Author Archives: adminoacido

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Comparison of cannabinoids with known analgesics using a novel high throughput zebrafish larval model of nociception.

Category : Dolor

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Comparison of cannabinoids with known analgesics using a novel high throughput zebrafish larval model of nociception.

Behav Brain Res. 2017 Sep 18;:

Authors: Ellis LD, Berrue F, Morash M, Achenbach JC, Hill J, McDougall JJ

Abstract
It has been established that both adult and larval zebrafish are capable of showing nociceptive responses to noxious stimuli; however, the use of larvae to test novel analgesics has not been fully explored. Zebrafish larvae represent a low-cost, high-throughput alternative to traditional mammalian models for the assessment of product efficacy during the initial stages of drug development. In the current study, a novel model of nociception using zebrafish larvae is described. During the recovery from an acute exposure to low levels of acetic acid, larvae display innate changes in behaviour that may be indicative of nociception. To assess the usefulness of this model for testing potential analgesics, three known synthetic pain medications were assessed (ibuprofen, acetaminophen and tramadol) along with three naturally occurring products (honokiol, tetrahydrocannabinol and cannabidiol). When the effect of each compound on both the acetic acid recovery and control activity was compared there appeared to be both similarities and differences between the compounds. One of the most interesting effects was found for cannabidiol which appeared to oppose the activity change during the recovery period of AA exposed larvae while having a nominal effect on control activity. This would appear to be in line with current research that has demonstrated the nociceptive properties of cannabidiol. Here we have provided a novel model that will complement existing zebrafish models and will expand on the potential use of zebrafish larvae for studying both nociception and new analgesics.

PMID: 28935439 [PubMed – as supplied by publisher]

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[Stress and psychotic transition: A literature review].

Category : Antiinflamatorio

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[Stress and psychotic transition: A literature review].

Encephale. 2016 Aug;42(4):367-73

Authors: Chaumette B, Kebir O, Mam Lam Fook C, Bourgin J, Godsil BP, Gaillard R, Jay TM, Krebs MO

Abstract
BACKGROUND: Psychiatric disorders are consistent with the gene x environment model, and non-specific environmental factors such as childhood trauma, urbanity, and migration have been implicated. All of these factors have in common to dysregulate the biological pathways involved in response to stress. Stress is a well-known precipitating factor implicated in psychiatric disorders such as depression, bipolar disorder, anxiety, and possibly schizophrenia. More precisely, psychosocial stress induces dysregulation of the hypothalamic-pituitary-adrenal axis (HPA) and could modify neurotransmission, which raises the question of the involvement of stress-related biological changes in psychotic disorders. Indeed, the literature reveals dysregulation of the HPA axis in schizophrenia. This dysregulation seems to be present in the prodromal phases (UHR subjects for ultra-high risk) and early schizophrenia (FEP for first episode psychosis). Thus, and following the stress-vulnerability model, stress could act directly on psychotic onset and precipitate the transition of vulnerable subjects to a full-blown psychosis.
OBJECTIVE: The present paper reviews the literature on stress and onset of schizophrenia, with consideration for the causal role vs. associated role of HPA axis dysregulation in schizophrenia and the factors that influence it, in particular during prodromal and earlier phases. We also discuss different methods developed to measure stress in humans.
METHODOLOGY: We performed a bibliographic search using the keywords ‘cortisol’, ‘glucocorticoid’, ‘HPA’ with ‘UHR’, ‘CHR’, ‘at-risk mental state’, ‘first episode psychosis’, ‘schizotypal’, ‘prodromal schizophrenia’ in Medline, Web of Knowledge (WOS), and EBSCO completed by a screening of the references of the selected articles.
RESULTS: Stress has been studied for many years in schizophrenia, either by subjective methods (questionnaires), or objective methods (standardized experimental protocols) with biological sampling and/or brain imaging methods. These methods have suggested a link between dysregulation of the HPA axis and psychotic symptoms both through abnormal basal levels of cortisol and flattened reactivity to social stress. Imaging results suggest indirect modifications, including abnormal pituitary or hippocampal volume. Several factors dysregulating the HPA axis have also been highlighted, such as consumption of drugs (i.e. cannabis), childhood trauma or genetic factors (such as COMT, or MTHFR variants). Psychological stress induces subcortical dopaminergic activation attributable to hypothalamic-pituitary-adrenal (HPA) axis dysregulation. This dysregulation is present in the prodromal phase (UHR) in patients who have experienced a first psychotic episode (FEP) and in siblings of schizophrenic patients. Stress dysregulation is a plausible hypothesis to understand the psychosis onset.
DISCUSSION: The effect of stress on brain pathways could participate to the mechanisms underlying the onset of psychotic symptoms, both as a precipitating factor and as a marker of a predisposing vulnerability. This dysregulation fits into the gene x environment model: in subjects with genetic predispositions, stressful environmental factors can modify biological pathways implicated in psychiatric disorders, promoting the emergence of symptoms. However, many confounding factors obscure the literature, and further studies are needed in schizophrenic patients, UHR and FEP patients to clarify the precise role of stress in psychotic transition. Identification of stress biomarkers could help diagnosis and prognosis, and pave the way for specific care strategies based on stress-targeted therapies.

