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 "Frontiers in Psychiatry".“”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

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Cannabidiol reverses memory impairments and activates components of the Akt/GSK3β pathway in an experimental model of estrogen depletion

Behavioural Brain Research“Clinical and preclinical evidence has indicated that estrogen depletion leads to memory impairments and increases the susceptibility to neural damage.

Here, we have sought to investigate the effects of Cannabidiol (CBD) a non-psychotomimetic compound from Cannabis sativa, on memory deficits induced by estrogen depletion in rats, and its underlying mechanisms.

Results revealed that ovariectomy impaired avoidance memory, and CBD was able to completely reverse estrogen depletion-induced memory impairment. Ovariectomy also reduced Akt/GSK3β pathway’s activation by decreasing the phosphorylation levels of Akt and GSK3β and Bcl2 levels, which were ameliorated by CBD.

The present results indicate that CBD leads to a functional recovery accompanied by the Akt/GSK3β survival pathway’s activation, supporting its potential as a treatment for estrogen decline-induced deterioration of neural functioning and maintenance.”

https://pubmed.ncbi.nlm.nih.gov/34450240/

“In the present study, we aimed to understand the possible neuroprotective effect of CBD against estrogen depletion-induced emotional memory deficits, using an animal model of ovariectomy-induced estrogen depletion. Once CBD and estradiol modulate a common pathway, we speculated whether CBD would be able to reverse the deleterious effect of estradiol decline observed in menopause. Results revealed that ovariectomy impaired avoidance memory, and CBD was able to completely reverse estrogen depletion-induced memory impairment.”

https://www.sciencedirect.com/science/article/abs/pii/S0166432821004435?via%3Dihub

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Neuroprotective and Symptomatic Effects of Cannabidiol in an Animal Model of Parkinson’s Disease

ijms-logo“Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the Substantia Nigra pars compacta, leading to classical PD motor symptoms. Current therapies are purely symptomatic and do not modify disease progression.

Cannabidiol (CBD), one of the main phytocannabinoids identified in Cannabis Sativa, which exhibits a large spectrum of therapeutic properties, including anti-inflammatory and antioxidant effects, suggesting its potential as disease-modifying agent for PD.

The aim of this study was to evaluate the effects of chronic treatment with CBD (10 mg/kg, i.p.) on PD-associated neurodegenerative and neuroinflammatory processes, and motor deficits in the 6-hydroxydopamine model. Moreover, we investigated the potential mechanisms by which CBD exerted its effects in this model.

CBD-treated animals showed a reduction of nigrostriatal degeneration accompanied by a damping of the neuroinflammatory response and an improvement of motor performance. In particular, CBD exhibits a preferential action on astrocytes and activates the astrocytic transient receptor potential vanilloid 1 (TRPV1), thus, enhancing the endogenous neuroprotective response of ciliary neurotrophic factor (CNTF).

These results overall support the potential therapeutic utility of CBD in PD, as both neuroprotective and symptomatic agent.”

https://pubmed.ncbi.nlm.nih.gov/34445626/

https://www.mdpi.com/1422-0067/22/16/8920

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Cannabidiol reduces lesion volume and restores vestibulomotor and cognitive function following moderately severe traumatic brain injury

Experimental Neurology“Despite the high incidence of traumatic brain injury (TBI), there is no universal treatment to safely treat patients. Blunt brain injuries destroy primary neural tissue that results in impaired perfusion, excessive release of glutamate, inflammation, excitotoxicity, and progressive secondary neuronal cell death.

We hypothesized that administration of cannabidiol (CBD) directly to a brain contusion site, will optimize delivery to the injured tissue which will reduce local neural excitation and inflammation to spare neural tissue and improve neurological outcome following TBI.

CBD was infused into a gelfoam matrix forming an implant (CBDi), then applied over the dura at the contusion site as well as delivered systemically by injection (CBD.IP). Post-injury administration of CBDi+IP greatly reduced defecation scores, lesion volume, the loss of neurons in the ipsilateral hippocampus, the number of injured neurons of the contralateral hippocampus, and reversed TBI-induced glial fibrillary acidic protein (GFAP) upregulation which was superior to either CBD.IP or CBDi treatment alone.

