Cannabis, a Miracle Drug with Polyvalent Therapeutic Utility: Preclinical and Clinical-Based Evidence

/WebMaterial/ShowPic/1319420“Cannabis sativa L. is an annual herbaceous dioecious plant which was first cultivated by agricultural human societies in Asia. Over the period of time, various parts of the plant like leaf, flower, and seed were used for recreational as well as therapeutic purposes. The main chemical components of Cannabis sativa are termed as cannabinoids, among them the key psychoactive constituent is Δ-9-tetrahydrocannabinol and cannabidiol (CBD) as active nonpsychotic constituent. Upon doing extensive literature review, it was found that cannabis has been widely studied for a number of disorders. Very recently, a pure CBD formulation, named Epidiolex, got a green flag from both United States Food and Drug Administration and Drug Enforcement Administration for 2 rare types of epilepsies. This laid a milestone in medical cannabis research.

This review intends to give a basic and extensive assessment, from past till present, of the ethnological, plant, chemical, pharmacological, and legal aspects of C. sativa. Further, this review contemplates the evidence the studies obtained of cannabis components on Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis, multiple sclerosis, emesis, epilepsy, chronic pain, and cancer as a cytotoxic agent as well as a palliative therapy. The assessment in this study was done by reviewing in extensive details from studies on historical importance, ethnopharmacological aspects, and legal grounds of C. sativa from extensive literature available on the scientific databases, with a vision for elevating further pharmaceutical research to investigate its total potential as a therapeutic agent.”

https://pubmed.ncbi.nlm.nih.gov/34676349/

“This study has analyzed and reviewed the historical, botanical, chemical, ethnopharmacological, and legal aspects of C. sativa from the first human use to the present medical applications with an analysis of its multiple therapeutic applications for various diseased conditions in the contemporary scientific context. There is an abundance of support for its several medicative uses as well as a possible benefit in various diseased conditions. Extensive pharmacological examination is still needed to better understand the clinical significance and uses of active cannabinoids in the treatment and prevention of chronic diseases. Also, cannabis can be chemically standardized and under prescription can be used. With the majority of the United States currently legalizing medicinal cannabis and/or restricted CBD-only use, physicians need to be educated on the history and correct clinical use of cannabis, as a result of which patients can know more and more about possible treatment utilizing cannabis. Medical cannabis has shown to have clinical efficacy in our past, and in present, data show its therapeutic effects. Extensive research in the field of cannabis can be very fruitful for the medicine world.”

https://www.karger.com/Article/FullText/515042

Health Outcomes among Adults Initiating Medical Cannabis for Chronic Pain: A 3-month Prospective Study Incorporating Ecological Momentary Assessment (EMA)

“In response to the need of more rigorous data on medical cannabis and chronic pain, we conducted a 3-month prospective study incorporating ecological momentary assessment (EMA) to examine the effects of medical cannabis on pain, anxiety/depression, sleep, and quality of life.

Data were collected from 46 adults (Mean age=55.7±11.9, 52.2% male) newly initiating medical cannabis treatment for chronic pain. Participants completed a baseline survey, EMA for approximately 1 week pre- and up to 3 weeks post- medical cannabis treatment, and a 3-month follow-up survey.

The self-reported EMA data (2535 random and 705 daily assessments) indicated significant reductions in momentary pain intensity (b = -16.5, p < .001, 16.5 points reduction on 0-100 visual analog) and anxiety (b = -0.89, p < .05), and significant increase in daily sleep duration (b = 0.34, p < .01) and sleep quality (b = 0.32, p <.001) after participants initiated medical cannabis for a few weeks.

At 3 months, self-reported survey data showed significantly lower levels of worst pain (t = -2.38, p < .05), pain interference (t = -3.82, p < .05), and depression (t = -3.43, p < .01), as well as increased sleep duration (t = 3.95, p < .001), sleep quality (t = -3.04, p < .01), and quality of life (t = 4.48, p < .001) compared to baseline.

