Cannabinoids for Behavioral Symptoms in Dementia: An Overview

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“Dementia, with loss of memory, cognitive abilities, and independent daily functioning, is increasing worldwide, related to an aging population. Currently, there is no curative treatment for dementia. Treatment of the frequently occurring behavioral and psychological symptoms of dementia (BPSD) is partially effective and associated with significant side effects.

Cannabinoids are lipophilic molecules acting on the CB1 end CB2 receptors, essential for main biological processes such as sleep, appetite, memory, and pain. Cannabinoids might have a positive impact on amyloid formation in Alzheimer’s disease, the main form of dementia, and on BPSD symptoms. Most knowledge currently concerns delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD).

In the context of dementia and BPSD, THC might be beneficial for associated spasticity and possible pain or lack of appetite and CBD probably works better on sleep, agitation, and anxiety. This overview of prospective clinical studies and randomized clinical trials, published between 2005 and April 2023, using cannabinoids for BPSD suggests that older studies using low-dose oral synthetic THC showed no positive results.

Still, more recent studies using THC/CBD-based oral medication at higher doses show promising results and are feasible and safe in this elderly polymedicated population. Several RCTs are ongoing and planned worldwide, and we hope other trials will follow to establish clinical efficiency and optimal dosing, as well as other outcomes such as deprescribing other medications and facilitation of care. We suggest that researchers also address the more sociological aspects of prescribing cannabinoids for dementia and BPSD in their specific context.”

https://pubmed.ncbi.nlm.nih.gov/38447959/

https://www.thieme-connect.de/products/ejournals/abstract/10.1055/a-2262-7837

Cannabinoids in the Treatment of Selected Mental Illnesses: Practical Approach and Overview of the Literature

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“Although an increasing number of patients suffering from mental illnesses self-medicate with cannabis, current knowledge about the efficacy and safety of cannabis-based medicine in psychiatry is still extremely limited. So far, no cannabis-based finished product has been approved for the treatment of a mental illness.

There is increasing evidence that cannabinoids may improve symptoms in autism spectrum disorder (ASD), Tourette syndrome (TS), anxiety disorders, and post-traumatic stress disorder (PTSD). According to surveys, patients often use cannabinoids to improve mood, sleep, and symptoms of attention deficit/hyperactivity disorder (ADHD).

There is evidence suggesting that tetrahydrocannabinol (THC) and THC-containing cannabis extracts, such as nabiximols, can be used as substitutes in patients with cannabis use disorder.

Preliminary evidence also suggests an involvement of the endocannabinoid system (ECS) in the pathophysiology of TS, ADHD, and PTSD. Since the ECS is the most important neuromodulatory system in the brain, it possibly induces beneficial effects of cannabinoids by alterations in other neurotransmitter systems.

Finally, the ECS is an important stress management system. Thus, cannabinoids may improve symptoms in patients with mental illnesses by reducing stress. Practically, cannabis-based treatment in patients with psychiatric disorders does not differ from other indications. The starting dose of THC-containing products should be low (1-2.5 mg THC/day), and the dose should be up-titrated slowly (by 1-2.5 mg every 3-5 days). The average daily dose is 10-20 mg THC. In contrast, cannabidiol (CBD) is mainly used in high doses>400 mg/day.”

https://pubmed.ncbi.nlm.nih.gov/38428836/

https://www.thieme-connect.de/products/ejournals/abstract/10.1055/a-2256-0098

Chemistry and pharmacological aspects of furanoid cannabinoids and related compounds: Is furanoid cannabinoids open a new dimension towards the non-psychoactive cannabinoids?

