Understanding the many benefits of cannabis in cancer treatment


Image: Understanding the many benefits of cannabis in cancer treatment

A cancer diagnosis is both devastating and terrifying. Patients are almost always directed towards conventional cancer treatments like surgery, chemotherapy and radiation, and are made to feel that any other, more “natural” treatments are not only ineffective but dangerous.

The truth is, however, that mainstream cancer treatments wreak havoc on the body, leaving it defenseless against disease and breaking it down at the exact time when it needs to be as strong as possible. With its less than impressive success rate of between 2 and 4 percent, along with its devastating effects on the body, it is unsurprising that three out of every four doctors say they would refuse chemotherapy as a treatment option if they themselves became ill.

While doctors like to promote the idea that there are no treatments scientifically proven to work besides the usual surgery/chemotherapy/radiation regimen, the truth is there is a strong body of evidence that many natural, non-invasive treatments are effective in the fight against cancer. One of the most well-researched and solidly proven of all these natural medicines is cannabis.

The miraculous power of cannabinoids

As noted by Dr. Mark Sircus, writing for Green Med Info, there is no confusion about whether marijuana is an effective cancer treatment. Cannabis has been scientifically proven to kill cancer cells without the devastating and body weakening effects of conventional cancer treatments.

The marijuana plant contains about 113 powerful chemical compounds known as cannabinoids. The most well-known of these compounds are tetrahydrocannabinol (THC) – the chemical that induces marijuana’s “high” – and cannabidiol – a non-psychoactive compound which has been extensively studied as a cure for many diseases.

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These and other cannabinoids are what make marijuana such a potent anti-cancer treatment, as reported by Green Med Info:

Cannabinoids are found to exert their anti-cancer effects in a number of ways and in a variety of tissues.

  • Triggering cell death, through a mechanism called apoptosis
  • Stopping cells from dividing
  • Preventing new blood vessels from growing into tumors
  • Reducing the chances of cancer cells spreading through the body, by stopping cells from moving or invading neighboring tissue
  • Speeding up the cell’s internal ‘waste disposal machine’ – a process known as autophagy – which can lead to cell death

All these effects are thought to be caused by cannabinoids locking onto the CB1 and CB2 cannabinoid receptors. Almost daily we are seeing new or confirming evidence that Cannibinoids can be used to great benefit in cancer treatment of many types.

https://www.brighteon.com/embed/5849729304001

What the science says

Scientific studies published in a host of peer-reviewed journals have confirmed marijuana’s powerful ability to fight breast, lung, ovarian, pancreatic, prostate and other cancers.

A meta-analysis of over 100 published studies, performed by researchers from Germany’s Rostock University Medical Centre, concluded that cannabis both boosts immunity and fights cancer.

The Daily Mail reported:

Scientists are calling for more studies to be done on humans after studying the cancer-fighting effects of chemicals in the drug.

Studies suggest chemicals called phytocannabinoids could stop cancer cells multiplying and spreading, block the blood supply to tumors, and reduce cancer’s ability to survive chemotherapy. …

The new research review admits cannabis has ‘anti-cancer effects’ and says more research needs to be done in real patients to confirm the findings.

It takes real courage to receive a cancer diagnosis and decide not to follow mainstream advice but seek alternative treatments. But even for those who choose to receive conventional cancer treatments like radiation and chemotherapy, cannabis can still be an important part of their overall wellness plan. As Dr. Sircus admonishes, “Every cancer patient and every oncologist should put medical marijuana on their treatment maps.”

The influence of cannabinoids on generic traits of neurodegeneration


Abstract

In an increasingly ageing population, the incidence of neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease are rising. While the aetiologies of these disorders are different, a number of common mechanisms that underlie their neurodegenerative components have been elucidated; namely neuroinflammation, excitotoxicity, mitochondrial dysfunction and reduced trophic support. Current therapies focus on treatment of the symptoms and attempt to delay the progression of these diseases but there is currently no cure. Modulation of the endogenous cannabinoid system is emerging as a potentially viable option in the treatment of neurodegeneration. Endocannabinoid signalling has been found to be altered in many neurodegenerative disorders. To this end, pharmacological manipulation of the endogenous cannabinoid system, as well as application of phytocannabinoids and synthetic cannabinoids have been investigated. Signalling from the CB1 and CB2 receptors are known to be involved in the regulation of Ca2+ homeostasis, mitochondrial function, trophic support and inflammatory status, respectively, while other receptors gated by cannabinoids such as PPARγ, are gaining interest in their anti-inflammatory properties. Through multiple lines of evidence, this evolutionarily conserved neurosignalling system has shown neuroprotective capabilities and is therefore a potential target for neurodegenerative disorders. This review details the mechanisms of neurodegeneration and highlights the beneficial effects of cannabinoid treatment.

Introduction

Neurodegeneration is the culmination of progressive loss of structure and function in neuronal cells, resulting in severe neuronal death. The widespread prevalence of neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HD), and the lack of effective treatments, pose a significant social and economic burden (Brookmeyer et al., 2007; Zuccato et al., 2010; Taylor et al., 2013). Age remains the highest risk factor for these diseases and with a degree of neurodegeneration also occurring during normal ageing the threat to the quality of life and health of the global population is ever present (Marchalant et al., 2009). Although neurodegenerative diseases are a heterogeneous group of disorders, current research has identified a number of common underlying mechanisms namely protein misfolding, neuroinflammation, excitotoxicity and oxidative stress. These triggers are known to contribute to the progression of symptoms, functional alteration and microanatomical deficits found in neurodegenerative states.

Inflammation within the CNS is centred around the activation of the resident immune cells, the microglia (Akiyama et al., 2000; Taylor et al., 2013). Maintained in a quiescent state and associated with the production of neurotrophic and anti-inflammatory factors, microglia become activated by the recognition of highly conserved structural motifs on either pathogens (pathogen associated molecular patterns; PAMPs) or from damaged or stressed cells (damage associated molecular patterns; DAMPs) (Arroyo et al., 2011). The binding of PAMPs or DAMPS to pattern-recognition receptors, such as the Toll-like receptors (TLR) or receptors for advanced glycation end-products (RAGE), cause the migration of microglia followed by the synthesis and release of proinflammatory cytokines and reactive oxygen species (ROS) (Yan et al., 1996; Arroyo et al., 2011). Oxidative stress is a cytotoxic condition brought on by the increased intracellular production or accumulation of ROS and reactive nitrogen species (RNS) (Taylor et al., 2013). ROS are normal products of the mitochondrial respiratory chain but activated microglia generate excessive amounts as a result of intracellular peroxidases, oxidative processes and NADPH oxidase activity (Block and Hong, 2007). Regulation of ROS and RNS is vital to cell survival as their increased production leads to the damage of proteins, lipids, carbohydrates and nucleic acids resulting in significant disruption of cellular function (Mehta et al., 2013). Furthermore, oxidative stress can lead to the activation of the mitochondrial permeability transition pore causing the collapse of the trans-membrane electrochemical gradient and the release of proapoptotic factors like cytochrome c, procaspases and caspase activated DNase (Emerit et al., 2004). Excitotoxicity is the pathological process of damaging and killing neuronal cells as a result of excessive stimulation of ionotrophic receptors by glutamate and similar substances (Mehta et al., 2013). This process leads to impairment of intracellular Ca2+ buffering, generation of ROS and RNS, activation of the mitochondrial permeability transition pore and secondary excitotoxicity (Dong et al., 2009). In an attempt to reduce the intracellular Ca2+ load, neurons expend considerable energy using ion pumps on the endoplasmic reticulum, plasma membrane and mitochondria, reducing ATP levels and causing excitotoxic lesions (Beal, 2000). Activation of the proapoptotic cascade is associated with a number of insults such as generation of ROS/RNS, mitochondrial dysfunction, excitotoxicity and trophic factor withdrawal. This process depends upon initiator and effector caspases which cause DNA cleavage, proteolytic cascades and mitochondrial permeability resulting in the release of proapoptotic factors such as cytochrome c and DIABLO (Bredesen et al., 2006). A dynamic interplay between these neurodegenerative processes has been reported in AD, PD and HD and is the focus of many prospective therapeutic agents (Bredesen et al., 2006; Lin and Beal, 2006). Decreased neurogenesis and neurotrophic support has also emerged as a common characteristic in neurodegenerative states often presenting early in disease progression (Simuni and Sethi, 2008). Genes which have been identified as problematic in neurodegenerative disorders such as those for α-synuclein, presenilin 1, tau and huntingtin are also involved in brain plasticity and their aberrant aggregation is detrimental to adult neurogenesis (Winner et al., 2011).