In our sample of primarily middle-aged and older adults with chronic pain, medical cannabis was associated with reduced pain intensity/inference, lower anxiety/depression, and improved sleep and quality of life.”

https://pubmed.ncbi.nlm.nih.gov/34671723/

https://publications.sciences.ucf.edu/cannabis/index.php/Cannabis/article/view/97

Analgesic Potential of Terpenes Derived from Cannabis sativa

Pharmacological Reviews“Pain prevalence among adults in the United States has increased 25% over the past two decades, resulting in high health-care costs and impacts to patient quality of life. In the last 30 years, our understanding of pain circuits and (intra)cellular mechanisms has grown exponentially, but this understanding has not yet resulted in improved therapies. Options for pain management are limited. Many analgesics have poor efficacy and are accompanied by severe side effects such as addiction, resulting in a devastating opioid abuse and overdose epidemic. These problems have encouraged scientists to identify novel molecular targets and develop alternative pain therapeutics.

Increasing preclinical and clinical evidence suggests that cannabis has several beneficial pharmacological activities, including pain relief.

Cannabis sativa contains more than 500 chemical compounds, with two principle phytocannabinoids, Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD). Beyond phytocannabinoids, more than 150 terpenes have been identified in different cannabis chemovars. Although the predominant cannabinoids, Δ9-THC and CBD, are thought to be the primary medicinal compounds, terpenes including the monoterpenes β-myrcene, α-pinene, limonene, and linalool, as well as the sesquiterpenes β-caryophyllene and α-humulene may contribute to many pharmacological properties of cannabis, including anti-inflammatory and antinociceptive effects.

The aim of this review is to summarize our current knowledge about terpene compounds in cannabis and to analyze the available scientific evidence for a role of cannabis-derived terpenes in modern pain management.

SIGNIFICANCE STATEMENT: Decades of research have improved our knowledge of cannabis polypharmacy and contributing phytochemicals, including terpenes. Reform of the legal status for cannabis possession and increased availability (medicinal and recreational) have resulted in cannabis use to combat the increasing prevalence of pain and may help to address the opioid crisis. Better understanding of the pharmacological effects of cannabis and its active components, including terpenes, may assist in identifying new therapeutic approaches and optimizing the use of cannabis and/or terpenes as analgesic agents.”

https://pubmed.ncbi.nlm.nih.gov/34663685/

“Cannabis sativa has been used for medical, recreational, and spiritual purposes for thousands of years. Modern scientific studies have provided increasing amounts of preclinical and clinical evidence about its beneficial pharmacological effects, including pain relief. Recent changes in the legislation of cannabis usage and possession have resulted in cannabis-based products becoming widely used alternatives in fighting against many different illnesses. Medical marijuana has been applied to treat a host of indications, but the most frequent, and evidence-backed indication, is pain. Overall, cannabis terpenes have a high potential for pain management, alone or as adjunctive therapeutics, and are attractive compounds for the development of terpene-based analgesics given their generally-recognized-as-safe status with low side effect and toxicity profiles.”

The Effect of Medical Cannabis on Pain Level and Quality of Sleep among Rheumatology Clinic Outpatients

logo“Introduction: Medical cannabis (MC) is becoming increasingly popular for the treatment of chronic pain conditions.

In this study, we evaluated the effect of MC treatment on pain level and quality of sleep of patients with different medical conditions at the rheumatology clinic.

Conclusions: MC had a favorable effect on pain level and quality of sleep among all spectrums of problems at the rheumatology clinic.”

https://pubmed.ncbi.nlm.nih.gov/34531934/

“MC has a favorable effect on pain level and sleep quality among nearly the entire spectrum of resistant “chronic pain syndromes” seen or referred to rheumatology clinics, including inflammatory diseases resistant to biological treatment, although the effect of MC on synovitis was relatively mild.

