection bias. The self-reported subjective assessment used may be biased by the patient’s positive expectation of treatment, which could lead to a possible placebo effect. Further studies can investigate the use of CBD to treat several symptoms simultaneously. Ninety-one percent of the patients reported a decrease in nightmare symptoms. In another small study of 11 patients with PTSD, oral CBD was administered open-labeled and the patient’s PTSD symptoms were evaluated initially and on consecutive days up to 8 weeks after utilizing the PCL-5 test and score. Furthermore, a study by Das et al including 48 healthy volunteers was evaluated for anxiety provoking electric shock anticipation and received either pure CBD without THC or placebo. All patients were instructed to remain anonymous and to answer the questions as honestly as possible. Limited studies have been done in Canada and in Europe, as well as several in California. Average pain improvement on a 0–10 pain scale was 5.0 (from 7.8 to 2.8), which translates to a 64% relative decrease in average pain. Clinical research regarding the therapeutic benefits of cannabis (“marijuana”) has been almost non-existent in the United States since cannabis was given Schedule I status in the Controlled Substances Act of 1970.