PMID: 27161263 [PubMed – indexed for MEDLINE]

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[Delta-9-tetrahydrocannabinol-cannabidiol in the treatment of spasticity in chronic spinal cord injury: a clinical experience].

Category : Dolor

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[Delta-9-tetrahydrocannabinol-cannabidiol in the treatment of spasticity in chronic spinal cord injury: a clinical experience].

Rev Neurol. 2017 Oct 01;65(7):295-302

Authors: Grao-Castellote C, Torralba-Collados F, Gonzalez LM, Giner-Pascual M

Abstract
INTRODUCTION: Spasticity in chronic spinal cord injury is a condition that can have negative repercussions on the patient’s quality of life. Its treatment is complex and sometimes the outcome is insufficient. Cannabinoids have recently been used in multiple sclerosis to successfully treat spasticity that is refractory to other therapies.
AIM: To quantify the clinical response of a group of patients with spastic chronic spinal cord injury to the orally administered drug delta-9-tetrahydrocannabinol-cannabidiol (Sativex ®) as medication for use in special situations.
PATIENTS AND METHODS: The research consists of a six-month observational study in patients with chronic spinal cord injuries with refractory spasticity. The variables collected were: modified Ashworth scale, Penn spasm frequency scale, Numeric Rating Scale, and Visual Analogue Scale for pain. Additionally, clinical variables and side effects of the treatment were also collected.
RESULTS: Fifteen patients took part in this study. A significant improvement was observed on three of the scales recorded: modified Ashworth scale (z = -2.97; p = 0.003), Penn spasm frequency scale (z = -2.76; p = 0.006) and Numeric Rating Scale (z = -3.21; p = 0.001). The use of the drug was withdrawn in two patients due to side effects.
CONCLUSIONS: Sativex can be considered an alternative in patients with spasticity associated with chronic spinal cord injury for whom other therapeutic measures have been insufficient. Further studies need to be conducted before the use of this drug can be recommended and so as to define a complete profile of its long-term side effects.

PMID: 28929471 [PubMed – in process]

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Current Status and Prospects for Cannabidiol Preparations as New Therapeutic Agents.

Category : Epilepsia

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Current Status and Prospects for Cannabidiol Preparations as New Therapeutic Agents.

