A B C D E F G H I J K L M N O P Q R S T U V W X Y Z
Plasma and brain pharmacokinetic profile of cannabidiol (CBD), cannabidivarine (CBDV), Δ(9)-tetrahydrocannabivarin (THCV) and cannabigerol (CBG) in rats and mice following oral and intraperitoneal administration and CBD action on obsessive-compulsive behaviour.
Binge alcohol consumption in the rat induces substantial neurodegeneration in the hippocampus and entorhinal cortex.
Oxidative stress and cytotoxic edema have both been shown to be involved in such neurotoxicity, whereas N-methyl-d-aspartate (NMDA) receptor activity has been implicated in alcohol withdrawal and excitoxic injury.
Because the nonpsychoactive cannabinoid cannabidiol (CBD) was previously shown in vitro to prevent glutamate toxicity through its ability to reduce oxidative stress, we evaluated CBD as a neuroprotectant in a rat binge ethanol model. When administered concurrently with binge ethanol exposure, CBD protected against hippocampal and entorhinal cortical neurodegeneration in a dose-dependent manner.
Similarly, the common antioxidants butylated hydroxytoluene and α-tocopherol also afforded significant protection. In contrast, the NMDA receptor antagonists dizocilpine (MK-801) and memantine did not prevent cell death. Of the diuretics tested, furosemide was protective, whereas the other two anion exchanger inhibitors, L-644,711 [(R)-(+)-(5,6-dichloro2,3,9,9a-tetrahydro 3-oxo-9a-propyl-1H-fluoren-7-yl)oxy acetic acid] and bumetanide, were ineffective.
In vitro comparison of these diuretics indicated that furosemide is also a potent antioxidant, whereas the nonprotective diuretics are not. The lack of efficacy of L-644,711 and bumetanide suggests that the antioxidant rather than the diuretic properties of furosemide contribute most critically to its efficacy in reversing ethanol-induced neurotoxicity in vitro, in our model. This study provides the first demonstration of CBD as an in vivo neuroprotectant and shows the efficacy of lipophilic antioxidants in preventing binge ethanol-induced brain injury.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
Edited by Anthony Cerami, The Kenneth S. Warren Laboratories, Tarrytown, NY, and approved June 2, 2000 (received for review March 10, 2000)
The therapeutic potential of cannabidiol (CBD), the major nonpsychoactive component of cannabis, was explored in murine collagen-induced arthritis (CIA). CIA was elicited by immunizing DBA/1 mice with type II collagen (CII) in complete Freund's adjuvant.
The CII used was either bovine or murine, resulting in classical acute CIA or in chronic relapsing CIA, respectively. CBD was administered after onset of clinical symptoms, and in both models of arthritis the treatment effectively blocked progression of arthritis. CBD was equally effective when administered i.p. or orally. The dose dependency showed a bell-shaped curve, with an optimal effect at 5 mg/kg per day i.p. or 25 mg/kg per day orally.
Clinical improvement was associated with protection of the joints against severe damage. Ex vivo, draining lymph node cells from CBD-treated mice showed a diminished CII-specific proliferation and IFN-γ production, as well as a decreased release of tumor necrosis factor by knee synovial cells.
In vitro effects of CBD included a dose-dependent suppression of lymphocyte proliferation, both mitogen-stimulated and antigen-specific, and the blockade of the Zymosan-triggered reactive oxygen burst by peritoneal granulocytes.
It also was found that CBD administration was capable of blocking the lipopolysaccharide-induced rise in serum tumor necrosis factor in C57/BL mice. Taken together, these data show that CBD, through its combined immunosuppressive and anti-inflammatory actions, has a potent anti-arthritic effect in CIA....read more
Italian researchers investigated the anti-tumour effects of five natural cannabinoids of the cannabis plant (cannabidiol, cannabigerol, cannabichromene, cannabidiol-acid and THC-acid) in breast cancer. Cannabidiol (CBD) was the most potent cannabinoid in inhibiting the growth of human breast cancer cells that had been injected under the skin of mice. CBD also reduced lung metastases deriving from human breast cancer cells that had been injected into the paws of the animals.