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“Cannabinoids have emerged as compelling candidates for medicinal applications, notably following the recent approval of non-psychoactive cannabidiol (CBD) as a medicine. This endorsement has stimulated a growing interest in this class of compounds for drug discovery. Within the cannabis plant, a rich reservoir of over 125 compounds exists. Tetrahydrocannabinol (THC), a member of the dibenzopyran class, is widely recognized for its psychoactive effects. Conversely, the furanoid class, represented by cannabielsoin-type (CBE) and cannabifuran-type (CBF) compounds, has not been reported with psychoactivity and demonstrates a spectrum of pharmacological potential. The transition from the pyran structure of THC to the furan structure of CBE seems to mark a shift from psychoactive to non-psychoactive properties, but a comprehensive examination of other members in this class is essential for a complete understanding. Building on these observations, our thorough review delves into the subject, offering a comprehensive exploration of furanoid cannabinoids, covering aspects such as their biosynthesis, classification, synthesis, and medicinal potential. The aim of this review is to encourage and catalyze increased research focus in this promising area of cannabinoid exploration.”

https://pubmed.ncbi.nlm.nih.gov/38417219/

“Cannabis has a long history of treating various ailments”

https://www.sciencedirect.com/science/article/abs/pii/S0223523424000448?via%3Dihub

Cannabidiol induces systemic analgesia through activation of the PI3Kγ/nNOS/NO/KATP signaling pathway in neuropathic mice. A KATP channel S-nitrosylation-dependent mechanism

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“Background: Cannabidiol (CBD) is the second most abundant pharmacologically active component present in Cannabis sp. Unlike Δ-9-tetrahydrocannabinol (THC), it has no psychotomimetic effects and has recently received significant interest from the scientific community due to its potential to treat anxiety and epilepsy. CBD has excellent anti-inflammatory potential and can be used to treat some types of inflammatory and neuropathic pain. In this context, the present study aimed to evaluate the analgesic mechanism of cannabidiol administered systemically for the treatment of neuropathic pain and determine the endogenous mechanisms involved with this analgesia.

Methods: Neuropathic pain was induced by sciatic nerve constriction surgery, and the nociceptive threshold was measured using the paw compression test in mice.

Results: CBD produced dose-dependent antinociception after intraperitoneal injection. Selective inhibition of PI3Kγ dose-dependently reversed CBD-induced antinociception. Selective inhibition of nNOS enzymes reversed the antinociception induced by CBD, while selective inhibition of iNOS and eNOS did not alter this antinociception. However, the inhibition of cGMP production by guanylyl cyclase did not alter CBD-mediated antinociception, but selective blockade of ATP-sensitive K+ channels dose-dependently reversed CBD-induced antinociception. Inhibition of S-nitrosylation dose-dependently and completely reversed CBD-mediated antinociception.

Conclusion: Cannabidiol has an antinociceptive effect when administered systemically and this effect is mediated by the activation of PI3Kγ as well as by nitric oxide and subsequent direct S-nitrosylation of KATP channels on peripheral nociceptors.”

https://pubmed.ncbi.nlm.nih.gov/38428514/

“Canabidiol (CBD) induces significant analgesia at 20 mg/kg in neuropathic mice.”

https://www.sciencedirect.com/science/article/abs/pii/S1089860324000284?via%3Dihub

Exploring the therapeutic potential of cannabidiol for sleep deprivation-induced hyperalgesia

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“Hyperalgesia resulting from sleep deprivation (SD) poses a significant a global public health challenge with limited treatment options. The nucleus accumbens (NAc) plays a crucial role in the modulation of pain and sleep, with its activity regulated by two distinct types of medium spiny neurons (MSNs) expressing dopamine 1 or dopamine 2 (D1-or D2) receptors (referred to as D1-MSNs and D2-MSNs, respectively). However, the specific involvement of the NAc in SD-induced hyperalgesia remains uncertain.

Cannabidiol (CBD), a nonpsychoactive phytocannabinoid, has demonstrated analgesic effects in clinical and preclinical studies. Nevertheless, its potentcy in addressing this particular issue remains to be determined.

Here, we report that SD induced a pronounced pronociceptive effect attributed to the heightened intrinsic excitability of D2-MSNs within the NAc in Male C57BL/6N mice. CBD (30 mg/kg, i.p.) exhibited an anti-hyperalgesic effect. CBD significantly improved the thresholds for thermal and mechanical pain and increased wakefulness by reducing delta power. Additionally, CBD inhibited the intrinsic excitability of D2-MSNs both in vitro and in vivo. Bilateral microinjection of the selective D2 receptor antagonist raclopride into the NAc partially reversed the antinociceptive effect of CBD. Thus, these findings strongly suggested that SD activates NAc D2-MSNs, contributing heightened to pain sensitivity.