Pharmacotherapy. 2016 Jul;36(7):781-96

Authors: Fasinu PS, Phillips S, ElSohly MA, Walker LA

Abstract
States and the federal government are under growing pressure to legalize the use of cannabis products for medical purposes in the United States. Sixteen states have legalized (or decriminalized possession of) products high in cannabidiol (CBD) and with restricted ∆(9) -tetrahydrocannabinol (∆(9) -THC) content. In most of these states, the intent is for use in refractory epileptic seizures in children, but in a few states, the indications are broader. This review provides an overview of the pharmacology and toxicology of CBD; summarizes some of the regulatory, safety, and cultural issues relevant to the further exploitation of its antiepileptic or other pharmacologic activities; and assesses the current status and prospects for clinical development of CBD and CBD-rich preparations for medical use in the United States. Unlike Δ(9) -THC, CBD elicits its pharmacologic effects without exerting any significant intrinsic activity on the cannabinoid receptors, whose activation results in the psychotropic effects characteristic of Δ(9) -THC, and CBD possesses several pharmacologic activities that give it a high potential for therapeutic use. CBD exhibits neuroprotective, antiepileptic, anxiolytic, antipsychotic, and antiinflammatory properties. In combination with Δ(9) -THC, CBD has received regulatory approvals in several European countries and is currently under study in trials registered by the U.S. Food and Drug Administration in the United States. A number of states have passed legislation to allow for the use of CBD-rich, limited Δ(9) -THC-content preparations of cannabis for certain pathologic conditions. CBD is currently being studied in several clinical trials and is at different stages of clinical development for various medical indications. Judging from clinical findings reported so far, CBD and CBD-enriched preparations have great potential utility, but uncertainties regarding sourcing, long-term safety, abuse potential, and regulatory dilemmas remain.

PMID: 27285147 [PubMed – indexed for MEDLINE]

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Beyond Cannabis: Plants and the Endocannabinoid System.

Category : Antiinflamatorio

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Beyond Cannabis: Plants and the Endocannabinoid System.

Trends Pharmacol Sci. 2016 Jul;37(7):594-605

Authors: Russo EB

Abstract
Plants have been the predominant source of medicines throughout the vast majority of human history, and remain so today outside of industrialized societies. One of the most versatile in terms of its phytochemistry is cannabis, whose investigation has led directly to the discovery of a unique and widespread homeostatic physiological regulator, the endocannabinoid system. While it had been the conventional wisdom until recently that only cannabis harbored active agents affecting the endocannabinoid system, in recent decades the search has widened and identified numerous additional plants whose components stimulate, antagonize, or modulate different aspects of this system. These include common foodstuffs, herbs, spices, and more exotic ingredients: kava, chocolate, black pepper, and many others that are examined in this review.

PMID: 27179600 [PubMed – indexed for MEDLINE]

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Results of a Double-Blind, Randomized, Placebo-Controlled Study of Nabiximols Oromucosal Spray as Adjunctive Therapy in Advanced Cancer Patients With Chronic Uncontrolled Pain.

Category : Dolor

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Results of a Double-Blind, Randomized, Placebo-Controlled Study of Nabiximols Oromucosal Spray as Adjunctive Therapy in Advanced Cancer Patients With Chronic Uncontrolled Pain.

J Pain Symptom Manage. 2017 Sep 15;:

Authors: Lichtman AH, Lux EA, McQuade R, Rossetti S, Sanchez R, Sun W, Wright S, Kornyeyeva E, Fallon MT

Abstract
CONTEXT: Prior phase 2/3 studies found that cannabinoids might provide adjunctive analgesia in advanced cancer patients with uncontrolled pain.
OBJECTIVE: To assess adjunctive nabiximols (Sativex(®)), an extract of Cannabis sativa containing two potentially therapeutic cannabinoids (Δ9-tetrahydrocannabinol [27 mg/mL] and cannabidiol [25mg/mL]), in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy.
METHODS: Phase 3, double-blind, randomized, placebo-controlled trial in patients with advanced cancer and average pain NRS scores ≥ 4 and ≤ 8 despite optimized opioid therapy. Patients randomized to nabiximols (n=199) or placebo (n=198) self-titrated study medications over a 2-week period, followed by a 3-week treatment period at the titrated dose.
RESULTS: Median percent improvements in average pain NRS score from baseline to end of treatment in the nabiximols and placebo groups were 10.7% versus 4.5% (p=0.0854) in the ITT population (primary variable) and 15.5% versus 6.3% (p=0.0378) in the Per Protocol population. Nabiximols was statistically superior to placebo on two of three quality-of-life instruments at week 3 and on all three at week 5. In exploratory post hoc analyses, US patients, but not patients from the rest of the world (ROW), experienced significant benefits from nabiximols on multiple secondary endpoints. Possible contributing factors to differences in nabiximols efficacy include: 1) the US participants received lower doses of opioids at baseline than the ROW; and 2) the subgroups had different distribution of cancer pain types, which may have been related to differences in pathophysiology of pain. The safety profile of nabiximols was consistent with earlier studies.
CONCLUSIONS: Although not superior to placebo on the primary efficacy endpoint, nabiximols had benefits on multiple secondary endpoints, particularly in US patients. Nabiximols might have utility in patients with advanced cancer who receive a lower opioid dose, such as individuals with early intolerance to opioid therapy.