Researchers found that the anti-tumour effects of CBD were caused by induction of apoptosis (programmed cell death). They concluded that their data "support the further testing of cannabidiol and cannabidiol-rich extracts for the potential treatment of cancer."
These observations are supported by investigations of US scientists who found out that exposure of leukaemia cells to CBD led to a reduction in cell viability and induction of apoptosis. In living animals CBD caused a reduction in number of leukaemia cells. The scientists noted that CBD "may be a novel and highly selective treatment for leukemia."
(Sources: Ligresti A, Schiano Moriello A, Starowicz K, Matias I, Pisanti S, De Petrocellis L, Laezza C, Portella G, Bifulco M, Di Marzo V. Anti-tumor activity of plant cannabinoids with emphasis on the effect of cannabidiol on human breast carcinoma. J Pharmacol Exp Ther. 2006 May 25; [electronic publication ahead of print]; McKallip RJ, Jia W, Schlomer J, Warren JW, Nagarkatti PS, Nagarkatti M. Cannabidiol-induced apoptosis in human leukemia cells: A novel role of cannabidiol in the regulation of p22phox and Nox4 expression. Mol Pharmacol. 2006 Jun 5; [electronic publication ahead of print])
Anti-tumor effects of cannabidiol, a non-psychotropic cannabinoid, on human glioma cell lines
Paola Massi , Angelo Vaccani , Stefania Ceruti , Arianna Colombo , Maria Pia Abbracchio , Daniela Parolaro
Dept. of Pharm. Chem. and Toxicol. University of Milan, Milan, Italy
Dept. of Sruct. & Funct. Biol. Center of Neuroscience, University of Insubria Busto Arsizio (VA) Ita
Dept. Pharmacol. Sci., Center of Excellence for neurodeg. diseases, Univ. of Milan, Milan Italy
Address correspondence to: E-mail: email@example.com
Abstract: Recently, cannabinoids have been shown to possess antitumor properties. Because the psycho-activity of cannabinoid compounds limits their medicinal usage, we undertook the present study to evaluate the in vitro antiproliferative ability of CBD, a non- psychoactive cannabinoid compound, on U87 and U373 human glioma cell lines. The addition of CBD to the culture medium led to a dramatic drop of mitochondrial oxidative metabolism (MTT test) and viability in glioma cells, in a concentration-dependent manner, already evident 24 h after CBD exposure with an apparent IC50 of 25 µM.
The antiproliferative effect of CBD was partially prevented by the CB2 receptor antagonist SR144528 and -tocopherol. By contrast, the CB1 cannabinoid receptor antagonist SR141716, capsazepine (vanilloid receptor antagonist), the inhibitors of ceramide generation or PTX did not counteract CBD effects. We also show, for the first time, that the antiproliferative effect of CBD was correlated to induction of apoptosis, as determined by cytofluorimetric analysis and ssDNA staining, which was not reverted by cannabinoid antagonists. Finally, CBD administered s.c. to nude mice at the dose of 0.5 mg/mouse, significantly inhibited the growth of subcutaneously implanted U87 human glioma cells.
Concluding, the non-psychoactive CBD was able to produce a significant antitumor activity both in vitro and in vivo, thus suggesting a possible application of CBD as an antineoplastic agent.
Amyotroph Lateral Scler Other Motor Neuron Disord. 2005 Sep;6(3):182-4.
Department of Neurology, University of Washington,, WA 98195, USA.
Therapeutic options for amyotrophic lateral sclerosis (ALS), the most common adult-onset motor neuron disorder, remain limited. Emerging evidence from clinical studies and transgenic mouse models of ALS suggests that cannabinoids, the bioactive ingredients of marijuana (Cannabis sativa) might have some therapeutic benefit in this disease.
However, Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the predominant cannabinoid in marijuana, induces mind-altering effects and is partially addictive, compromising its clinical usefulness.
We therefore tested whether cannabinol (CBN), a non-psychotropic cannabinoid, influences disease progression and survival in the SOD1 (G93A) mouse model of ALS. CBN was delivered via subcutaneously implanted osmotic mini-pumps (5 mg/kg/day) over a period of up to 12 weeks.