Cannabis should be seriously considered in every “chronic pain condition” whenever the accepted modalities of treatment are insufficient for alleviating patient’s pain and sleep problems.”

https://www.hindawi.com/journals/prm/2021/1756588/

A Review of the Potential Use of Pinene and Linalool as Terpene-Based Medicines for Brain Health: Discovering Novel Therapeutics in the Flavours and Fragrances of Cannabis

Archive of &quot;Frontiers in Psychiatry&quot;.“”Medicinal cannabis” is defined as the use of cannabis-based products for the treatment of an illness. Investigations of cannabis compounds in psychiatric and neurological illnesses primarily focus on the major cannabinoids, cannabidiol (CBD) and Δ9-tetrahydrocannabinol (Δ9-THC), which are hypothesised to benefit multiple illnesses manifesting cognitive impairment, neurodegeneration and neuro-inflammation, as well as chronic pain, epilepsy and post-traumatic stress disorder, respectively.

The cannabis plant contains >500 compounds, including terpenes responsible for the flavour and fragrance profiles of plants. Recently, research has begun providing evidence on the potential use of certain plant-derived terpenes in modern medicine, demonstrating anti-oxidant, anti-inflammatory, and neuroprotective effects of these compounds.

This review examined the effects of two key terpenes, pinene and linalool, on parameters relevant to neurological and psychiatric disorders, highlighting gaps in the literature and recommendations for future research into terpene therapeutics.

Overall, evidence is mostly limited to preclinical studies and well-designed clinical trials are lacking. Nevertheless, existing data suggests that pinene and linalool are relevant candidates for further investigation as novel medicines for illnesses, including stroke, ischemia, inflammatory and neuropathic pain (including migraine), cognitive impairment (relevant to Alzheimer’s disease and ageing), insomnia, anxiety, and depression.

Linalool and pinene influence multiple neurotransmitter, inflammatory and neurotrophic signals as well as behaviour, demonstrating psycho-activity (albeit non-intoxicating).   Optimising the phytochemical profile of cannabis chemovars to yield therapeutic levels of beneficial terpenes and cannabinoids, such as linalool, pinene and CBD, could present a unique opportunity to discover novel medicines to treat psychiatric and neurological illnesses; however, further research is needed.”

https://pubmed.ncbi.nlm.nih.gov/34512404/

“Overall, it appears that the importance of the terpene profile of plants to humans extends further than mere olfactory and gustatory delight. Rather, these compounds have the potential for use as treatments for serious chronic neurological and psychiatric illnesses.”

https://www.frontiersin.org/articles/10.3389/fpsyt.2021.583211/full

Pharmacological characterisation of the CB 1 receptor antagonist activity of cannabidiol in the rat vas deferens bioassay

European Journal of Pharmacology“Cannabidiol is increasingly considered for treatment of a wide range of medical conditions. Binding studies suggest that cannabidiol binds to CB1 receptors. In the rat isolated vas deferens bioassay, a single electrical pulse causes a biphasic contraction from nerve-released ATP and noradrenaline. WIN 55,212-2 acts on prejunctional CB1 receptors to inhibit release of these transmitters. In this bioassay, we tested whether cannabidiol and SR141716 were acting as competitive antagonists of this receptor. Monophasic contractions mediated by ATP or noradrenaline in the presence of prazosin or NF449 (P2X1 inhibitor), respectively, were measured to a single electrical pulse delivered every 30 min. Following treatment with cannabidiol (10-100 μM) or SR141716 (0.003-10 μM), cumulative concentrations of WIN 55,212-2 (0.001-30 μM) were applied followed by a single electrical pulse. The WIN 55,212-2 concentration-contraction curve EC50 values were applied to global regression analysis to determine the pKB. The antagonist potency of cannabidiol at the CB1 receptor in the rat vas deferens bioassay matched the reported receptor binding affinity. Cannabidiol was a competitive antagonist of WIN 55,212-2 with pKB values of 5.90 when ATP was the effector transmitter and 5.29 when it was noradrenaline. Similarly, SR141716 was a competitive antagonist with pKB values of 8.39 for ATP and 7.67 for noradrenaline as the active transmitter. Cannabidiol’s low micromolar CB1 antagonist pKB values suggest that at clinical blood levels (1-3 μM) it may act as a CB1 antagonist at prejunctional neuronal sites with more potency when ATP is the effector than for noradrenaline.”