The endogenous cannabinoid (eCB) system

The eCB system is composed of the endocannabinoid signalling molecules, 2-arachidonoyl glycerol (2AG) and anandamide (AEA) and their G-protein coupled cannabinoid CB1 and CB2 receptors (Piomelli, 2003: receptor nomenclature follows Alexander et al., 2013). Endocannabinoid signalling molecules are synthesized in the post-synaptic terminal as a result of depolarization and work in a retrograde fashion on presynaptic CB receptors. The primary pathway through which AEA is synthesized involves the Ca2+-dependent cleavage of its membrane precursor N-arachidonoyl phosphatidylethanolamine by phospholipase D (Di Marzo et al., 1994). In most cases, 2AG is synthesized by the hydrolysis of two sn-1 diacylglycerol lipase isozymes, diacylglycerol lipase-α (DGLα) and diacylglycerol lipase-β (DGLβ) (Bisogno et al., 2003). The CB1 receptor is highly expressed in the CNS at the terminals of central and peripheral neurons where they regulate neurotransmitter release and psychoactivity (Sanchez and Garcia-Merino, 2012). CB2 receptor expression is associated with the peripheral immune system, neurons within the brainstem and microglia during neuroinflammation (Van Sickle et al., 2005; Nunez et al., 2008). CB1 and CB2 receptors have also been associated with postnatal oligodendrogenesis. CB1 activation increases the number of glial precursors in the subventricular zone of postnatal rats while CB2 activation increases polysialylated neural cell adhesion molecule expression which is necessary for the migration of oligodendrocyte precursors (Arevalo-Martin et al., 2007). CB receptors act via the Gi or Go protein to stimulate the MAPK pathway and inhibit adenylate cyclase, attenuating the conversion of ATP to cyclic AMP (Howlett et al., 2002). CB receptor activation is also tightly linked to ion channel regulation through inhibition of voltage-dependent Ca2+ channels and activation of K+ channels (Mackie et al., 1993; Deadwyler et al., 1995; Hampson et al., 2000). The TRPV1 receptor is also activated by the endocannabinoid AEA and has been linked to its anti-inflammatory actions (Zygmunt et al., 1999). Degradation of endocannabinoids is carried out by two enzymes: fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL) which act upon AEA and 2AG respectively (Cravatt et al., 1996; Ben-Shabat et al., 1998). A number of exogenous ligands to CB receptors are also known such as the phytocannabinoids derived from the Cannabis sativa plant as well as synthetic CB1/CB2 agonists and antagonists. Manipulation of the eCB system has also been carried out by the inhibition of endocannabinoid biosynthesis, membrane transport and degradation (Bisogno et al., 2005). The eCB system has been identified as a possible therapeutic target against neurodegeneration as a number of alterations in the eCB system have been noted in AD, PD and HD, as discussed below ( Figure 1).

Introduction

Neurodegeneration is the culmination of progressive loss of structure and function in neuronal cells, resulting in severe neuronal death. The widespread prevalence of neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HD), and the lack of effective treatments, pose a significant social and economic burden (Brookmeyer et al., 2007; Zuccato et al., 2010; Taylor et al., 2013). Age remains the highest risk factor for these diseases and with a degree of neurodegeneration also occurring during normal ageing the threat to the quality of life and health of the global population is ever present (Marchalant et al., 2009). Although neurodegenerative diseases are a heterogeneous group of disorders, current research has identified a number of common underlying mechanisms namely protein misfolding, neuroinflammation, excitotoxicity and oxidative stress. These triggers are known to contribute to the progression of symptoms, functional alteration and microanatomical deficits found in neurodegenerative states.

Inflammation within the CNS is centred around the activation of the resident immune cells, the microglia (Akiyama et al., 2000; Taylor et al., 2013). Maintained in a quiescent state and associated with the production of neurotrophic and anti-inflammatory factors, microglia become activated by the recognition of highly conserved structural motifs on either pathogens (pathogen associated molecular patterns; PAMPs) or from damaged or stressed cells (damage associated molecular patterns; DAMPs) (Arroyo et al., 2011). The binding of PAMPs or DAMPS to pattern-recognition receptors, such as the Toll-like receptors (TLR) or receptors for advanced glycation end-products (RAGE), cause the migration of microglia followed by the synthesis and release of proinflammatory cytokines and reactive oxygen species (ROS) (Yan et al., 1996; Arroyo et al., 2011). Oxidative stress is a cytotoxic condition brought on by the increased intracellular production or accumulation of ROS and reactive nitrogen species (RNS) (Taylor et al., 2013). ROS are normal products of the mitochondrial respiratory chain but activated microglia generate excessive amounts as a result of intracellular peroxidases, oxidative processes and NADPH oxidase activity (Block and Hong, 2007). Regulation of ROS and RNS is vital to cell survival as their increased production leads to the damage of proteins, lipids, carbohydrates and nucleic acids resulting in significant disruption of cellular function (Mehta et al., 2013). Furthermore, oxidative stress can lead to the activation of the mitochondrial permeability transition pore causing the collapse of the trans-membrane electrochemical gradient and the release of proapoptotic factors like cytochrome c, procaspases and caspase activated DNase (Emerit et al., 2004). Excitotoxicity is the pathological process of damaging and killing neuronal cells as a result of excessive stimulation of ionotrophic receptors by glutamate and similar substances (Mehta et al., 2013). This process leads to impairment of intracellular Ca2+ buffering, generation of ROS and RNS, activation of the mitochondrial permeability transition pore and secondary excitotoxicity (Dong et al., 2009). In an attempt to reduce the intracellular Ca2+ load, neurons expend considerable energy using ion pumps on the endoplasmic reticulum, plasma membrane and mitochondria, reducing ATP levels and causing excitotoxic lesions (Beal, 2000). Activation of the proapoptotic cascade is associated with a number of insults such as generation of ROS/RNS, mitochondrial dysfunction, excitotoxicity and trophic factor withdrawal. This process depends upon initiator and effector caspases which cause DNA cleavage, proteolytic cascades and mitochondrial permeability resulting in the release of proapoptotic factors such as cytochrome c and DIABLO (Bredesen et al., 2006). A dynamic interplay between these neurodegenerative processes has been reported in AD, PD and HD and is the focus of many prospective therapeutic agents (Bredesen et al., 2006; Lin and Beal, 2006). Decreased neurogenesis and neurotrophic support has also emerged as a common characteristic in neurodegenerative states often presenting early in disease progression (Simuni and Sethi, 2008). Genes which have been identified as problematic in neurodegenerative disorders such as those for α-synuclein, presenilin 1, tau and huntingtin are also involved in brain plasticity and their aberrant aggregation is detrimental to adult neurogenesis (Winner et al., 2011).