Vestibulomotor performance on the beam-balance test was restored by 12 days post-TBI and sustained through 28 days. CBDi+IP treated rats exhibited preinjury levels of spontaneous alternation on the spontaneous alternation T-maze. In the object recognition test, they had greater mobility and exploration of novel objects compared to contusion or implant alone consistent with reduced anxiety and restored cognitive function.

These results suggest that dual therapy by targeting the site of injury internally with a CBD-infused medical carrier followed by systemic supplementation may offer a more effective countermeasure than systemic or implant treatment alone for the deleterious effects of penetrating head wounds.”

https://pubmed.ncbi.nlm.nih.gov/34428457/

“CBD improved vestibulomotor function and learning and memory cognitive performance post-TBI. Local delivery at the contusion site and systemic injection of CBD reduced TBI-induced lesion volume. Dual treatment, direct and systemic CBD, is superior to single treatment.”

https://www.sciencedirect.com/science/article/abs/pii/S0014488621002521?via%3Dihub

http://www.thctotalhealthcare.com/category/brain-trauma/

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Cannabis sativa as a Treatment for Obesity: From Anti-Inflammatory Indirect Support to a Promising Metabolic Re-Establishment Target

View details for Cannabis and Cannabinoid Research cover image“Introduction: Obesity is defined as an excess of accumulation of fat that can be harmful to health. Storage of excess fat in the adipose tissue triggers an inflammatory process, which makes obesity a low-grade chronic inflammatory disease. Obesity is considered a complex and multifactorial disease; hence, no intervention strategy appears to be an ideal treatment for all individuals. Therefore, new therapeutic alternatives are often studied for the treatment of this disease. Currently, herbal medicines are gaining ground in the treatment of obesity and its comorbidities. In this context, much attention is being paid to Cannabis sativa derivatives, and their therapeutic functions are being widely studied, including in treating obesity. 

Objective: Highlight the pharmacological properties of Δ9-tetrahydrocannabivarin (THCV), Δ9-tetrahydrocannabidinol (THC), and cannabidiol (CBD), the predominant isolated components of Cannabis sativa, as well as its therapeutic potential in the treatment of obesity. 

Results: Evidence shows that Cannabis sativa derivatives have therapeutic potential due to their anti-inflammatory properties. In addition, people who use cannabis have a lower body mass index than those who do not, making the plant an option to reduce and reverse inflammation and comorbidities in obesity. 

Conclusion: It is concluded that phytocannabinoids derived from Cannabis sativa have therapeutic potential due to its anti-inflammatory, antioxidant, and neuroprotective properties, making the plant a study option to reduce and reverse inflammation and comorbidities associated with obesity.”

https://pubmed.ncbi.nlm.nih.gov/34242511/

https://www.liebertpub.com/doi/10.1089/can.2021.0016

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Δ 9 -Tetrahydrocannabinol promotes functional remyelination in the mouse brain

British Journal of Pharmacology“Background and purpose: Research on demyelinating disorders aims to find novel molecules that are able to induce oligodendrocyte precursor cell differentiation to promote central nervous system remyelination and functional recovery.

Δ9 -Tetrahydrocannabinol (THC), the most prominent active constituent of the hemp plant Cannabis sativa, confers neuroprotection in animal models of demyelination. However, the possible effect of THC on myelin repair has never been studied.

Experimental approach: By using oligodendroglia-specific reporter mouse lines in combination with two models of toxin-induced demyelination, we analysed the effect of THC on the processes of oligodendrocyte regeneration and functional remyelination.

Key results: We show that THC administration enhanced oligodendrocyte regeneration, white matter remyelination and motor function recovery. THC also promoted axonal remyelination in organotypic cerebellar cultures. THC remyelinating action relied on the induction of oligodendrocyte precursor differentiation upon cell cycle exit and via CB1 cannabinoid receptor activation.