PMID: 28923526 [PubMed – as supplied by publisher]

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Vicki & Aubrie Hill and Intractable Epilepsy

Category : Noticias

The story of Aubrey Hill and her mom who moved to California to get reliable access to cannabis oil to treat her intractable epilepsy — with positive results.
A patient story with a happy ending
patient testimony on using cannabis for epilepsy

A few weeks ago I met Vicki and Aubrie at an event here in Northern California. When they found out that I was the medical director for Hawaiian Ethos, Vicki couldn’t wait to talk to me. With courage and persistence over many years, they have figured out what works best for Aubrie’s epilepsy, and were eager to have me tell their tale. There is a wealth of scientific evidence on the use of cannabis in seizure disorders but nothing carries the message as well as a good story with a happy ending.

This is the story of a vibrant young girl and her determined, brave mother. In 2000, at age five, Aubrie got her scheduled MMR booster. Ten days later she developed a low-grade fever that lasted for 24 days. As the fever persisted, she was getting dehydrated and going deeper into what her mother called a ‘deep, strange sleep.’ She lost her ability to speak and her personality changed, with a loss of interest in her surroundings – unusual for this active five year old. After three weeks, her mother insisted she be hospitalized in Huntsville, Alabama where they lived, because she knew something was terribly wrong. Aubrie was seen by neurologists and, along with a myriad of other diagnoses, they assumed she might have multiple sclerosis. After one week in the hospital she experienced her first seizure, had a lumbar puncture, and they found grey matter in her cerebrospinal fluid. She was diagnosed with meningitis, transferred to Birmingham for ICU care and given 21 days of antibiotics, and started on several seizure medications.

Image

Aubrey Hill

After the 21 days of antibiotics, the doctors realized it was not infectious meningitis at all and gave her steroids for Acute Disseminated Encephalomyelitis (ADEM), a rare side effect of the MMR booster. She improved immediately and was apparently back to normal.

But it turned out she was not normal. For the next two years, unbeknown to her parents, she was having conversations with cartoon characters in her mind. Finally, her mother observed a partial-complex seizure that looked like the original ADEM. They took her to the University of Alabama Children’s Hospital where she was given multiple anti-seizure medications, none of which were effective. At this point, she was getting partial-complex seizures 3-4 times a week and they were increasing in intensity and frequency.

The left temporal lobe appeared to be the source of the seizures, so she was referred to neurosurgeons who recommended surgery for a seizure disorder that was not responsive to any of the medications available. The family finally agreed to this so the surgeons removed a large amount of brain tissue: the left temporal lobe, some of the hippocampus and some of the frontal lobe. Then, in the ICU, right after surgery, she had her first grand mal seizure. She was in 8th grade.

A young girl this age wants to get her driver’s license. Despite medications, she was still having small seizures regularly but was able to hide them from her parents for a while. But when it became evident she was not seizure-free, another surgery was recommended. Aubrie consented. Again, in the ICU after the surgery, she had a large seizure and noticed that she had lost vision on the right side of her visual field. Six years later, the family was finally informed what the doctors already knew: she had had a stroke causing hemianopia (blindness over half her field of vision). There were also cognitive issues, and alexia without apraxia – difficulty seeing words, an inability to read, and difficulty pronouncing the right words for what she meant to say. She was in 9th grade. The trauma for a girl at this age was intense.