We found that this treatment significantly delays disease onset by more than two weeks while survival was not affected.
Further research is necessary to determine whether non-psychotropic cannabinoids might be useful in ameliorating symptoms in ALS.
Autoimmunity. 2006 May
Hadassah University Hospital, Department of Bone Marrow Transplantation & Cancer Immunotherapy, POB 12000, Jerusalem, 91120, Israel.
Cannabidinoids are components of the Cannabis sativa (marijuana) plant that have been shown capable of suppressing inflammation and various aspects of cell-mediated immunity. Cannabidiol (CBD), a non-psychoactive cannabidinoid has been previously shown by us to suppress cell-mediated autoimmune joint destruction in an animal model of rheumatoid arthritis.
We now report that CBD treatment significantly reduces the incidence of diabetes in NOD mice from an incidence of 86% in non-treated control mice to an incidence of 30% in CBD-treated mice. CBD treatment also resulted in the significant reduction of plasma levels of the pro-inflammatory cytokines, IFN-gamma and TNF-alpha.
Th1-associated cytokine production of in vitro activated T-cells and peritoneal macrophages was also significantly reduced in CBD-treated mice, whereas production of the Th2-associated cytokines, IL-4 and IL-10, was increased when compared to untreated control mice. Histological examination of the pancreatic islets of CBD-treated mice revealed significantly reduced insulitis.
Our results indicate that CBD can inhibit and delay destructive insulitis and inflammatory Th1-associated cytokine production in NOD mice resulting in a decreased incidence of diabetes possibly through an immunomodulatory mechanism shifting the immune response from Th1 to Th2 dominance.
Department of Pharmacology and Toxicology, Medical College of Georgia, 1120 15th St., Augusta, GA 30912, USA.
Diabetic retinopathy is characterized by blood-retinal barrier (BRB) breakdown and neurotoxicity. These pathologies have been associated with oxidative stress and proinflammatory cytokines, which may operate by activating their downstream target p38 MAP kinase.
In the present study, the protective effects of a nonpsychotropic cannabinoid, cannabidiol (CBD), were examined in streptozotocin-induced diabetic rats after 1, 2, or 4 weeks. Retinal cell death was determined by terminal dUTP nick-end labeling assay; BRB function by quantifying extravasation of bovine serum albumin-fluorescein; and oxidative stress by assays for lipid peroxidation, dichlorofluorescein fluorescence, and tyrosine nitration.
Experimental diabetes induced significant increases in oxidative stress, retinal neuronal cell death, and vascular permeability. These effects were associated with increased levels of tumor necrosis factor-alpha, vascular endothelial growth factor, and intercellular adhesion molecule-1 and activation of p38 MAP kinase, as assessed by enzyme-linked immunosorbent assay, immunohistochemistry, and/or Western blot.
CBD treatment significantly reduced oxidative stress; decreased the levels of tumor necrosis factor-alpha, vascular endothelial growth factor, and intercellular adhesion molecule-1; and prevented retinal cell death and vascular hyperpermeability in the diabetic retina.
Consistent with these effects, CBD treatment also significantly inhibited p38 MAP kinase in the diabetic retina. These results demonstrate that CBD treatment reduces neurotoxicity, inflammation, and BRB breakdown in diabetic animals through activities that may involve inhibition of p38 MAP kinase.
PMID: 16400026 [PubMed - indexed for MEDLINE]PMCID: PMC1592672Free PMC Article
Consroe P, Sandyk R, Snider SR
International Journal of Neuroscience 1986;30(4):277-282
20-50% improvement of dystonia; deterioration of tremor and hypokinesia in 2 patients with Parkinson's disease
Dose(s)100-600 mg per day
Duration (days) 42
Participants 5 patients with dystonia
Design Open study
Address of author(s)
Cannabidiol (CBD), a nonpsychoactive cannabinoid of Cannabis, was given to 5 patients with dystonic movement disorders in a preliminary open pilot study.