The endogenous cannabinoid (eCB) system

The eCB system is composed of the endocannabinoid signalling molecules, 2-arachidonoyl glycerol (2AG) and anandamide (AEA) and their G-protein coupled cannabinoid CB1 and CB2 receptors (Piomelli, 2003: receptor nomenclature follows Alexander et al., 2013). Endocannabinoid signalling molecules are synthesized in the post-synaptic terminal as a result of depolarization and work in a retrograde fashion on presynaptic CB receptors. The primary pathway through which AEA is synthesized involves the Ca2+-dependent cleavage of its membrane precursor N-arachidonoyl phosphatidylethanolamine by phospholipase D (Di Marzo et al., 1994). In most cases, 2AG is synthesized by the hydrolysis of two sn-1 diacylglycerol lipase isozymes, diacylglycerol lipase-α (DGLα) and diacylglycerol lipase-β (DGLβ) (Bisogno et al., 2003). The CB1 receptor is highly expressed in the CNS at the terminals of central and peripheral neurons where they regulate neurotransmitter release and psychoactivity (Sanchez and Garcia-Merino, 2012). CB2 receptor expression is associated with the peripheral immune system, neurons within the brainstem and microglia during neuroinflammation (Van Sickle et al., 2005; Nunez et al., 2008). CB1 and CB2 receptors have also been associated with postnatal oligodendrogenesis. CB1 activation increases the number of glial precursors in the subventricular zone of postnatal rats while CB2 activation increases polysialylated neural cell adhesion molecule expression which is necessary for the migration of oligodendrocyte precursors (Arevalo-Martin et al., 2007). CB receptors act via the Gi or Go protein to stimulate the MAPK pathway and inhibit adenylate cyclase, attenuating the conversion of ATP to cyclic AMP (Howlett et al., 2002). CB receptor activation is also tightly linked to ion channel regulation through inhibition of voltage-dependent Ca2+ channels and activation of K+ channels (Mackie et al., 1993; Deadwyler et al., 1995; Hampson et al., 2000). The TRPV1 receptor is also activated by the endocannabinoid AEA and has been linked to its anti-inflammatory actions (Zygmunt et al., 1999). Degradation of endocannabinoids is carried out by two enzymes: fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL) which act upon AEA and 2AG respectively (Cravatt et al., 1996; Ben-Shabat et al., 1998). A number of exogenous ligands to CB receptors are also known such as the phytocannabinoids derived from the Cannabis sativa plant as well as synthetic CB1/CB2 agonists and antagonists. Manipulation of the eCB system has also been carried out by the inhibition of endocannabinoid biosynthesis, membrane transport and degradation (Bisogno et al., 2005). The eCB system has been identified as a possible therapeutic target against neurodegeneration as a number of alterations in the eCB system have been noted in AD, PD and HD, as discussed below.

Alzheimer’s disease

AD is a progressive age-related neurodegenerative disorder that affects over 26 million people worldwide (Brookmeyer et al., 2007). It is estimated that 10% of people over 65 and 25% of people over 80 years of age are afflicted by this debilitating disease, and that number is set to rise to 1 in every 85 people by 2050 (Hebert et al., 2003; Brookmeyer et al., 2007). AD is defined by the progressive deterioration of cognition and memory and is the most common form of dementia among the elderly (Minati et al., 2009). The characteristic hallmarks of AD include the formation of neuritic plaques, containing aggregated forms of the amyloid-β (Aβ) peptide and dystrophic neurites, and neurofibrillary tangles caused by the hyperphosphorylation of the microtubule associated protein, tau, resulting in severe neurodegeneration.

Over the past two decades, neuroinflammation has emerged as an integral process in the pathogenesis of AD. Post-mortem analysis of the brains of AD patients has revealed an increase in the amount of activated microglia and astrocytes as well as a significantly higher levels of proinflammatory cytokines, IL-1, IL-6 and TNF-α and ROS (Akiyama et al., 2000; Rojo et al., 2008). Furthermore, clinical studies have identified a positive correlation between TNF-α levels and cognitive decline (Holmes et al., 2009) and numerous trials have shown that anti-inflammatory drugs delay the onset or slow the progression of AD (Arroyo et al., 2011). Fibrillated Aβ can be recognized by immune cells and phagocytosed. However, once the peptides oligomerize, aggregate and form neuritic plaques this is not possible, leading to the chronic activation of the immune system (Salminen et al., 2009). Activation of TLR, nucleotide-binding oligomerization domain-like receptors and RAGE by Aβ can stimulate phagocytosis but also results in reduced antioxidant defence and the release of proinflammatory cytokines and proapoptotic mediators (Salminen et al., 2009; Heneka et al., 2010). The pathophysiological relevance of neuroinflammation to neurodegeneration in AD has been well established through multiple lines of evidence. Direct evidence of neurotoxicity has been shown as a result of the release of IL-1, IL-6 and TNF-α (Allan and Rothwell, 2001). Colocalization of the inflammatory response to areas most affected by AD pathology and the absence of such a response in areas less affected implies a strong relationship between the two (Akiyama et al., 2000).

The dysregulation of intracellular Ca2+ concentration and excessive activation of NMDA receptors are characteristic of AD (Sonkusare et al., 2005). Accumulation of glutamate as a result of Aβ-mediated reduction in astrocytic uptake, as well as direct activation of NMDA receptors, leads to excessive NMDA activity and excitotoxicity (Sonkusare et al., 2005; Texido et al., 2011). Aβ has been shown to increase voltage-dependant Ca2+ channel activity (MacManus, 2000) and to form Ca2+ permeable pores in membrane bilayers (Alarcon et al., 2006). Aβ-induced excitotoxicity has long been associated with the neurodegenerative process as rises in intracellular Ca2+ concentration have been shown to activate a number of apoptotic pathways including the activation of caspase-3, calpain and lysosomal cathepsins (Hajnoczky et al., 2003; Harvey et al., 2012). Activated microglia, which can be seen in excess around neuritic plaques, are a major source of ROS production and oxidative stress in the CNS. ROS can further perpetuate the inflammatory response by activating proinflammatory pathways (Taylor et al., 2013).

Several components of the eCB system are altered in AD. In the post-mortem brains of patients with AD, CB2 receptor expression was significantly increased in areas containing microglia associated with the neuritic plaques, such as the entorhinal cortex and parahippocampus (Benito et al., 2003; Solas et al., 2013). This increase in CB2 expression is thought to be an attempt to counteract the chronic inflammation found in AD as CB2 receptor activation reduces microglial activation and cytokine production (Ramirez et al., 2005; Koppel and Davies, 2010). CB1 receptor expression in the AD brain remains a contentious issue with reports of both intact and increased expression levels (Lee et al., 2010; Solas et al., 2013). However, Farkas et al. (2012) have recently reported an initial rise, followed by a steady decline in CB1 receptor expression in the prefrontal cortex of AD patients. When patients were grouped depending on the progression of AD, at the earliest stages of disease progression (Braak stages I-II) CB1 receptor density was at its highest when compared to aged-matched controls and those CB1 receptor levels were found to decline with the progression of AD while remaining above age-matched control levels (Farkas et al., 2012). Furthermore, pharmacological investigation has shown that the CB1 receptor becomes functionally impaired by nitrosylation in the AD brain, affecting the G protein coupling and downstream signaling (Ramirez et al., 2005). Lipidomic analysis of post-mortem brain tissue from AD patients has revealed significantly reduced levels of AEA and its precursors in the midfrontal and temporal cortex when compared to age-matched controls (Jung et al., 2012). Interestingly, increased degradation of AEA may also occur as a consequence of the up-regulation of the metabolizing enzyme, FAAH, on plaque-associated astrocytes that has been noted in the AD brain (Benito et al., 2003). Inhibition of MGL in an in vivo model of AD has recently been shown to suppress the production and accumulation of Aβ via reduced expression of β-site amyloid precursor protein cleaving enzyme 1, a key enzyme in the synthesis of Aβ (Chen et al., 2012). 2AG signalling in AD patients (Braak stage VI) is functionally impaired with increased expression of DGLα and DGLβ as well as the hydrolyzing enzyme MGL although membrane-associated 2AG hydrolysis by MGL was decreased (Mulder et al., 2011).