Then, when Aubrie was 18, puberty came along. With the onset of puberty, she developed tonic-clonic grand mal seizures, some lasting more than 20 minutes. They were violent and often difficult to stop with any medications at hand. She was tried on 17 different medications and ended up on 2: Vimpat and Depakote – at maximum dosages. The other fifteen drugs had to be abandoned with “unacceptable side-effects.” Still, every time her period would come around, or the full moon, she would have at least one grand mal seizure, often requiring ER visits due to the severity and inability to control with home medications. She would have more than 4 in a 24-hour period during this early-puberty time.

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Aubrey hugged by Emerald Pharms director Chelsea Lucich

Aubrie had a boyfriend, and they began to secretly smoke recreational marijuana. She was stealing money from her mother to buy it and telling no one. But her mother noticed that she suddenly changed from a suicidal miserable girl who wouldn’t come out of her room into a happy young woman with an enormous appetite. Asked ‘What gives?’ Aubrie told her about the cannabis. Vicki said no more stealing, but it’s obviously good for you so I’ll get it for you in a safe way. So, Mom took over finding marijuana for her daughter in the prohibitive state of Alabama. It did not seem to affect the seizures, but it did make her happy and helped her gain some weight back. At $400/ounce every month for substandard weed, they would parse it out to last the whole month. It was worth it.

Then Vicki found some oil being made in Santa Barbara, CA. Over an 8-month period, she sold some land she had inherited, and spent $16K for the oil that helped, but still didn’t stop the seizures. She knew she was on the right track.

Through Facebook, she connected with a grower in Tuolumne County, CA and he suggested she take the green herb, crush it, and sprinkle that and the kief over her daughter’s pizza. This increased dosage decreased the severity of the seizures, but she still had grand mals every month around her period time. They decided to move to California, where they could really learn and use this medicine.

Vicki sold her house in Huntsville, and $20K in debt, she, Aubrie, and their Maltese dog landed at an Airbnb in Santa Rosa, CA with no local connections or set plans. Two days after landing in CA, Aubrie had a grand mal and Vicki knew she had to get some cannabis quickly. They drove to Tuolumne County where her new friend provided medicine that was rich in THCA. It helped, but she needed large amounts. The THCA decreased the severity and frequency of the seizures, and she could stop one from coming on if the aura was noticed and the medicine was given under Aubrie’s tongue. For the next year they regularly drove to Tuolumne County (4 hours each way) to get this medicine. They then added THC to the mix and found that this would stop the seizures immediately, but would not prevent them. Plus, Aubrie was stoned all the time, not a great situation. But they knew they were getting closer. As Vicki is quick to point out: “There are worse things than Aubrie stoned. She can function with THC, but she could not function on the maximum doses of Depakote.”

A year ago through Emerald Pharms, they found Care By Design and purified CBD products. Aubrie started taking CBD oil capsules twice a day, each with 30mg of CBD for a total of 60mg a day. She stayed on 200mg of Vimpat twice a day, with no side effects. And she took a single dose of Ativan 0.5mg every night, allowing her to sleep well through the night. The seizures decreased in frequency dramatically.

Image

Fit &
healthy

Still, during full moons and her period, Aubrie could get grand mals. They had several visits to the local hospital when rectal Diastat would not work for stopping violent seizures. (Diastat, which would knock her out for hours, often causes withdrawal seizures within 24 hours of taking it.)

Earlier this year, they met a physician who specializes in pediatric epilepsy and it was recommended that Aubrie take 300mg each day of CBD, according to her size and weight. So they increased the CBD. She is up to 125mg twice a day and it is holding her nicely. In addition, she is using a concentrated oil-extract that has 8.48mg CBD and 12.65mg THC, taking mom-made capsules in MCT (medium-chain triglyceride) oil twice a day. She has had stretches as long as 2-3 weeks with no seizures which they consider a miracle. If she gets an aura, she takes THC or THCA, which have been successful in stopping the seizure before it starts.