CBD exhibits antinociceptive effects by activating D2R, thereby inhibiting the excitability of D2-MSNs and promoting wakefulness under SD conditions.”

https://pubmed.ncbi.nlm.nih.gov/38428482/

“CBD could be a candidate for treating sleep deprivation induced hyperalgesia.”

https://www.sciencedirect.com/science/article/abs/pii/S0028390824000601?via%3Dihub

Supporting gut health with medicinal cannabis in people with advanced cancer: potential benefits and challenges

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“The side effects of cancer therapy continue to cause significant health and cost burden to the patient, their friends and family, and governments. A major barrier in the way in which these side effects are managed is the highly siloed mentality that results in a fragmented approach to symptom control. Increasingly, it is appreciated that many symptoms are manifestations of common underlying pathobiology, with changes in the gastrointestinal environment a key driver for many symptom sequelae. Breakdown of the mucosal barrier (mucositis) is a common and early side effect of many anti-cancer agents, known to contribute (in part) to a range of highly burdensome symptoms such as diarrhoea, nausea, vomiting, infection, malnutrition, fatigue, depression, and insomnia.

Here, we outline a rationale for how, based on its already documented effects on the gastrointestinal microenvironment, medicinal cannabis could be used to control mucositis and prevent the constellation of symptoms with which it is associated. We will provide a brief update on the current state of evidence on medicinal cannabis in cancer care and outline the potential benefits (and challenges) of using medicinal cannabis during active cancer therapy.”

https://pubmed.ncbi.nlm.nih.gov/37884682/

https://www.nature.com/articles/s41416-023-02466-w

Cannabinoids for Cancer-related Pain Management: An Update on Therapeutic Applications and Future Perspectives

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“Pain is a debilitating phenomenon that dramatically impairs the quality of life of patients. Many chronic conditions, including cancer, are associated with chronic pain. Despite pharmacological efforts that have been conducted, many patients suffering from cancer pain remain without treatment. To date, opioids are considered the preferred therapeutic choice for cancer-related pain management.

Unfortunately, opioid treatment causes side effects and inefficiently relieves patients from pain, therefore alternative therapies have been considered, including Cannabis Sativa and cannabinoids.

Accumulating evidence has highlighted that an increasing number of patients are choosing to use cannabis and cannabinoids for the management of their soothing and non-palliative cancer pain and other cancer-related symptoms. However, their clinical application must be supported by convincing and reproducible clinical trials.

In this review, we provide an update on cannabinoid use for cancer pain management. Moreover, we tried to turn a light on the potential use of cannabis as a possible therapeutic option for cancer-related pain relief.”

https://pubmed.ncbi.nlm.nih.gov/38423660/

https://ar.iiarjournals.org/content/44/3/895

The effect of cannabinoids on wound healing: A review

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“Background and aims: Cannabis and its various derivatives are commonly used for both recreational and medicinal purposes. Cannabinoids have been shown to have anti-inflammatory properties. Inflammation is an important component of wound healing and the effect of cannabinoids on wound healing has become a recent topic of investigation. The objective of this article is to perform a comprehensive review of the literature to summarize the effects of cannabinoids on wound healing of the skin and to guide future avenues of research.

Methods: A comprehensive literature review was performed to evaluate the effects of cannabinoids on cutaneous wound healing.

Results: Cannabinoids appear to improve skin wound healing through a variety of mechanisms. This is supported through a variety of in vitro and animal studies. Animal studies suggest application of cannabinoids may improve the healing of postsurgical and chronic wounds. There are few human studies which evaluate the effects of cannabinoids on wound healing and many of these are case series and observational studies. They do suggest cannabinoids may have some benefit. However, definitive conclusions cannot be drawn from them.

Conclusion: While further human studies are needed, topical application of cannabinoids may be a potential therapeutic option for postsurgical and chronic wounds.”

https://pubmed.ncbi.nlm.nih.gov/38410495/

https://onlinelibrary.wiley.com/doi/10.1002/hsr2.1908

The effects of cannabidiol against Methotrexate-induced lung damage

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“Methotrexate (MTX) is a widely used medication for various cancers, yet its use is associated with adverse effects on organs, notably the lungs.