Parkinson’s disease

PD is the second most common neurodegenerative disease affecting 1% of people over 60 and 4% of people over 80 years of age (de Lau and Breteler, 2006). PD is characterized by the progressive loss of dopaminergic neurons primarily in the substantia nigra (SN) affecting the circuits of the basal ganglia resulting in bradykinesia, rigidity and tremors (Bartels and Leenders, 2009). In a rat model of PD, symptomatology followed an approximate 50% reduction of dopaminergic neurons in the SN combined with an 80% loss of dopamine levels in the striatum (Deumens et al., 2002). In degenerating neurons, Lewy bodies form containing neurofilaments with aggregated α-synuclein (Wakabayashi et al., 2007). The disease has been associated with genetic mutations, inflammation, exogenous toxins and oxidative stress (Bartels and Leenders, 2009).

The link between PD and dopamine loss has been affirmed by PET studies showing a presynaptic dopamine deficit in PD patients and post mortem biochemical analysis revealing decreased levels of dopamine metabolites in the affected areas (Bartels and Leenders, 2009). Intracellular degradation of dopamine generates high levels of ROS, promotes H+ leakage from the mitochondria and reduces levels of glutathione, a key antioxidant enzyme (Hald and Lotharius, 2005). This intrinsic increase in ROS and concomitant decrease in antioxidant enzymes may be the reason for the high levels of oxidative stress found in PD patients. Furthermore, ROS have been shown to induce excitotoxicity through the activation of NMDA receptors and induction of proinflammatory cascades (Barnham et al., 2004). Indeed, PET scans and post-mortem analysis have reported an increased number of activated microglia in the PD brain (McGeer et al., 1988; Gerhard et al., 2006). In line with this, post mortem analysis has also revealed an increased amount of proinflammatory cytokines, namely IL1-β, IL-2, IL-4, IL-6 and TNF-α (Taylor et al., 2013).

The eCB system has been shown to modulate GABAergic and glutamatergic transmission in the basal ganglia (Kofalvi et al., 2005) which affects motor function (Fernández-Ruiz, 2009) and has therefore gained interest as a possible therapeutic target for motor disorders. A recent study has shown a decrease in the availability of CB1 receptors in the SN of PD patients when compared with healthy controls (Van Laere et al., 2012). However, a marked increase in CB1 receptors was found in the nigrostriatal, mesolimbic and mesocortical dopaminergic projection areas of the same patients. It is important to note that no difference in CB1 availability was found between patients that had developed levodopa-induced dyskinesias and those without such symptoms (Van Laere et al., 2012). AEA levels in the cerebrospinal fluid of untreated PD patients were found to be more than double that found in age-matched controls. Interestingly, AEA levels returned to control levels in patients receiving chronic dopamine replacement therapy (Pisani et al., 2010). Furthermore, a sevenfold increase in 2AG levels was found in the globus pallidus of the reserpine-treated animal model of PD and this has been linked to suppression of locomotion (Di Marzo et al., 2000). A decrease in endocannabinoid degradation has also been noted in an animal model of PD with reduced levels of FAAH and AEA membrane transporter found in the striatum (Gubellini et al., 2002). This increase in endocannabinoid tone and CB1 receptor activity in the brain of PD patients has been proposed to be an attempt to normalize striatal function following dopamine depletion as enhanced CB1 receptor signalling reduces glutamate release and activates the pool of G-proteins usually activated by the dopamine D2 receptor (Meschler and Howlett, 2001; Brotchie, 2003).

Huntington’s disease

HD is a progressive neurodegenerative disease that affects 4–10 people per 100 000. The average age of onset is 40 years and it is fatal within 15–20 years (Ross and Tabrizi, 2011). The disease is inherited in an autosomal dominant fashion and is caused by an expanded cytosine, adenine, guanine repeat in the huntingtin gene. Expansion of this gene results in an elongated glutamine repeat at the NH2 terminus of the huntingtin protein (HTT) (Macdonald, 1993). The exact functions of HTT are not fully known although it is believed to play a role in vesicular transport and regulation of gene transcription (Cattaneo et al., 2005; Sadri-Vakili and Cha, 2006). Mutation of HTT can result in intracellular toxic protein aggregation through the formation of abnormal conformations, typically β-sheet structures, protein modifications and the disruption of cellular processes such as protein degradation and metabolic pathways (Ross and Tabrizi, 2011). The resulting clinical features of this are atrophy of the cerebral cortex, severe striatal neuronal loss and up to a 95% reduction of GABAergic medium spiny projection neurons (Halliday et al., 1998; Vonsattel, 2008). The pathological processes implicated in HD are the loss of trophic factors, specifically brain-derived neurotrophic factor (BDNF), excitotoxicity, oxidative stress and inflammation resulting in progressive neurodegeneration. Symptoms associated with HD include progressive motor dysfunction, cognitive decline and psychiatric disturbance (Ross and Tabrizi, 2011).

A number of studies have reported the dependency of medium spiny neurons on BDNF which is depleted by approximately 35% in animal models of HD (Baquet et al., 2004; Zuccato and Cattaneo, 2007). Reduced BDNF mRNA expression has also been reported in the post mortem analysis of brain tissue from HD patients (Zuccato et al., 2008). Decreased levels of BDNF have been closely linked to the HD phenotype since BDNF partial knock-out mice showed very similar phenotypes to HD models, namely progressive brain damage and hindlimb clasping as well as reduced striatal volumes (Baquet et al., 2004). Indeed, BDNF replacement is believed to be a possible therapeutic for HD and has been shown to decrease excitotoxicity and attenuate motor dysfunction and cell loss in animal models of HD (Kells et al., 2004; Kells et al., 2008). This may prove beneficial as mounting evidence implicates excitotoxicity in the pathophysiology of HD. Hassel et al. (2008) have reported a 43% decrease in glutamate uptake in HD patients and defective activity of the glutamate transporter, GLT1. The subsequent accumulation of extracellular glutamate could well be the cause of excessive NMDA activity and excitotoxicity. Mutant HTT has also been found to bind directly to mitochondria, disrupting metabolic activity and up-regulating the proapoptotic factors Bcl2-associated X protein and p53-up-regulated modulator of apoptosis (Bae et al., 2005). Neuroinflammatory processes are also gaining interest in the investigation of HD. PET imaging, in vitro studies and post-mortem analysis have reported an increase in microglial activation in HD which correlates with neurodegeneration and the severity of the condition (Ross and Tabrizi, 2011).

A clear parallel has been made between the graded progression of HD and decreasing CB1 receptor density, particularly in the caudate nucleus, putamen and the globus pallidus (Glass et al., 2000). Recently, it has been reported that CB1 receptor down-regulation is specific to certain striatal subpopulation such as medium spiny neurons and neuropeptide Y/neuronal nitric oxide synthase-expressing interneurons (Horne et al., 2013). Much work has been carried out in analysing the components of the eCB system in R6/2 transgenic mice, a common model of HD. A loss of CB1 receptor density was found presymptomatically (Denovan-Wright and Robertson, 2000) as a result of mutant HTT-associated impairment of CB1 receptor gene expression (Blazquez et al., 2011). Genetic ablation of CB1 receptors aggravated HD symptoms in mice while pharmacological activation by Δ9-tetrahydrocannabinol (THC) attenuated symptomatology indicating that impairment of CB1 receptor function may be a primary pathogenic feature of HD (Blazquez et al., 2011). CB2 receptor expression, however, was found to increase in the striatal microglia of these transgenic mice and HD patients and this may confer neuroprotection as genetic ablation of CB2 receptors in transgenic HD mice results in increased microglial activation, aggravation of disease symptomatology and decreased life span (Palazuelos et al., 2009). In the striatum, a reduction in AEA, 2AG and their respective biosynthetic enzymes N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D and diacylglycerol lipase activity was found (Bisogno et al., 2008; Bari et al., 2013). In the cortex, a reduction in 2AG levels was accompanied by an increase in AEA levels while their respective hydrolytic enzymes MGL, was decreased, and FAAH increased (Bisogno et al., 2008; Bari et al., 2013). These data clearly indicate the alteration of multiple components of the eCB system in the progression of HD.