One year after starting the CBD, she is brighter, clearer and more active than she has been in years. She had made friends, will take an Uber to town to play pool, and has recently stated that she is ready to learn again. Aubrie is having a life.

At 22, Aubrie may never live independently, she wears an ID bracelet with her condition and medications listed, and she will never drive a car. But she is finally managing her ‘intractable’ seizure disorder and is happy to be alive.

Stacey Kerr MD is a teacher, physician, and author living and working in Northern California. Dr. Kerr was in private practice until she decided to write and educate full-time. After several years working with the Society of Cannabis Clinicians, and co-developing the first comprehensive online course in cannabinoid medicine, she is now serving as the Medical Director for Hawaiian Ethos, an evidence-based cannabis company on the Big Island of Hawaii.

This article was reprinted by Project CBD with permission. It may not be reproduced in any form without approval from the source.

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Statement on Cannabidiol for the FDA

Category : Noticias

Project CBD responds to the Food and Drug Administration’s call for statements on the use of CBD.
By On September 14, 2017

Project CBD's statement to the FDA on cannabidiol

Sept. 13, 2017

The legal and regulatory status of cannabidiol (CBD), a component of the cannabis plant with a huge therapeutic upside, has emerged as a contentious subject in the United States, even though CBD is not intoxicating, has a stellar safety profile, and has no intrinsic abuse liability. When, as expected, CBD becomes an approved pharmaceutical, it will be a matter of enforcement discretion on the FDA’s part as to whether producers of artisanal CBD-rich formulations will be allowed to operate. Accordingly, Project CBD makes the following recommendations to the FDA:

  • Do not make CBD a prescription-only drug. This would only serve the interests of a few pharmaceutical companies while hurting patients who have benefited from CBD-rich food supplements, topicals and other artisanal preparations.
  • Fast track clinical studies designed to compare the efficacy of CBD isolates and whole plant CBD rich extracts. Let’s learn more about the pros and cons of both in order to maximize their benefits and minimize harm.
  • Require safety warnings for CBD isolates regarding drug interactions.
  • While facilitating access to pharmaceutical CBD, don’t impede safe access to artisanal CBD-rich products. We recognize that the FDA is generally not in the business of approving plants as medicine. Nor should the FDA be in the business of undermining plant medicine in general and CBD-rich cannabis therapeutics, in particular.
  • Prohibit the use of toxic thinning agents and flavoring additives in CBD-rich vape oil products. Several additives (propylene glycol and polyethylene glycol, for example) that are commonly found in CBD vape oil cartridges become toxic when heated and inhaled. Most flavoring additives have not been safety tested for inhalation; some are known to be highly toxic when combusted.
  • Publish all FDA test results pertaining to CBD hemp oil products. Artisanal CBD producers have a mixed record thus far with respect to product safety, labeling accuracy, and quality control. The FDA has already documented instances of fraud and product mislabeling when it analyzed the content of several CBD hemp oil items. The bad apples – hemp oil extracts with little or no CBD or excess THC – should not be a pretext for the FDA to prohibit or restrict access to safe, non-pharmaceutical CBD products.
  • Don’t privilege pharmaceutical priorities at the expense of the fledgling, domestic CBD-rich agricultural sector and the CBD food supplement and topical industry. In Denver, Colorado, state law permits wholesale manufacturers of CBD extracts and edibles to source hemp biomass from within and outside Colorado provided that it originates from a farmer who cultivates CBD-rich plants under regulations guided by safe consumption criteria.
  • Implement procedures to harmonize the patchwork of state regulations regarding CBD. Thus far a coherent regulatory framework is lacking. It’s federally illegal to sell food supplements and other products infused with CBD across state lines, but there’s a gap in federal oversight of CBD manufacturing operations.