Oral doses of CBD rising from 100 to 600 mg/day over a 6 week period were administered along with standard medication. Dose-related improvement in dystonia was observed in all patients and ranged from 20 to 50%.
Side-effects of CBD were mild and included hypotension, dry mouth, psychomotor slowing, lightheadedness, and sedation. In 2 patients with coexisting Parkinsonian features, CBD at doses over 300 mg/day exacerbated the hypokinesia and resting tremor. CBD appears to have antidystonic and Parkinsonism-aggravating effects in humans.
|Title||Cannabidiol in dystonic movement disorders.|
|Author(s)||Sandyk R, Snider SR, Consroe P, Elias SM.|
|Journal, Volume, Issue||Psychiatry Res. 1986 Jul;18(3):291.|
|Major outcome(s)||Cannabidiol (CBD) reduced dystonic movements|
Letter to the editors:
We have therefore tested the efficacy of CBD in two patients with dystonic movement disorders.
Her condition was characterized by a lateral pulling of her neck to the right, which occurred at a frequency of 8-12/minute.
In addition, she had essential-type tremor affecting both hands, which was only partially relieved with atenolol (50mg/day). CBD (200mg, orally) produced an amelioration of the dystonic movements within 3 hours of the lateral neck movements to 2-4/minute.
The patient’s improvement was confirmed by an evaluation of two independent neurologists.
He had obtained mild benefit from high doses (25-45 mg/day) of trihexyphenidyl, but was confirmed to a wheelchair.
CBD (200 mg, orally) produced an amelioration of his symptoms (especially of his more severely affected right leg) within two hours of administration.
Following CBD administration, he was able to walk without support, an effect that lasted about 24 hours. In both cases, CBD produced no adverse effects.
Acute administration of delta-tetradydrocannabinol to rats greatly potentiated the hypokinetic effect of reserpine (Moss et al., 1984), suggesting that this compound may have antidyskinetic properties in humans and that further studies of CBD in other hyperkinetic movement disorders in humans and warranted.
All Conditions Benefited by Medical Marijuana
|Participants||2 case reports|
|Design||Uncontrolled case report|
|Type of publication||Medical journal|
|Address of author(s)|
|Title||Beneficial and adverse effects of cannabidiol in a Parkinson patient with sinemet-induced dystonic dyskinesia.|
|Author(s)||Snider SR, Consroe P.|
|Journal, Volume, Issue||Neurology 1985;35(Suppl):201.|
|Major outcome(s)||Improvement of dyskinesia|
The non-psychoactive cannabis derivative, cannabidiol (CBD), also improves dystonia (Consroe and Snider, in Cannbinoids as Therapeutic Agents, in press).
We report the effect of CBD on dystonia secondary to Sinemet in parkinsonism, a disorder thought to be a relative contraindication for cannabinoids (D.Moss et al, Pharmacol Biochem Behav 1981, 1984).
The patient, a 42-year- old man with an 8-year history of parkinsonism, developed peak-dose dyskinesia about 4 years ago and action dystonia affecting all limbs more recently.
Trihexyphenidyl and bromocriptine each produced only slight improvement. To stable optimal dosages of the three drugs, CBD was added, starting with 100 mg/d and increasing by 100 mg weekly. At 100 to 200 mg/d, there was a decrease in clinical fluctuations and in dyskinesia scores (by 30%) without a significant worsening of the parkinsonism.
At 300 to 400 mg/d, there was no further improvement in the dyskinesia, and adverse effects (dizziness, drowsiness, increased Parkinson symptoms) appeared.
CBD withdrawal resulted in 3 days of severe generalized dystonia and several weeks of increased sensitivity to Sinemet, suggestive of a “drug holiday” effect.
All Conditions Benefited by Medical Marijuana
|Participants||1 patient with parkinsonism and secondary dystonia.|
|Design||Uncontrolled case report|
|Type of publication||Medical journal|
|Address of author(s)|
|Title||Treatment of Meige's syndrome with cannabidiol.|
|Author(s)||Snider S.R, Consroe P.|
|Journal, Volume, Issue||Neurology 1984;34(Suppl):147.|
|Major outcome(s)||50% improvement in spasm severity and frequency|
Cannabidiol (CBD) is the major nonpsychoactive cannabinoid in marijuana.