Ageing

Ageing is a time-dependent and progressive deterioration of biological function that leads to death. The typical characteristics of ageing include a decrease in physiological capacity, reduced adaptive capabilities to changes in environment and an increased vulnerability to disease and death (Farooqui and Farooqui, 2009). Indeed, normal ageing presents many of the same pathophysiologic mechanisms found in neurodegenerative diseases and is believed to further aggravate disease progression. Many theories have been put forward to explain the degenerating nature of age such as Ca2+ dyshomeostasis, oxidative stress and mitochondrial dysfunction but a consensus is yet to be reached.

The atrophy of the human brain with age is believed to be as a result of neurodegeneration and the loss of myelinated axons (Peters, 2002). Increased Ca2+ influx has been reported in the CA1 hippocampal region of aged rats, mediated by increased voltage-operated Ca2+ channels (Landfield and Pitler, 1984; Thibault and Landfield, 1996). Furthermore, intracellular Ca2+ regulation is altered in the aged brain. Efflux of Ca2+ through plasma membrane pumps as well as its uptake to mitochondrial sinks is affected by ageing (Michaelis et al., 1996; Toescu, 2005) resulting in impairments in intracellular Ca2+ homeostasis. Oxidative stress is also prominent in the aged brain. Membrane lipid peroxidation coupled with oxidative damage of proteins and DNA is reported to increase with age (Sohal and Weindruch, 1996). Prolonged oxidative damage of mitochondrial DNA and lipids increases ROS generation resulting in further oxidative damage and vulnerability towards apoptosis (Paradies et al., 2011). Chronic activation of microglia and alterations in their morphologic and immunophenotypic nature have also been reported. Normal ageing is believed to prime microglia for an exaggerated response, preferentially releasing proinflammatory cytokines. Increased basal levels of IL-6 and enhanced LPS-induced levels of IL-6 and IL-1β have been reported in the aged brain (Nakanishi and Wu, 2009).

Conflicting reports have emerged on the state of the eCB system as a result of ageing. Decreased CB1 receptor density has been reported in the cerebellum and cerebral cortex of aged rats, while reduced CB1 mRNA levels were found in the hippocampus and brainstem (Berrendero et al., 1998). Conversely, Wang et al. (2003) have shown that there is no change in endocannabinoid tone or CB1 receptor density in the hippocampus limbic forebrain, amygdala or cerebellum of aged mice. However, decreased coupling of CB1 receptor to G-proteins was reported in the limbic forebrain.

The eCB system as a therapeutic target

The use of cannabinoids as a therapeutic remains a controversial issue. However, some success has been gained with the use of cannabinoid-based drugs to regulate appetite, sleep, pain and some psychotic tendencies. Dronabinol, derived from the phytocannabinoid THC, is beneficial in reducing anorexia, increasing body weight and improving behaviour in elderly AD patients (Volicer et al., 1997). Dronabinol has more recently been assessed in a pilot study with AD patients where it improved nocturnal motor activity and reduced agitation and aggression, without undesired side effects (Walther et al., 2006). In animal models of PD, THC attenuates motor inhibition and the loss of tyrosine hydroxylase-positive (dopamine producing) neurons. Furthermore, preclinical studies have investigated the anti-inflammatory and antioxidant capabilities of the phytocannabinoid cannabidiol (CBD), combined with THC, in the form of the cannabis-based medicine Sativex, which is already used as a therapeutic agent for multiple sclerosis. Sativex has been shown to successfully treat neuropathic pain and spasticity in multiple sclerosis patients (Nurmikko et al., 2007; Notcutt et al., 2012). Maresz et al. (2007) have demonstrated that CB1 and CB2 receptors are required for mediation of the immune system in animal models of multiple sclerosis. This combination is now emerging as a viable therapeutic option for PD and HD (Valdeolivas et al., 2012; Fernandez-Ruiz et al., 2013). The eCB system is believed to be a promising therapeutic target for delaying disease progression and ameliorating Parkinsonian symptoms (Garcia et al., 2011).

Cannabinoids and neuroinflammation

Chronic neuroinflammation has been identified as a key mediator of neurodegeneration in AD, PD and HD. Various models of inflammation have reported the beneficial effects of cannabinoid action on reducing the inflammatory burden ( Figure 2). The CB2 selective agonist, JWH015 a synthetic cannabinoid, has been shown to reduce interferon-γ-induced up-regulation of CD40 in cultured mouse microglial cell through interfering with the JAK/STAT pathway. Furthermore, this intervention suppressed the production of proinflammatory cytokines and promoted the phagocytosis of Aβ (Ehrhart et al., 2005). Mobilization of intracellular Ca2+ in response to ATP is a key mediator of microglial activation and inducer of the inflammatory response. CBD, along with the synthetic cannabinoids WIN 55212-2, a mixed CB1/CB2 receptor agonist and JWH-133, a CB2 receptor selective agonist, were all shown to decrease the ATP-induced rise in intracellular Ca2+ concentration in the N13 microglial cell line (Martin-Moreno et al., 2011). The effects of WIN 55212-2 and JWH-133 were fully reversed by the selective CB2 antagonist, SR144528 (100 nM) indicating a CB2 receptor-mediated effect. This antagonism was not seen in CBD-treated cells suggesting that CB2-independent mechanisms may also be beneficial. Furthermore, the Aβ-induced rise in the proinflammatory cytokine IL-6 was reduced almost sixfold by 20 mg kg−1 CBD or 0.5 mg kg−1 WIN 55212-2 in vivo (Martin-Moreno et al., 2011). Further in vivo studies using transgenic APP 2576 mice have reported that oral administration of JWH-133 (0.2 mg kg−1 day−1 for 4 months) decreased microglial activation, reduced COX-2 and TNF-α mRNA and reduced cortical levels of Aβ, with no impact on cognitive performance (Martin-Moreno et al., 2012). A number of studies have identified the PPARγ as a key mediator of the cannabinoid anti-inflammatory effect. The PPAR family are a group of nuclear hormone receptors known to be involved in gene expression, lipid and glucose metabolism and the inflammatory response. In cultured rat astrocytes, reactive gliosis was induced by treatment with 1 mg mL−1 Aβ for 24 h and this was significantly reduced by CBD in a concentration-dependant manner. The beneficial effects of CBD were blunted by PPARγ antagonism by GW9662, suggesting the involvement of PPARγ in the anti-inflammatory effects of CBD (Esposito et al., 2011). Hippocampal fractions isolated from adult rats injected with Aβ (10 μg mL−1) to the CA1 region and treated with CBD (10 mg kg−1) intraperitoneally for 15 days replicated the results found in vitro. Fakhfouri et al. (2012) have further elucidated the relationship between cannabinoids and PPARγ in vivo and have identified that Aβ, when administered intrahippocampally to adult rats, increased PPARγ transcriptional activity and protein expression is observed which was further increased as a result of i.c.v. administration of WIN 55212-2. The beneficial effects caused by WIN 55212-2 were partially halted by the antagonism of PPARγ by i.c.v. administration of GW9662.

A common model for inflammation in the brain is the infusion of lipopolysaccharide into the fourth ventricle of young rats. Marchalant et al. (2007) have shown that daily i.p. injections of WIN 55212-2 (0.5 mg kg−1) successfully reduced microglial activation in this model. However, when the dosing regimen was raised to 1 mg kg−1 day−1, microglial activation was potentiated by WIN 55212-2. Normal aging has also been shown to cause neuroinflammation and in this context cannabinoids have also been shown to confer neuroprotection. In rats aged 23 months, WIN 55212-2 injections of 2 mg kg−1 i.p. for 4 weeks reduced the number of activated microglia in the hippocampus and dentate gyrus (Marchalant et al., 2009). Interestingly, when incubated with the CB1 receptor antagonists SR141716A and SR144528, WIN 55212-2 had no effect. The same treatment was found to decrease the mRNA levels of the proinflammatory cytokine IL-6 as well as the anti-inflammatory cytokine IL1-RA. Protein levels of TNF-α and IL-1β were decreased while an increase in IL1-RA was seen (Marchalant et al., 2009). It is now clear that at multiple steps throughout the inflammatory process, cannabinoids can help to reduce the inflammatory burden during neurodegeneration.