Here’s why:

Extensive preclinical research has documented the anti-inflammatory properties of single-molecule CBD in animal models of various pathologies, including neuropathic pain, epilepsy, rheumatoid arthritis, irritable bowel syndrome, multiple sclerosis, obesity and diabetes. Scientists are beginning to understand the specific pharmacological mechanisms underlying CBD’s potential as a treatment for cancer, heart disease, addiction, depression and numerous other health disorders. Cannabidiol is a pleiotropic compound that produces many effects through multiple molecular pathways. It taps into how we function biologically on a very deep level: CBD can penetrate the cell membrane and bind to receptors on the nucleus (PPARs), which regulate gene expression and mitochondrial activity.

A 1998 study sponsored by the National Institutes of Health is the basis for a U.S. government patent on the antioxidant and neuroprotective qualities of plant cannabinoids, specifically CBD and psychoactive THC (tetrahydrocannabinol). CBD and THC were found to limit “neurological damage following ischemic insults, such as stroke and trauma.” Both compounds are described as having “particular application … in the treatment of neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease and HIV dementia.”

But double blind, randomized clinical trials that could “prove” CBD’s efficacy as a medical treatment have gotten short shrift in the United States because of marijuana prohibition. The few clinical studies involving single-molecule CBD that are underway pale in comparison to the enormous amount of anecdotal data already generated by cannabis clinicians and numerous patients in states where the therapeutic use of cannabis is legal.

Since the rediscovery of CBD-rich cannabis in Northern California in 2009, a growing number of physicians have been recommending CBD-infused oil extracts and concentrates for patients – often with good, and sometimes with jaw-dropping, results in difficult-to-treat cases. Until recently, however, single-molecule CBD formulations were not part of the grassroots medical marijuana experience. While scientists focused on the pharmacology of CBD isolates and other single-molecule cannabinoids, medical marijuana product-makers and providers have been dispensing an array of whole plant CBD-rich options – tinctures, sublingual sprays, gel caps, topicals, edibles, and raw herb – to a wide demographic of patients, many of whom turn to cannabis therapy as a last resort.

In addition to whole plant CBD-rich products sold by medical marijuana dispensaries, CBD isolates derived from industrial hemp are currently available via unregulated online storefronts and delivery services. If, as expected, GW Pharmaceuticals wins FDA approval of Epidiolex, an almost-pure CBD anti-seizure medication, in the near future, it will become available on a prescription basis at a hefty price. Millions of uninsured families in the United States won’t be able to afford it.

The pharmaceutical development of cannabinoid compounds is based upon controlled experimentation with molecular isolates in keeping with the assumption that sick people benefit most from predictable, reproducible medicine that never varies. While isolates can facilitate precision dosage and confidence in the chemical make-up of a drug, monomolecular medicine also has serious drawbacks.

Several scientific studies report that pure, single-molecule CBD, while possibly effective at high doses in preclinical tests, has a much tighter therapeutic window and is much less potent compared to a whole plant CBD-rich concentrate. Moreover, whether synthesized in a lab or heavily refined from industrial hemp paste, pure CBD isolates lack the full array of phytocannabinoids and medicinal terpenes found in whole plant CBD-rich cannabis, which includes hundreds of biologically active components. These constituents interact with CBD and THC to create what scientists refer to as an “entourage” or “ensemble” effect, so that the therapeutic impact of the whole plant is greater than the sum of its parts.

It’s not that single-molecule CBD won’t work — pure CBD can be helpful in certain cases, as clinical trials with epidiolex have shown. But whole plant CBD-rich oil has a much wider therapeutic window than a CBD isolate. This was demonstrated in a 2015 preclinical experiment by Israeli scientists who found that single-molecule CBD required a much higher dose to be effective as an anti-inflammatory and an analgesic compared to a whole plant CBD-rich oil extract. Moreover, if one missed the mark slightly, either too low or too high, then the CBD isolate had little impact on pain and inflammation — unlike the full spectrum CBD-rich oil, which was effective at a much lower, and broader, dosage range. “The therapeutic synergy observed with plant extracts results in the requirement for a lower amount of active components, with consequent reduced adverse effects,” the Israeli researchers concluded.