The anticonvulsant properties of CBD were demonstrated in humans 5 years ago.
Based on anecdotal reports of improvement of generalized dystonia with marijuana smoking, we decided to try CBD in a patient with severe cranial dystonia (Meige syndrome).
The patient, a 42-year-old man, first developed mild blepharospasm 9 years ago. The abnormal movements gradually spread to the oromandibular and neck muscles and worsened to the point that the patient was unable to drive.
Many drugs were tried, with disappointing results. CBD was initiated at 100 mg/day, in divided doses, and slowly increased over several weeks to 400 mg/day. Other drugs were kept the same. Spasm frequency, counted twice daily by a relative while the patient was either talking or driving, gradually decreased from 20 to 30 per min before CBD to 7 or 15 per min at a dosage of 400 mg/day.
Examinations at weekly intervals using a standard rating scale confirmed at least 50 % improvement in spasm severity and frequency.
Withdrawal of CBD for 24 hours resulted in reappearance of severe spasm at 25 to 30 per min. Side effects included dry mouth, transient morning headache, and slight sedation.
All Conditions Benefited by Medical Marijuana
|Participants||A 42 year old Meige syndrome patient|
|Design||Uncontrolled case report|
|Type of publication||Medical journal|
|Address of author(s)|
Pharmacology 21: 175-185 (1980)
Jomar M. Cunha, E.A. Carlini, Aparecido E. Pereira, Oswaldo L. Ramos,
Camilo Pimentel, Rubens Gagliardi, W.L. Sanvito, N. Lander and R. Mechoulam
Departments de Psicobiologia, Departamento de Medicina, Departamento de
Neurologia, Escola Paulista de Medicina; Departamento de Neurologia,
Faculdade de Medicina da Santa Case, Sao Paulo, [Brazil] and Department of
Natural Products, Pharmacy School, Hebrew University, Jerusalem
This work was supported by grant No. ROI DA 00875 from the US National
Institutes of Mental Health (principal investigator: E.A. Carlini).
In phase 1 of the study, 3 mg / kg daily of cannabidiol
(CBD) was given for 30 days to 8 healthy human volunteers. Another 8
volunteers received the same number of identical capsules containing
glucose as placebo in a double-blind setting.
Neurological and physical examinations, blood and urine analysis, ECG and EEG were performed atweekly intervals. In phase 2 of the study, 15 patients suffering from
secondary generalized epilepsy with temporal focus were randomly divided
into two groups. Each patient received, in a double-blind procedure,
200-300 mg daily of CBD or placebo. The drugs were administered for as
long as 4 1/2 months.
Clinical and laboratory examinations, EEG and ECG
were performed at 15- or 30-day intervals. Throughout the experiment the
patients continued to take the antiepileptic drugs prescribed before the
experiment, although these drugs no longer controlled the signs of the
disease. All patients and volunteers tolerated CBD very well and no signs
of toxicity or serious side effects were detected on examination. 4 of the
8 CBD subjects remained almost free of convulsive crises throughout the
experiment and 3 other patients demonstrated partial improvement in their
clinical condition. CBD was ineffective in 1 patient.
The clinical condition of 7 placebo patients remained unchanged whereas the condition of
1 patient clearly improved. The potential use of CBD as an antiepileptic
drug and its possible potentiating effect on other antiepileptic drugs are
Anecdotal reports on the antiepileptic properties of marihuana
(Cannabis sativa) are known since ancient times (Li, 1974). Rosenthal
(1971) mentioned medieval Arab manuscripts in which cannabis is described
as a treatment for epilepsy. During the 19th century several medical
reports were published on the ameliorative effects of cannabis extracts on
several forms of convulsions (O'Shaughnessy, 1842; Shaw, 1843;
In spite of these promising results and its low toxicity, the use
of cannabis preparations for medical purposes progressively decreased.