Cannabinoids, excitotoxicity and mitochondrial dysfunction

The excitotoxic increase of intracellular Ca2+ concentration in neurodegenerative disorders can lead to the activation of apoptotic and proinflammatory pathways, as well as disrupting metabolic processes leading to cell death. Endocannabinoids are most commonly synthesized in a Ca2+-dependent fashion as a result of depolarization and are believed to help reduce excitotoxic damage. Indeed, AEA levels increase rapidly in the hippocampi of mice after administration of the excitotoxin kainic acid (KA) (30 mg kg−1) and genetic ablation of the CB1 receptor lowered the threshold for KA-induced seizures with more than 75% of CB1-null mice dying within 1 h of KA injection. The neuroprotective capabilities of CB1 are suggested to act primarily on principal glutamatergic neurons. Furthermore, the intracellular events involved in this neuroprotection have been attributed to the CB1-mediated activation of ERKs and the subsequent expression of the immediate early genes c-fos and zif268 (Marsicano et al., 2003). Cannabinoid action, via CB1 receptors in particular, regulates intracellular Ca2+ levels through a number of mechanisms (Figure 2). Exposure of murine cortical cultures to 20 μM NMDA for 24 h results in 70% cell death and WIN 55212-2 has been shown to decrease cell death though the inhibition of nitric oxide signalling and PKA (Kim et al., 2006a). This CB1 receptor-mediated regulation of PKA has long been associated with neuroprotection against excitotoxicity (Kim et al., 2005). Another route for Ca2+ influx is through TNF-α mediated surface delivery of Ca2+ permeable AMPA receptors which contribute to in vitro excitotoxicity. WIN 55212-2 inhibits this TNF-α-induced increase in surface AMPA receptors and reduces excitotoxic damage in rat hippocampal cultures (Zhao et al., 2010). TNF-α also increased PKA activity (Zhang et al., 2002) which in turn can phosphorylate AMPA receptors at Ser845 and traffic them to the plasma membrane (Oh et al., 2006). It is therefore believed that the inhibition of PKA by CB1 receptor stimulation is beneficial in reducing excitotoxic damage by interfering with AMPA trafficking. Furthermore, the CB1 receptor agonists, WIN 55212-2 and AEA, inhibited glutamate release from rat hippocampal synaptosomes which would reduce NMDA activation and the resulting Ca2+ influx (Wang, 2003). As well as reducing the influx of Ca2+, cannabinoid action regulates intracellular Ca2+ homeostasis. WIN 55212-2 reduced the NMDA-mediated release of Ca2+ from intracellular stores in cultured rat hippocampal cells thereby increasing cell viability. This involved the CB1-mediated reduction in cAMP-dependant PKA phosphorylation of ryanodine receptors (Zhuang et al., 2005). Furthermore, in high-excitability conditions CBD (1 μM) increased the levels of Ca2+ uptake by mitochondria in cultured rat hippocampal neurons (Ryan et al., 2009). Intense elevation of intracellular Ca2+ is known to induce proapoptotic cascades. Activation of cytosolic calpains by Ca2+ results in permeabilization of the lysosome and the release of proapoptotic proteins such as the caspase and cathepsin family (Yamashima and Oikawa, 2009). Noonan et al. (2010) have shown in vitro that increasing endocannabinoid tone through inhibiting FAAH degradation of 2AG prevented the Aβ-induced increase in calpain activation, permeabilization of the lysosome and the resulting neurodegeneration.

Mitochondrial dysfunction has also been addressed by cannabinoid research (Figure 2). Oxygen-glucose deprivation/reoxygenation of neuronal-glial cultures causes mitochondrial depolarization and oxidative stress. In rat neuronal-glial cultures, the cannabinoid trans-caryophyllene (1 μM) has been shown to increase neuronal viability through a reduction of mitochondrial depolarization and oxidative stress, and by increasing the expression of BDNF. This study has identified CB2 receptor activation as a mechanism for enhancing the phosphorylation of AMP-activated protein kinase and cAMP responsive element-binding protein and increasing expression of the CREB target protein, BDNF (Choi et al., 2013). In an in vitro model of PD, 1-methyl-4-phenylpyridinium iodide, paraquat and lactacystin were used to inhibit mitochondrial function, generate free radicals and inhibit the ubiquitin proteasome respectively. These treatments resulted in cell death brought on by ROS generation, caspase-3 activation and cytotoxicity. THC (10 μM) was shown to reduce these effects in human neuroblastoma cells (SH-SY5Y) while increasing cell viability. This result was not reproduced by the CB1 receptor agonist WIN 55212-2 (1 μM) but was blocked by inhibition of PPARγ, the activity of which was increased by THC treatment (Carroll et al., 2012).

Cannabinoids and adult neurogenesis

Adult neurogenesis is the process by which new neurons are generated and integrated into the developed brain. Regulation of neurogenesis is strictly controlled through a number of different factors such as adrenal and sex hormones, neurotransmitter systems, trophic factors and inflammatory cytokines. The formation of new neurons and neuronal connections may prove vital to sustaining neuronal function in neurodegenerative disorders where neurogenesis is impaired such as AD and HD (Molero et al., 2009; Crews et al., 2010). The eCB system has been closely linked to the process of adult neurogenesis. DGLα and DGLβ synthesize the endocannabinoid 2AG, and DGLα and DGLβ null mice have an 80 and 50% reduction in 2AG respectively. These transgenic mice were shown to have impaired neurogenesis, believed to be as a result of the loss of 2AG-mediated transient suppression of GABAergic transmission at inhibitory synapses (Gao et al., 2010). Furthermore, mice lacking CB1 receptors displayed an almost 50% reduction in neurogenesis in the dentate gyrus and subventricular zone when compared to wild type. In line with this, the mixed CB1/CB2 receptor agonist WIN 55212-2 enhanced BrdU incorporation into murine neuronal culture in a CB1 receptor-mediated fashion (Kim et al., 2006b). CB1 receptor-mediated stimulation of adult neurogenesis has been shown to act through its opposition of the antineurogenic effect of nitric oxide (Kim et al., 2006b; Marchalant et al., 2009). Neuronal precursor cell proliferation and the number of migrating neurons have been shown to increase in neurogenic regions in response to seizure, ischaemia and excitotoxic and mechanical lesions indicating a possible contributing factor in the repair of lesioned circuits (Gould and Tanapat, 1997; Arvidsson et al., 2001; Parent et al., 2002; Lie et al., 2004). KA-induced neural progenitor proliferation is reduced in CB1 receptor deficient mice as well as in wild-type mice administered with the selective CB1 receptor antagonist SR141716A. This effect was attributed to the CB1-dependent expression of basic fibroblast growth factor and epidermal growth factor (Aguado et al., 2007). BDNF is vital for the survival of new neurons and is significantly reduced in neurodegenerative conditions such as HD (Zuccato and Cattaneo, 2007). De March et al. (2008) have shown that 2 weeks post-excitotoxic lesion in rats, transient up-regulation of BDNF coincides with higher binding activity and protein expression of CB1 receptor. This is believed to be an attempt to rescue the striatal neuronal population. In a reciprocal fashion, BDNF (10 ng mL−1) was shown in vitro to increase neuronal sensitivity to the endocannabinoids 2AG and noladin ether as measured by the phosphorylation of Akt (Maison et al., 2009). Indeed, CB1 receptor activation has been implicated in neural precursor proliferation and neurogenesis while CB1 and CB2 receptor activation is involved in neural progenitor cell proliferation, both of which are vital to the generation and survival of new neurons (Palazuelos et al., 2006; Aguado et al., 2007).

bph12492-fig-0003

Chemical structures of the common CB receptor agonists.