https://pubmed.ncbi.nlm.nih.gov/34416240/

https://www.sciencedirect.com/science/article/abs/pii/S0014299921005860?via%3Dihub

Medical cannabinoids for treatment of neuropsychiatric symptoms in dementia: systematic review

SciELO - Trends in Psychiatry and Psychotherapy“Introduction: Neuropsychiatric symptoms are an integral component of the natural history of dementia, occurring from prodromal to advanced stages of the disease process and leading to increased burden and morbidity. Clinical presentations are pleomorphic, and clinical management often requires combination of pharmacological and non-pharmacological interventions. However, limited efficacy and a non-negligible incidence of adverse events of psychotropic drugs reinforce the need for novel therapeutic options.

Aims: To review the evidence supporting the use of medical cannabinoids for the treatment of neuropsychiatric symptoms of dementia (NPS).

Results: Fifteen publications with original clinical data were retrieved, being 5 controlled clinical trials, 3 open-label/observational studies, and 7 case reports. Most studies indicated that the use of medical cannabinoids engendered favorable outcomes for the treatment of neuropsychiatric symptoms related to moderate and advanced stages of dementia, particularly agitation, aggressive behavior and sleep and sexual disinhibition.

Conclusion: Medical cannabinoids represent a promising pharmacological approach for the treatment of NPS, with preliminary evidence of benefit at least in moderate to severe dementia. Controlled trials with longitudinal design and larger samples are required to examine the long-term efficacy of these drugs in different types and stages of dementia, in addition to their adverse events and risk of interactions with other drugs. Many pharmacological details are yet to be determined, such as dosing, treatment duration and concentrations of active compounds (e.g., CBD/THC ratio) in commercial preparations of medical cannabinoids.”

https://pubmed.ncbi.nlm.nih.gov/34374269/

Cannabinoids for skin diseases and hair regrowth

“The use of cannabis for skin diseases and hair regrowth is at the preliminary stage.

Legalization: Many countries have approved cannabis for medical use; however, four countries Canada, Uruguay, South Africa, and Georgia have legalized it for both medical and recreational purposes.

The endocannabinoid system: The endocannabinoid system may maintain skin homeostasis; two notable endocannabinoids include 2-Arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (AEA).

Routes of administration and pharmacokinetics: Topical cannabinoids can avoid the first-pass metabolism and reduce respiratory side effects; however, the high hydrophobicity of cannabinoids may hinder percutaneous absorption.

Skin disorders and hair growth: Human clinical studies suggest that cannabinoids may be used in eczema, acne, pruritus, and systemic sclerosis treatment. Cannabidiol (CBD) may enhance hair growth via multiple mechanisms.

Safety: Topical cannabis may cause mild side effects such as pruritus, burning, erythema, and stinging; they are relatively safer than inhalation and oral cannabis. Cannabis use may be associated with allergic symptoms and reduced immune response to live vaccination.

Cannabinoids in practice: Despite growing interest, dermatologists should be cautious prescribing cannabinoids due to insufficient clinical data on both efficacy and safety.”

https://pubmed.ncbi.nlm.nih.gov/34363728/

https://onlinelibrary.wiley.com/doi/10.1111/jocd.14352

 

Use and caregiver-reported efficacy of medical cannabis in children and adolescents in Switzerland

SpringerLink“Evidence on the use and efficacy of medical cannabis for children is limited. We examined clinical and epidemiological characteristics of medical cannabis treatment and caregiver-reported effects in children and adolescents in Switzerland.