This was due to the absence of standardized preparations, the unknown
chemical composition, and the psychotropic secondary effects produced by
Cannabidiol (CBD) is the major neutral nonpsychoactive
cannabinoid in most cannabis preparations. It was first isolated by Adams
et al, in 1940 but its structure was elucidated only 23 years later
(Mechoulam and Shvo, 1963). The main active component of cannabis is
delta-1-tetrahydrocannabinol (delta-1-THC) which was isolated in pure
form and its structure was determined by Gaoni and Mechoulam in 1964. It
is also named delta-9-THC. Numerous other natural cannabinoids are known
today (Mechoulam, 1973; Mechoulam et al, 1976).
The unraveling of the chemistry of C. sativa brought a new interest
in its pharmacology, and quite expectedly many laboratories studied the
anticonvulsant properties of its components especially since early reports
had shown that some natural and synthetic cannabinoids protected rats from
convulsions (Loewe and Goodman, 1947) and were of therapeutic value in
epileptic children (Davis and Ramsey, 1949).
More recently many reports have appeared attributing anticonvulsant properties to delta-1-THC and other cannabinoids, in a variety of experimental procedures (Garriott et
al, 1968; Sofia et al, 1971; Consroe and Man, 1973; Karler et al, 1973,
1974; Plotnikoff, 1976). As a rule, delta-1-THC was the most studied
compound. Most of the results obtained confirmed the rather potent
anticonvulsant property of this drug. Its possible use as an antiepileptic
drug in humans has, however, been hindered by its known psychotropic
Since Brazilian workers (Carlini et al, 1973; Izquierdo et al,
1973) first demonstrated the anticonvulsant effects of CBD, there have
been several additional reports on the effectiveness of CBD and its
derivatives in protecting experimental animals from convulsions induced by
various procedures (Karler et al, 1973; Turkanis et al, 1974; Carlini et
al, 1975; Karler and Turkanis, 1976; Consroe and Wolkin, 1977). Consroe
and Wolkin (1977) demonstrated that CBD has a high protective index
comparable to that of phenobarbital and a spectrum of anticonvulsant
activity in rodents similar to that of phenytoin. CBD also enhances the
anti-convulsant potency of both phenytoin and phenobarbital (Consroe and
Wolkin, 1977; Chesher and Jackson, 1974; Chesher et al., 1975).
In addition to its favorable anticonvulsant effects and absence of
toxicity in animals, CBD seems to be devoid of psychotropic activity and
other undesirable side effects in humans. The lack of toxicity of CBD in
animals was demonstrated by intraperitoneal injection of 50 mg / kg daily
for 90 days in mice, oral ingestion of 5-20 mg / kg daily for 90 days and
50 mg / kg for 27 days by rats and intravenous injection of 1,000 mg / kg
in rabbits. No toxicity was observed (Cunha and Carlini, to be
published). In man, oral intake of doses from 15 to 160 mg / day (Karniol
et al, 1974; Hollister, 1973; Carlini et al, 1979), inhalation of 0.15 mg
/ kg (Dalton et al, 1976a), and intravenous injection of 30 mg
(Perez-Reyes et al, 1973; Hollister, 1973) were not followed by ill
effects. Chronic oral administration of 10 mg daily for 21 days did not
induce any change in neurological (including EEG), clinical (including
ECG), psychiatric, blood and urine examinations (Mincis et al, 1973).
Another recent investigation in our laboratory (Consroe et al.,
1979) showed that CBD neither interferes with several psychomotor and
psychological functions in humans nor potentiates alcohol effects on these
The above data led us to undertake the present investigation which
was performed in two phases. In phase 1, 3--6 mg / kg of CBD (roughly
corresponding to 200--400 mg / subject) was administered daily to healthy
human volunteers for 30 days. In phase 2, patients suffering from
secondary generalized epilepsy with temporal irritative activity received
200--300 mg of the drug for periods of up to 4.5 months.
Experiment 1 (Phase 1 of Study)
Material and Methods
16 adult volunteers (11 men and 5 women) aged 22-35, with an
average weight of 65 kg were chosen from the staff of Escola Paulista de
Medicina. They were in good health showing neither clinical nor laboratory
evidence of cardiovascular, renal, hepatic or other impairments. The
institutional review committee at Escola Paulista de Medicina previously
approved the protocol of the experiments.
