Comprehensive Review of Medicinal Marijuana, Cannabinoids, and Therapeutic Implications in Medicine and Headache: What a Long Strange Trip It’s Been ….

“The use of cannabis, or marijuana, for medicinal purposes is deeply rooted though history, dating back to ancient times. It once held a prominent position in the history of medicine, recommended by many eminent physicians for numerous diseases, particularly headache and migraine.

Through the decades, this plant has taken a fascinating journey from a legal and frequently prescribed status to illegal, driven by political and social factors rather than by science.

However, with an abundance of growing support for its multitude of medicinal uses, the misguided stigma of cannabis is fading, and there has been a dramatic push for legalizing medicinal cannabis and research.

Almost half of the United States has now legalized medicinal cannabis, several states have legalized recreational use, and others have legalized cannabidiol-only use, which is one of many therapeutic cannabinoids extracted from cannabis.

Physicians need to be educated on the history, pharmacology, clinical indications, and proper clinical use of cannabis, as patients will inevitably inquire about it for many diseases, including chronic pain and headache disorders for which there is some intriguing supportive evidence…

The literature suggests that the medicinal use of cannabis may have a therapeutic role for a multitude of diseases, particularly chronic pain disorders including headache.

Supporting literature suggests a role for medicinal cannabis and cannabinoids in several types of headache disorders including migraine and cluster headache, although it is primarily limited to case based, anecdotal, or laboratory-based scientific research.

Cannabis contains an extensive number of pharmacological and biochemical compounds, of which only a minority are understood, so many potential therapeutic uses likely remain undiscovered.

Cannabinoids appear to modulate and interact at many pathways inherent to migraine, triptan mechanisms ofaction, and opiate pathways, suggesting potential synergistic or similar benefits.

Modulation of the endocannabinoid system through agonism or antagonism of its receptors, targeting its metabolic pathways, or combining cannabinoids with other analgesics for synergistic effects, may provide the foundation for many new classes of medications.”

Cannabinoid receptor CB1 regulates STAT3 activity and its expression dictates the responsiveness to SR141716 treatment in human glioma patients’ cells.

“Herein we show that a majority of human brain tumor samples and cell lines over-expressed cannabinoid receptor CB1 as compared to normal human astrocytes (NHA), while uniformly expressed low levels of CB2. This finding prompted us to investigate the therapeutic exploitation of CB1 inactivation by SR141716 treatment, with regard to its direct and indirect cell-mediated effects against gliomas…

These results indicate that CB1 and STAT3 participate in a new oncogenic network in the complex biology of glioma and their expression levels in patients dictate the efficacy of the CB1 antagonist SR141716 in multimodal glioma destruction.

CB1 is implicated in the regulation of cellular processes linked to survival, proliferation, invasion and angiogenesis in several physio-pathological conditions. We shed light on previously unrecognized molecular mechanism of CB1-mediated modulation of human glioma progression and provide the first and original demonstration of CB1-STAT3 axis as a new target and predictor biomarkers of the benefit from specific therapies.

Indeed CB1 antagonism capable of tumoral cell division’ control while making the glioma immunovisible and engaging the immune system to fight it may represent a hopeful alternative to other established chemotherapeutics.

Because different aspects of glioma biology have been separately targeted with very limited success, we speculate that CB1 inhibitors which enclose in the same molecule cytotoxic potential and high activity to boost competent immune surveillance mechanisms, at a degree that seems to be correlated to the levels of CB1 immunoreactivity, might have profound implications for exploring new therapeutic anti-glioma actions.”

Prenatal elevation of endocannabinoids corrects the unbalance between dopamine systems and reduces activity in the Naples High Excitability rats.

“Several evidences suggest that endocannabinoids exert a neurotrophic effect on developing mesencephalic dopamine neurons.

Since an altered mesocorticolimbic system seems to underlie hyperactivity and attention deficit in clinical and animal studies of attention deficit hyperactivity disorder(ADHD), prenatal elevation of anandamide has been induced…

The data suggest a corrected unbalance between the two dopamine systems that apparently leads to reducedhyperactivity and modified scanning times in this animal model of ADHD.