We collected clinical data from children and adolescents (< 18 years) who received Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), or a combination of the two between 2008 and 2019 in Switzerland. Out of 205 contacted families, 90 agreed to participate. The median age at the first prescription was 11.5 years (interquartile range (IQR) 6-16), and 32 patients were female (36%). Fifty-one (57%) patients received CBD only and 39 (43%) THC. Patients were more likely to receive THC therapy if one of the following symptoms or signs were present: spasticity, pain, lack of weight gain, vomiting, or nausea, whereas seizures were the dominant indication for CBD therapy.

Improvements were reported in 59 (66%) study participants.

The largest treatment effects were reported for pain, spasticity, and frequency of seizures in participants treated with THC, and for those treated with pure CBD, the frequency of seizures. However, 43% of caregivers reported treatment interruptions, mainly because of lack of improvement (56%), side effects (46%), the need for a gastric tube (44%), and cost considerations (23%).

Conclusions: The effects of medical cannabis in children and adolescents with chronic conditions are unknown except for rare seizure disorders, but the caregiver-reported data analysed here may justify trials of medical cannabis with standardized concentrations of THC or CBD to assess its efficacy in the young.

What is Known: • The use of medical cannabis (THC and CBD) to treat a variety of diseases among children and adolescents is increasing. • In contrast to adults, there is no evidence to support the use of medical cannabis to treat chronic pain and spasticity in children, but substantial evidence to support the use of CBD in children with rare seizure disorders.

What is New: • This study provides important insights into prescription practices, dosages, and treatment outcomes in children and adolescents using medical cannabis data from a real-life setting.

• The effects of medical cannabis in children and adolescents with chronic conditions shown in our study support trials of medical cannabis for chronic conditions.”

https://pubmed.ncbi.nlm.nih.gov/34309706/

“For two thirds of participants treated with standardized THC or CBD preparations, the caregiver reported an improvement in their condition and well-being. Medical cannabis could be a promising and useful therapy for children and adolescents with neurological conditions.”

https://link.springer.com/article/10.1007%2Fs00431-021-04202-z

Medical marijuana utilization in gynecologic cancer patients

Gynecologic Oncology Reports“Medical marijuana (MM) use is common among cancer patients, but relatively little is known about the usage patterns and efficacy of MM used by gynecologic cancer patients.

Methods: Demographic and clinical data were collected for gynecologic cancer patients prescribed MM between May 2016 and February 2019. The electronic medical record was used to query formulation prescribed, usage patterns, length of use, symptom relief, and side effect profile. Descriptive statistics were calculated.

Results: Of 45 gynecologic cancer patients prescribed MM, 89% were receiving chemotherapy; 56% were undergoing primary treatment. MM was used for a median of 5.2 months (range 0.6-25.4). Over 70% of patients reported improvement in nausea/vomiting, compared to 36% of patients using MM for pain relief (p = 0.02). Of 41 patients with follow-up information, 71% found MM improved at least one symptom.

Conclusions: Among a small sample of gynecologic cancer patients prescribed MM for symptom management, self-reported follow-up indicated symptom relief for the majority of patients and minimal therapy-related side effects. This data can prove useful for counseling gynecologic cancer patients on the efficacy and side effects of MM.”

https://pubmed.ncbi.nlm.nih.gov/34258360/

“Among a small cohort of gynecologic cancer patients prescribed MM for symptom management, the majority reported improvement in at least one disease or treatment-related symptom and reported minimal side effects. Further larger prospective studies are needed to investigate specific formulations and indications in this patient population, but our data indicate that it is a safe and useful adjunct for symptom management among a diverse cohort of women with gynecologic cancer.”

https://www.sciencedirect.com/science/article/pii/S2352578921001247?via%3Dihub