Cannabidiol (CBD), known for its antioxidant and anti-inflammatory properties, was investigated for its potential protective effects against MTX-induced lung injury.

Thirty-two female Wistar Albino rats were divided into four groups: control, MTX (single 20 mg/kg intraperitoneal dose), MTX + CBD (single 20 mg/kg MTX with 0.1 ml of 5 mg/kg CBD for 7 days intraperitoneally) and CBD only (for 7 days). Lung tissues were analysed using histopathological, immunohistochemical and PCR methods after the study. Histopathological assessment of the MTX group revealed lung lesions like hyperemia, edema, inflammatory cell infiltration and epithelial cell loss. Immunohistochemical examination showed significant increases in Cas-3, tumour necrosis factor-alpha (TNF-α) and nuclear factor-kappa B (NF-κB) expressions. PCR analysis indicated elevated expressions of apoptotic peptidase activating factor 1 (Apaf 1), glucose-regulated protein 78 (GRP 78), CCAAT-enhancer-binding protein homologous protein (CHOP) and cytochrome C (Cyt C), along with reduced B-cell lymphoma-2 (BCL 2) expressions in the MTX group, though not statistically significant.

Remarkably, CBD treatment reversed these findings.

This study highlights CBD’s potential in mitigating MTX-induced lung damage, suggesting its therapeutic promise.”

https://pubmed.ncbi.nlm.nih.gov/38388876/

“The findings from this study underscore the remarkable effectiveness of CBD in preventing histopathological damage within the lungs induced by MTX. The marked reduction observed in hyperemia, edema and infiltration, coupled with its notable reparative effects on epithelial loss, highlights the multifaceted benefits of CBD in mitigating pulmonary issues of MTX. Importantly, the statistical analysis revealed a significant improvement across all histopathological scoring parameters (p < 0.001). This reinforces the potential of CBD as a promising therapeutic agent for MTX-induced lung lesions and warrants further exploration in clinical settings. This study has demonstrated for the first time the reparative effects of CBD on the pathological findings induced by MTX in the lungs. There is now a need for novel and comprehensive research on the therapeutic utilization of CBD for this purpose.”

https://onlinelibrary.wiley.com/doi/10.1111/bcpt.13992

Anthelmintic Effect of Cannabidiol against Echinococcus granulosus sensu stricto

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“Cystic echinococcosis is a global parasitic zoonosis caused by infection with the larval stage of Echinococcus granulosus sensu lato. Cystic echinococcosis affects more than 1 million people worldwide, causing important economic costs in terms of management and livestock associated losses. Albendazole is the main drug used in treating human cystic echinococcosis. In spite of this, its low aqueous solubility, poor absorption, and consequently erratic bioavailability are the cause of its chemotherapeutic failures. Based on the described problem, new treatment alternatives urgently need to be developed.

The aim of the present research was to study the in vitro and in vivo efficacy of cannabidiol (CBD), the second most abundant component of the Cannabis sativa plant, was demonstrated against E. granulosus sensu stricto. CBD (50 µg/mL) caused a decrease in protoscoleces viability of 80 % after 24 h of treatment which was consistent with the observed tegumental alterations. Detachment of the germinal layer was observed in 50 ± 10% of cysts treated with 50 µg/mL of CBD during 24 h. In the clinical efficacy study, all treatments reduced the weight of cysts recovered from mice compared with the control group. However, this reduction was only significant with ABZ suspension and the CBD + ABZ combination.

As we could observe by the SEM study, the co-administration of CBD with ABZ suspension caused greater ultrastructural alteration of the germinal layer in comparison with that provoked with the monotherapy. Further in vivo research will be conducted by changing the dose and frequency of CBD and CBD + ABZ treatments and new available CBD delivery systems will also be assayed to improve bioavailability in vivo.”

https://pubmed.ncbi.nlm.nih.gov/38393124/

https://www.mdpi.com/2414-6366/9/2/35