Summary

Neurodegenerative diseases are a heterogeneous group of age-related disorders. While AD, PD and HD have a variety of different genetic and environmental causes, the principal factor involved is the progressive and severe loss of neurons. It is widely accepted that neuroinflammation, excitotoxicity and oxidative stress are key mediators of neurodegeneration, and impaired neurogenesis as well as reduced trophic support leave neuronal systems unable to cope. The eCB system is emerging as a key regulator of many neuronal systems that are relevant to neurodegenerative disorders. Activation of CB1 receptors regulates many neuronal functions such as Ca2+ homeostasis and metabolic activity while the CB2 receptor is mainly involved in regulating the inflammatory response.

Here, we have put forward the mechanisms of neurodegeneration in the three most prevalent neurodegenerative disorders, AD, PD and HD, as well as showing the vulnerability of the brain as a result of age. We have summarized evidence of the beneficial role of modulating the cannabinoid system to reduce the burden of neurodegeneration. Pharmacological modulation of the eCB system ( Figure 3) has been shown to reduce chronic activation of the neuroinflammatory response, aid in Ca2+ homeostasis, reduce oxidative stress, mitochondrial dysfunction and the resulting proapoptotic cascade, while promoting neurotrophic support.

Cannabinoids, like those found in marijuana, occur naturally in human breast milk


Woven into the fabric of the human body is an intricate system of proteins known as cannabinoid receptors that are specifically designed to process cannabinoids such as tetrahydrocannabinol (THC), one of the primary active components of marijuana. And it turns out, based on the findings of several major scientific studies, that human breast milk naturally contains many of the same cannabinoids found in marijuana, which are actually extremely vital for proper human development.

Cell membranes in the body are naturally equipped with these cannabinoid receptors which, when activated by cannabinoids and various other nutritive substances, protect cells against viruses, harmful bacteria, cancer, and other malignancies. And human breast milk is an abundant source of endocannabinoids, a specific type of neuromodulatory lipid that basically teaches a newborn child how to eat by stimulating the suckling process.

If it were not for these cannabinoids in breast milk, newborn children would not know how to eat, nor would they necessarily have the desire to eat, which could result in severe malnourishment and even death. Believe it or not, the process is similar to how adult individuals who smoke pot get the “munchies,” as newborn children who are breastfed naturally receive doses of cannabinoids that trigger hunger and promote growth and development.

“[E]ndocannabinoids have been detected in maternal milk and activation of CB1 (cannabinoid receptor type 1) receptors appears to be critical for milk sucking … apparently activating oral-motor musculature,” says the abstract of a 2004 study on the endocannabinoid receptor system that was published in the European Journal of Pharmacology.

“The medical implications of these novel developments are far reaching and suggest a promising future for cannabinoids in pediatric medicine for conditions including ‘non-organic failure-to-thrive’ and cystic fibrosis.”

Studies on cannabinoids in breast milk help further demystify the truth about marijuana

There are two types of cannabinoid receptors in the body — the CB1 variety which exists in the brain, and the CB2 variety which exists in the immune system and throughout the rest of the body. Each one of these receptors responds to cannabinoids, whether it be from human breast milk in children, or from juiced marijuana, for instance, in adults.

This essentially means that the human body was built for cannabinoids, as these nutritive substances play a critical role in protecting cells against disease, boosting immune function, protecting the brain and nervous system, and relieving pain and disease-causing inflammation, among other things. And because science is finally catching up in discovering how this amazing cannabinoid system works, the stigma associated with marijuana use is, thankfully, in the process of being eliminated.

In another study on the endocannabinoids published in the journal Pharmacological Reviews back in 2006, researchers from the Laboratory of Physiologic Studies at the National Institute on Alcohol Abuse and Alcoholism uncovered even more about the benefits of cannabinoids. These include their ability to promote proper energy metabolism and appetite regulation, treat metabolic disorders, treat multiple sclerosis, and prevent neurodegeneration, among many other conditions.

With literally thousands of published studies now showing their safety and usefulness, cannabinoids, and particularly marijuana from which it is largely derived, truly are a health-promoting “super” nutrient with virtually unlimited potential in health promotion and disease prevention.

Be sure to check out how juicing raw marijuana leaves, which contain a diverse array of health-promoting cannabinoids, is an excellent non-psychoactive way to prevent and treat a host of diseases, including cancer:

Learn more: http://www.naturalnews.com/036526_cannabinoids_breast_milk_THC.html#ixzz3w7GpAcul

The US Finally Admits Cannabis Kills Cancer Cells


A group of federal researchers commissioned by the government to prove that cannabis has “no accepted medical use” may have unwittingly let information slip through the cracks, revealing how cannabis actually kills cancer cells. 

The research, which was conducted by a team of scientists at St. George’s University of London, found that the two most common cannabinoids in marijuana, tetrahydrocannabinol (THC) and cannabidiol (CBD), weakened the ferocity of cancer cells and made them more susceptible to radiation treatment, said Mike Adams of Herbal Dispatch.

The study, which was published last year in the medical journal Molecular Cancer Therapies, details the “dramatic reductions” in fatal variations of brain cancer when these specific cannabinoids were used in conjunction with radiation therapy.

We’ve shown that cannabinoids could play a role in treating one of the most aggressive cancers in adults,” wrote lead researcher Dr. Wai Liu, in a November 2014 op-ed for The Washington Post. The results are promising… it could provide a way of breaking through glioma [tumors] and saving more lives.”

Recent animal studies have shown that marijuana can kill certain cancer cells and reduce the size of others, the NIDA report said.Evidence from one animal study suggests that extracts from whole-plant marijuana can shrink one of the most serious types of brain tumours. Research in mice showed that these extracts, when used with radiation, increased the cancer-killing effects of the radiation.”

NIDA’s newfound pro-pot position is especially curious given that it was revealed on the heels of a recent proposal introduced to both Congress and the House of Representatives which attempts to legalize medical marijuana on a national level. The bill, which is called the CARERS Act, seeks to downgrade the Schedule I status of marijuana to a Schedule II in order to make the herb more flexible in the eyes of the federal government as an accepted form of medicine.
In addition, the bill would also remove cannabidiol, the non-intoxicating compound of the pot plant, from the Controlled Substances Act and allow it to be distributed on a state-to-state basis without violating federal statutes.

Cannabis became a schedule I drug in 1970 with the passing of the Controlled Substances Act, which classified cannabis as having a high potential for abuse, no medical usage, and unsafe to use without medical supervision.

This federal research basically contradicts cannabis’ schedule I status. Could this mean reform is closer than we’d originally imagined?

Stay tuned for the latest updates on cannabis reform.

What are your thoughts on this? Do you think we are about to see a major change in the legal status of cannabis? Do you feel it should be looked at as a potent medicine? Share with us in the comment section below!

Cannabinoids increasingly recognized as powerful medicine for pain control, Alzheimer’s prevention, stress relief and more


You may have noticed the flurry of new dietary supplements containingcannabinoids (CBDs) — active chemical constituents of the cannabis plant. People everywhere are discovering the power of CBDs to reduce pain, enhance mood, relax the nerves and even help prevent chronic disease.

But what most people don’t know — thanks to the systematic suppression of indigenous knowledge about plant-based medicine — is that CBDs have a long and rich history of medicinal use around the world. The history is fascinating, and it shows why the present-day system of monopoly medicine has worked so diligently to criminalize the cannabis plant and imprison its supporters. The following text is contributed by Natural News researchers:

5,000 years of medicinal use

Cannabis was used as a medicine well before the Christian era, especially in Asia and India (1). The introduction of cannabis to Western medicine took place during the 19th century and reached its peak during the last decade of that century, manifesting itself in the widespread use of cannabis extracts and tinctures. In the first decades of the 20th century, however, the medical use of cannabis declined, mostly due to difficulties to obtain consistent results from batches of plant material.