Other scientists and clinicians have reported similar findings. A 2016 study by Italian researchers found that a whole plant CBD-rich oil extract attenuated inflammation and hypermotility in an animal model of colitis, whereas “pure CBD did not ameliorate colitis” symptoms. “These findings sustain the rationale of combining CBD with other minor Cannabis constituents and support the clinical development of CBD [as a] botanical drug substance for irritable bowel disease treatment.”

Problematic drug interactions are much more likely with high doses of single-molecule CBD, which can inhibit the metabolism of 60 percent of marketed pharmaceuticals. At high doses, CBD will deactivate certain cytochrome P450 enzymes in the liver, thereby altering how we metabolize a wide range of medications, including clobazam, an anti-epileptic drug. This was evident in GW’s epidiolex trials, when children with intractable seizure disorders were given CBD dosages ranging from 5 to 50 mg per kg of body weight. Doctors had to adjust the amount of clobazam the children were taking because of potentially dangerous interactions with epidiolex. Compare the high dose regimen employed by GW Pharmaceuticals to 1 mg per kg of artisanal whole plant CBD-rich oil that cannabis clinicians in California and elsewhere recommend as an initial dosage for treating pediatric epilepsy.

In cancer treatment, the precise dosing of chemotherapy is extremely important; it can be a challenge for doctors to find the maximum effective dose that will not be catastrophically toxic. Many chemotherapy drugs are oxidized by cytochrome P450 enzymes before their inactivation or excretion. This means that for patients also using CBD, the same dose of chemotherapy may produce higher blood concentrations. If CBD inhibits the metabolism of chemotherapy drugs and dosage adjustments aren’t made, the chemotherapy agent could accumulate within the body to highly toxic levels.

There is no clearly established cut-off dose below which CBD does not interact with other drugs. Any pharmaceutical or nutraceutical scheme to exploit the health benefits of cannabidiol must reckon with the fact that therapeutically relevant doses of CBD isolates can potentially impact a wide range of medications. Drug interactions are especially important to consider when using life-saving or sense-saving drugs, drugs with narrow therapeutic windows, or medications with major adverse side effects. By and large, however, there have been few problems reported by cancer patients and others who medicate with artisanal CBD-rich cannabis products. The same can’t be said for CBD isolates.

We recognize there is therapeutic value in CBD isolates as well as in whole plant CBD-rich remedies. The FDA should not ordain pharmaceutical CBD as the only legitimate medical option. Single-molecule medicine is the predominant corporate way, the Big Pharma way, but there’s ample evidence that it’s not always the best way to benefit from cannabis therapeutics. Pure CBD is a molecule, not a miracle, and it doesn’t work for everyone. No-THC and low-THC cannabis oil products represent a small slice of the cannabis therapy spectrum. Patients of all ages and economic means should have access to a range of cannabis-based therapeutic options with different concentrations and ratios of CBD and THC, along with other whole plant components.

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[Cannabis use in Epilepsy. Current situation in Argentina and abroad].

Category : Epilepsia

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[Cannabis use in Epilepsy. Current situation in Argentina and abroad].

Vertex. 2016 Nov;XXVII(130):457-462

Authors: Kochen S

Abstract
Although at present we have over 20 different types of drugs for epilepsy, 30 to 40% of patients continue to have seizures. Preliminary data from human studies suggest that cannabis, cannabidiol in particular, is effective in the treatment of some patients with epilepsy. However, the available data are limited and do not allow defnitive conclusions. Only randomized clinical trials with controlled double-blind, placebo-controlled utilizing secure preparations and one or more cannabinoids, will provide comprehensive information on the effcacy and safety of use. In order to perform these trials it is necessary to have legislation authorizing the use of cannabis on epilepsy.

PMID: 28898306 [PubMed – in process]

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