This, in turn, might open new strategies in the treatment of a subset of ADHD cases.”

Association between cannabinoid receptor gene (CNR1) and childhood attention deficit/hyperactivity disorder in Spanish male alcoholic patients

“The CB1 receptor is encoded by the CNR1 gene (6q14–q15), which is known to carry a nine-allele microsatellite polymorphism containing repeats of a single trinucleotide, ATT, which localizes to the 3’UTR of the gene and has been related to drug dependency states in Caucasian populations.

Moreover, a link has been found between this polymorphism and the properties of the event-related wave p300, some studies having suggested that p300 variations might function as a marker for an underlying, hereditary, predisposition to alcoholism.

Moreover, a direct relationship has been found between p300 wave fluctuations and attention deficit/hyperactivity disorder (ADHD). In recent years, the relationship between ADHD and addictions has been stressed. ADHD has been linked to the malfunctioning of catecholaminergic systems, which also play a fundamental role in the brain’s rewarding system.

These data suggest that the link between the cannabinoid system and the p300 wave could be related to some aspects of ADHD.

In this study, we found a quantitative relationship between the largest-sized alleles of the CNR1 gene and the presence of ADHD during childhood in Spanish male alcoholic patients…

To the best of our knowledge, this is the first study relating the CNR1-gene polymorphisms with ADHD in alcoholic patients.

These data are consistent with the fact that the cannabinoid system is known to affect dopaminergic transmission, with the malfunctioning of the dopaminergic system being regarded as a potential physiopathological cause of ADHD. Further studies are needed to determine the functional basis of the observed association.”

Subtypes of attention deficit-hyperactivity disorder (ADHD) and cannabis use.

“The current study examined the association between subtypes of attention-deficit/hyperactivity disorder (ADHD) and cannabis use within a sample of 2811 current users.

When asked about the ADHD symptoms they have experienced when not using cannabis, a higher proportion of daily users met symptom criteria for an ADHD diagnoses of the subtypes that include hyperactive-impulsive symptoms than the inattentive subtype.

For nondaily users, the proportions of users meeting symptom criteria did not differ by subtype.

These results have implications for identifying which individuals with ADHD might be more likely to self-medicate using cannabis. Furthermore, these findings indirectly support research linking relevant cannabinoid receptors to regulatory control.”

Association of the cannabinoid receptor gene (CNR1) with ADHD and post-traumatic stress disorder.

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“Attention deficit hyperactivity disorder (ADHD) is a highly heritable disorder affecting some 5-10% of children and 4-5% of adults. The cannabinoidreceptor gene (CNR1) is a positional candidate gene due to its location near an identified ADHD linkage peak on chromosome 6, its role in stress and dopamine regulation, its association with other psychiatric disorders that co-occur with ADHD, and its function in learning and memory.

…the CNR1 gene may be a risk factor forADHD and possibly PTSD, and that this gene warrants further investigation for a role in neuropsychiatric disorders.

These data provide support for a putative role of endogenous cannabinoids in ADHD, and PTSD.

The CNR1gene may contribute to shared underlying risk continua, such as emotional dysregulation in response to stress, across these diverse diagnostic groups. Increased amygdala activity, poor stress reactivity as reflected by HPA response, and poor prefrontal cortical modulation is a plausible underlying mechanism of liability that may be shared across disorders.

Taken together with the current findings, we suggest that this gene may be an important risk variant in the emotional regulation difficulties underlying ADHD, PTSD, and possibly other co-morbid conditions (such as mood disorder); however, the role of CNR1 is likely small, particularly at the level of psychiatric diagnosis, so future work using more refined phenotypes or endophenotypes of affect regulation are necessary.”

Endocannabinoids activate transient receptor potential vanilloid 1 receptors to reduce hyperdopaminergia-related hyperactivity: therapeutic implications.

“Knockout (KO) mice invalidated for the dopamine transporter (DAT) constitute a powerful animal model of neurobiological alterations associated with hyperdopaminergia relevant to schizophrenia and attention-deficit/hyperactivity disorder (ADHD).