Conclusions and implications: Overall, our study identifies THC administration as a promising pharmacological strategy aimed to promote functional CNS remyelination in demyelinating disorders.”

https://pubmed.ncbi.nlm.nih.gov/34216154/

“Our study provides a novel therapeutic advantage of THC-based interventions in multiple sclerosis by promoting remyelination and functional recovery. New clinical trials with improved designs on cannabinoids in people with multiple sclerosis are needed now, considering these compounds as potential remyelinating/disease-modifying drugs to try to overcome previous failures. Our work also suggests that at least part of the neuroprotective action of phytocannabinoids in multiple sclerosis animal models and potentially in patients as well may be due to an enhanced CNS remyelination. Finally, this study also identifies THC as a potent inductor of oligodendrocyte progenitor cell differentiation under demyelination in mice, opening the possibility for this molecule to become a candidate drug to promote oligodendrocyte regeneration and remyelination in the treatment of demyelinating disorders.”

https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bph.15608

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The Pharmacological Effects of Plant-Derived versus Synthetic Cannabidiol in Human Cell Lines

/WebMaterial/ShowPic/1344608“Introduction: Cannabidiol (CBD) can be isolated from Cannabis sativa L. or synthetically produced. The aim of this study was to compare the in vitro effects of purified natural and synthetic CBD to establish any pharmacological differences or superiority between sources. 

Conclusion: Our results suggest that there is no pharmacological difference in vitro in the antiproliferative, anti-inflammatory, or permeability effects of purified natural versus synthetic CBD. The purity and reliability of CBD samples, as well as the ultimate pharmaceutical preparation, should all be considered above the starting source of CBD in the development of new CBD medicines.

This study demonstrates for the first time that the anticancer, neuroprotective, and intestinal barrier protective properties of purified CBD are similar regardless of the source from which CBD is derived. From a pharmacological perspective, where a molecular target is implicated (i.e., 5HT1A in stroke and CB1 in gut permeability), the effects of CBD were similar. This suggests that any beneficial effects that could be achieved in a clinical setting for purified CBD are likely to be similar at a pharmacodynamic level.”

https://www.karger.com/Article/FullText/517120

“Study finds no in-vitro pharmacological difference in the antiproliferative, anti-inflammatory, or permeability effects of purified natural versus synthetic CBD”

https://www.streetinsider.com/Globe+Newswire/Artelo+Biosciences+Announces+Publication+of+Study+Results+Comparing+the+Pharmacological+Effects+of+Plant-Derived+Versus+Synthetic+Cannabidiol+in+Human+Cell+Lines/18767297.html

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Protective Effects of Cannabidivarin and Cannabigerol on Cells of the Blood-Brain Barrier Under Ischemic Conditions

View details for Cannabis and Cannabinoid Research cover image“Preclinical studies have shown cannabidiol is protective in models of ischemic stroke. Based on results from our recent systematic review, we investigated the effects of two promising neuroprotective phytocannabinoids, cannabigerol (CBG) and cannabidivarin (CBDV), on cells of the blood-brain barrier (BBB), namely human brain microvascular endothelial cells (HBMECs), pericytes, and astrocytes.

Results: In astrocytes CBG and CBDV attenuated levels of interleukin-6 (IL-6) and lactate dehydrogenase (LDH), whereas CBDV (10 nM-10 μM) also decreased vascular endothelial growth factor (VEGF) secretion. CBDV (300 nM-10 μM) attenuated levels of monocyte chemoattractant protein (MCP)-1 in HBMECs. In astrocytes, CBG decreased levels of DNA damage proteins, including p53, whereas CBDV increased levels of DNA damage markers. Antagonists for CB1, CB2, PPAR-γ, PPAR-α, 5-HT1A, and TRPV1 had no effect on CBG (3 μM) or CBDV (1 μM)-mediated decreases in LDH in astrocytes. GPR55 and GPR18 were partially implicated in the effects of CBDV, but no molecular target was identified for CBG.

Conclusions: We show that CBG and CBDV were protective against OG mediated injury in three different cells that constitute the BBB, modulating different hallmarks of ischemic stroke pathophysiology. These data enhance our understanding of the protective effects of CBG and CBDV and warrant further investigation into these compounds in ischemic stroke. Future studies should identify other possible neuroprotective effects of CBG and CBDV and their corresponding mechanisms of action.”

https://pubmed.ncbi.nlm.nih.gov/33998890/

“This study provides novel data on the neuroprotective and anti-inflammatory properties of CBG and CBDV in an in vitro model of IR. These data, together with evidence from other studies, corroborate the protective properties of these compounds and further studies are needed to elucidate the mechanism of action of CBG and CBDV and whether they can modulate BBB permeability in more clinically relevant in vivo models of ischemic stroke. There is lack of effective treatments for ischemic stroke, a condition that will increase in prevalence in coming years, to which cannabinoids may offer a unique therapeutic strategy.” 