As early as 5,000 years ago, cannabis was found to have positive effects on the central nervous system. It showed consistent results in pain relief, stimulation of appetite and calming of nerves. Evidence for the medical use of cannabis goes back to Emperor Chen Nung, the father of Chinese agriculture and a discoverer of medicinal plants. Chen is believed to be the author of the oldest known Chinese pharmacy guide, in which he writes about cannabis’ medicinal uses to treat rheumatism, menstrual fatigue, constipation, malaria, and even absentmindedness.

Powerful medicinal alkaloids

During the 19th century, medicinal cannabis was widely used. At the time it was recognized that preparations of cannabis that were being distributed through pharmacies was varied; as the active ingredient was not yet known, quality control was almost impossible, which is part of the reason why use of cannabis plants fell out of practice.

One practical explanation for this was that the cannabis cultivated in places like China, India and Morocco might take as long as one year to reach Western markets. And since storage conditions were less than optimal in sailing vessels of the day, quality of the plant constituents degraded during storage.

During the Victorian Era, many alkaloids were extracted from plants for their unique properties. Plant chemists were successful because alkaloids they sought were water soluble organic bases that formed crystalline solids when combined with certain acids. Among the compounds isolated in the 19th century were quinine, cocaine and morphine; these represented significant advances in plant chemistry.

The molecules on the cannabis plant, though, were almost completely insoluble in water. The chemical nature of cannabinoids prevented early plant chemists during the Victorian period from creating efficient extracts of these polar compounds. The active ingredient, delta 9-Tetrahydrocannabinilol (or Delta-9-THC), was not isolated and summarily identified until 1964 (5).

Cannabinoid receptors discovered in the human body

In the 1990s, researchers made discoveries essential for the establishment of the cannabinoid research field. By the end of the decade scientists had discovered two distinct cannabinoid receptors (CB1 and CB2), isolated endogenous cannabinoids (Anandamide and 2-Arachidonylglycerol), synthesized a cadre of ligands, and generated cannabinoid receptor knockout mice (i.e., CB1 KO) (Gerard et al., 1990; Matsuda et al., 1990; Zimmer et al., 1999).

Efforts to identify and clone the CB1 receptor demonstrate that it is one of the most abundant proteins in the brain. Thus, cannabinoid receptors became an attractive target for drug development. The availability of synthetic THC and novel analogs has allowed researchers to begin characterizing the role of this neuronal G-protein coupled receptor (GPCR). The complex physiological mechanisms involving cannabinoid receptors and their ligands in mammals is referred to as the endocannabinoid system (ECS) (4).

According to History of Cannabis as a Medicine: A Review:

The identification of the chemical structure of cannabis components and the possibility of obtaining its pure constituents were related to a significant increase in scientific interest in such plant, since 1965. This interest was renewed in the 1990’s with the description of cannabinoid receptors and the identification of an endogenous cannabinoid system in the brain. A new and more consistent cycle of the use of cannabis derivatives as medication begins, since treatment effectiveness and safety started to be scientifically proven.

Cannabinoids effective against brain aging and Alzheimer’s

That said, cannabinoids are a class of diverse chemical compounds that act on cannabinoid receptors on cells that repress neurotransmitter release in the brain. In fact, the human brain contains an extensive network of special receptor sites that modulate nervous system function only when activated by the appropriate cannabinoid compounds, many of which are found in abundance in the marijuana plant. And emerging research continues to uncover the unique role these cannabinoids play in protecting brain function, which in turn helps deter the aging process and even reverse the damaging effects of Alzheimer’s disease and other forms of dementia and cognitive abnormality (2).

Notes the Cannabis International Foundation:

Cannabis provides highly digestible globular protein, which is balanced for all of the Essential Amino Acids. Cannabis provides the ideal ratio of omega 6 to omega 3 Essential Fatty Acids. Critically, cannabis is the only known source of the Essential Cannabinoid Acids. It is clear that all 7 billion individuals would benefit from access to cannabis as a unique functional food.

New Study Shows Cannabinoids Improve Efficiency Of Mitochondria And Remove Damaged Brain Cells.


A recent study conducted by Andras Biokei-Gorzo at the Institute of Molecular Psychiatry at the University of Bonn in Germany is suggesting that marijuana(or the activation of the brain’s cannabinoid system) triggers the release of antioxidants, which act as a cleansing mechanism. This process is known to remove damaged cells and improve the efficiency of mitochondria. Mitochondria is the energy

source that powers cells.

 mj

These discoveries shed new insight on how natural marijuana cannabinoids hold the capacity to literally kill the brain inflammation responsible for causing cognitive decline, neural failure, and brain degeneration. By supplying these receptor sites with cannabinoids, patients may be able to overcome brain conditions like Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and more, not to mention premature brain aging. The human brain contains an extensive network of special receptor sites that modulate nervous system function only when activated by the appropriate cannabinoid compounds, which are found in the marijuana plant.

Cannabinoids refer to any of a group of related compounds that include cannabinol and the active constituents of cannabis. They activate canbinoid receptors in the body. The body itself produces  compounds called endocannabinoids and they play a role in many processes within the body that help to create a healthy environment. Cannabinoids also play a role in immune system generation and re-generation. The body regenerates best when it’s saturated with Phyto-Cannabinoids. Cannabinoids can also be found in Cannabis. Cannabinoids may very well be the best cancer fighting substance out there!

Cannabinoid system activity is neuroprotective, and increasing it could be a promising strategy for slowing down the progression of brain aging and for alleviating the systems of neurodegenerative disorders -Andras Biokei

Gery Wenk, a professor of neuroscience, immunology and medical genetics at Ohio State University conducted some of the research that came out of the study from Germany. He stated that this is a positive step, and that it is encouraging to see the potential development of cannabinoid solutions without going overboard. Here is what he said.

I’ve been trying to find a drug that will reduce brain inflammation and restore cognitive function in rats for over 25 years; cannabinoids are the first and only class of drugs that have ever been effective. I think that the perception about this drug is changing and in the future people will be less fearful. – Gerry Wenk, Professor of neuroscience, immunology and medical genetics at Ohio State University

Biokei-Gorzo and his collegues said that the greatest hurdle for moving forward with their research are the social and political challenges. This isn’t something new, our world seems to be dominated by belief systems instead of obvious fact. It’s discouraging to see beliefs  and persuasion overrule truth. At the same time it’s very encouraging to see truth slowly creep its way into the norm. That’s always how it has been done throughout human history. It’s quite evident that the powers that be do not want to legalize marijuana, and we know that they do not have our best interest at hand. If it was legalized, I’m sure it would be distributed and tweaked by big pharmaceutical companies.

On the other hand there have been a number of studies that show how marijuana can actually reduce brain power and impair working memory. The amount of studies that show the potential benefits of marijuana is outstanding, and the potential harmful effects are in the few, if any at all. As far as medicinal use goes, I think that is a no brainer. I definitely believe nature intended marijuana to be used for its health and healing properties.

Sources:

http://rstb.royalsocietypublishing.org/content/367/1607/3326.abstract?sid=20cf2c23-e4fd-49e3-9398-ec8be2e00226

http://healthland.time.com/2012/10/29/how-cannabinoids-may-slow-brain-aging/

http://www.drugscience.org/Petition/C3D.html

http://www.naturalnews.com/040456_marijuana_cannabinoids_dementia.html

http://www.rawhemp.tk/

http://www.phoenixtears.ca/

http://cannabisinternational.org/

http://edrv.endojournals.org/content/27/1/73.fullhttp://cannabisclinicians.org/wp-content/uploads/2011/12/OS-2011-Terpenes+Minor-CBs.pdf