These data indicate a dysregulated striatal endocannabinoid neurotransmission associated with hyperdopaminergic state.

Restoring endocannabinoid homeostasis in active synapses might constitute an alternative therapeutic strategy for disorders associated with hyperdopaminergia.

In this process, TRPV1 receptors seem to play a key role and represent a novel promising pharmacological target.”

The endocannabinoid system misfires in ADHD mice (Commentary on Castelli et al.)

European Journal of Neuroscience

“Attention-deficit hyperactivity disorder (ADHD) is characterized by short attention span, hyperactivity and impulsiveness and affects both children and adults. Its social and economic significance can hardly be overrated, with a recent literature review estimating a worldwide prevalence of more than 5% (Polanczyk et al., 2007). With importance comes controversy, and the biological basis of ADHD, its diagnostic criteria and its treatments continue to divide opinions.

Neuroscientists have tackled ADHD at several levels. Brain imaging has revealed abnormalities in ADHD patients, particularly in the neural networks linking the frontal cortex to the basal ganglia (Cubillo et al., 2011). The genetic factors underlying ADHD are also being unravelled. Several lines of research point to an involvement of the dopaminergic system, and the dopamine transporter (DAT) in particular. DAT polymorphism is correlated with ADHD (Gizer et al., 2009). Intriguingly, abnormalities of the DAT and its pharmacology may explain the apparent paradox that stimulants such as amphetamine and methylphenidate (Ritalin), which inhibit DAT activity and increase extracellular dopamine, are effective (and widespread) treatments for ADHD symptoms.

Given these findings, the use of animal models of ADHD carrying mutations in the DAT gene holds great promise. In a study published in this issue of EJNCastelli et al. (2011) used a knock-in transgenic mouse in which a mutant version of the DAT gene results in a protein that becomes insensitive to cocaine, while retaining at least in part its functionality (Chen et al., 2006). These DAT mutant mice are hyperactive and respond paradoxically to both cocaine and methylphenidate: these drugs, which induce hyperlocomotor states in normal mice, reduce motor activity in the DAT mutants (Tilley & Gu, 2008).

Castelli et al. (2011) focused on the endocannabinoid system in the striatum of these DAT mutant mice. There are good reasons to investigate in this direction. Dopamine promotes endocannabinoid release in the striatum (Yin & Lovinger, 2006) and striatal dopamine levels are elevated in DAT mutant mice.

In normal animals, striatal projection neurons release endocannabinoids in response to ionotropic and metabotropic receptor activation. Endocannabinoids then act as retrograde messengers, diffusing in the extracellular space and binding presynaptic CB1 receptors located on glutamatergic and GABAergic terminals. In both cases, this decreases neurotransmitter release.

Castelli et al. (2011) found that endocannabinoid signalling is dramatically impaired in DAT mutant mice. Surprisingly, the mice present a specific deficit of the endocannabinoid-mediated control of GABA release, while control of glutamate is unaffected. The potential implications of these findings are fascinating: the striatum, whose intrinsic circuits are mostly GABAergic, is involved in the action selection process (Kimchi & Laubach, 2009). Thus, the inability of striatal projection neurons to suppress inhibition may be directly linked to abnormal action selection – a cardinal feature of ADHD.

This is one of several changes induced by the mutated DAT gene in the striatal network, including those of dopamine signalling previously described by the same group (Napolitano et al., 2010). However, this is the first indication that the endocannabinoid-mediated control of synaptic inhibition may be selectively impaired in ADHD, and raises the possibility that drugs able to restore this process may prove effective in its treatment.”

Loss of striatal cannabinoid CB1 receptor function in attention-deficit / hyperactivity disorder mice with point-mutation of the dopamine transporter.

“Abnormal dopamine (DA) transmission in the striatum plays a pivotal role in attention-deficit/hyperactivity disorder (ADHD).

As striatal DA signalling modulates the endocannabinoid system (ECS), the present study was aimed at investigating cannabinoid CB1 receptor (CB1R) function in a model of ADHD…

Our results point to CB1Rs as novel molecular players in ADHD, and suggest that therapeutic strategies aimed at interfering with the ECS might prove effective in this disorder.”