https://www.liebertpub.com/doi/10.1089/can.2020.0159

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Cannabidiol in Neurological and Neoplastic Diseases: Latest Developments on the Molecular Mechanism of Action

ijms-logo“As the major nonpsychotropic constituent of Cannabis sativa, cannabidiol (CBD) is regarded as one of the most promising therapeutic agents due to its proven effectiveness in clinical trials for many human diseases. Due to the urgent need for more efficient pharmacological treatments for several chronic diseases, in this review, we discuss the potential beneficial effects of CBD for Alzheimer’s disease, epilepsy, multiple sclerosis, and neurological cancers. Due to its wide range of pharmacological activities (e.g., antioxidant, anti-inflammatory, and neuroprotective properties), CBD is considered a multimodal drug for the treatment of a range of neurodegenerative disorders, and various cancer types, including neoplasms of the neural system. The different mechanisms of action of CBD are here disclosed, together with recent progress in the use of this cannabis-derived constituent as a new therapeutic approach.”

https://pubmed.ncbi.nlm.nih.gov/33919010/

https://www.mdpi.com/1422-0067/22/9/4294

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L-Theanine Prevents Long-Term Affective and Cognitive Side-Effects of Adolescent Δ-9-Tetrahydrocannabinol Exposure and Blocks Associated Molecular and Neuronal Abnormalities in the Mesocorticolimbic Circuitry

Journal of Neuroscience“Chronic adolescent exposure to Δ-9-Tetrahydrocannabinol (THC) is linked to elevated neuropsychiatric risk and induces neuronal, molecular and behavioural abnormalities resembling neuropsychiatric endophenotypes. Previous evidence has revealed that the mesocorticolimbic circuitry, including the prefrontal cortex (PFC) and mesolimbic dopamine (DA) pathway are particularly susceptible to THC-induced pathological alterations, including dysregulation of DAergic activity states, loss of PFC GABAergic inhibitory control and affective and cognitive abnormalities. There are currently limited pharmacological intervention strategies capable of preventing THC-induced neuropathological adaptations.

L-theanine is an amino acid analogue of L-glutamate and L-glutamine derived from various plant sources, including green tea leaves. L-theanine has previously been shown to modulate levels of GABA, DA and glutamate in various neural regions and to possess neuroprotective properties.

Using a pre-clinical model of adolescent THC exposure in male rats, we report that L-theanine pre-treatment prior to adolescent THC exposure is capable of preventing long-term, THC-induced dysregulation of both PFC and VTA DAergic activity states, a neuroprotective effect which persists into adulthood. In addition, pre-treatment with L-theanine blocked THC-induced downregulation of local GSK-3 and Akt signaling pathways directly in the PFC, two biomarkers previously associated with cannabis-related psychiatric risk and sub-cortical DAergic dysregulation.

Finally, L-theanine powerfully blocked the development of both affective and cognitive abnormalities commonly associated with adolescent THC exposure, further demonstrating functional and long-term neuroprotective effects of L-theanine in the mesocorticolimbic system.

SIGNIFICANCE STATEMENT With the increasing trend of cannabis legalization and consumption during adolescence, it is essential to expand knowledge on the potential effects of adolescent cannabis exposure on brain development and identify potential pharmacological strategies to minimize THC-induced neuropathology. Previous evidence demonstrates that adolescent THC exposure induces long-lasting affective and cognitive abnormalities, mesocorticolimbic dysregulation and schizophrenia-like molecular biomarkers that persist into adulthood.

We demonstrate for the first time that L-theanine, an amino acid analogue of L-glutamate and L-glutamine, is capable of preventing long-term THC side-effects. L-theanine prevented development of THC-induced behavioral aberrations, blocked cortical downregulation of local GSK-3 and Akt signaling pathways and normalized dysregulation of both PFC and VTA DAergic activity, demonstrating powerful and functional neuroprotective effects against THC-induced developmental neuropathology.”

https://pubmed.ncbi.nlm.nih.gov/33268546/

https://www.jneurosci.org/content/early/2020/11/24/JNEUROSCI.1050-20.2020

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