On the first day of the experiment the patients were submitted to
a complete medical check-up, including clinical and neurological
examinations, EEG, ECG, blood tests (hematocrit, hemoglobin, leukocyte and
erythrocyte counts, bilirubin, oxaloacetic and puruvic transaminases and
creatinine) and urine tests ; (osmolarity, pH, albumin, leukocyte and
erythrocyte counts, cylinders and crystals) in the Department of Medicine
of the Hospital Sao Paulo of Escola Paulista de Medicina. On the 7th day,
they returned to the hospital, signed the informed consent and were
randomly divided in two groups of 8. Each group started the ingestion of
identical gelatine capsules containing either glucose as placebo (control
group) or CBD (experimental group). The experiment was performed on a
double-blind basis and the subjects were instructed to ingest the assigned
capsules, one in the morning and the second in the afternoon for 30 days.
Each capsule contained an amount of CBD (or glucose) equivalent to 1.5 mg
/ kg, i.e. a daily dosage of 3.0 mg / kg. 1 volunteer took 4 capsules of
CBD daily (6 mg / kg) on the last 3 days of the experiment.
On the 3rd, 7th, 15th, 31st and 37th days after the beginning of
drug ingestion, the subjects returned to the hospital to undergo the
examinations described above.
Cannabidiol, in crystalline from (m.p. 66--67) was isolated from
hashish of undetermined age. It was of Lebanese origin and was supplied by
the Israeli Police. The isolation procedure has been described (Gaoni and
Mechoulam, 1971). Part of the CBD was a gift from Makor Chemicals, P.O.B.
During the entire period of the experiment, the subjects did not
report any symptoms suggestive of psychotropic effect of CBD. Of the 8
volunteers receiving the placebo, 1 gave up on the 21st day of the
experiment for personal reasons; a second placebo subject reported
sudoresis and 'palpitations' from the 7th to the 10th day in the veins of
the feet, legs and head, stating that he had to uncover his feet to feel
the palpitations less in order to sleep. Clinical and laboratory
examinations were normal and the symptoms subsided after the 11th day
without any measures on the part of the investigators.
Of the 8 volunteers receiving CBD, 2 reported somnolence, 1 during
the first week and the other throughout the entire period of the
experiment. A 3rd subject, with a history of mild insomnia, reported being
able to sleep better during the first week of medication.
Neurological and clinical examinations, EEG and ECG tracings, and
blood and urine analyses (detailed above) were within normal limits in
the 16 subjects before, during and after the experiment.
It has been suggested that delta-1-THC and other cannabinoids may
possess therapeutic potential as antidepressive drugs in patients with
cancer (Regelson et al., 1975) or in the treatment of glaucoma (Hepler
and Frank, 1971), asthma (Tashkin et al., 1972), etc. For a recent review
see Mechoulam and Carlini (1978). However, acute administration of 20--60
mg of delta-1-THC induces a marked psychic change and has peripheral
effects such as an increase in heart rate (Isbell et al., 1967; Kiplinger
et al., 1971; Karniol et al., 1975) which would limit its therapeutic
In contrast, the present experiment shows that 3 mg / kg / day of
CBD administered for 30 days (1 volunteer received 6 mg / kg / day during
the last 3 days of experiment) did not induce any psychic or other side
effects and was well tolerated by the 8 subjects. Thus CBD does not appear
to have any toxic effect in humans when administered at the above dosage
over a long period. This confirms our previous data obtained in animal
(Cunha and Carlini, to be published).
In our opinion these findings justified the trial of the drug in
Experiment 2 (Phase 2 of Study)
Material and Methods
15 Epileptic patients, 11 women and 4 men, aged 14-49 (average 24
years), with a documented history of frequent convulsions for at least 1
year, were selected. These patients were not reacting satisfactorily to
the prescribed antiepileptic drugs they were receiving (table 1) in spite
of special care to assure that the patients were taking them properly. The
patients were diagnosed as cases of secondary generalized epilepsy; EEG
tracings revealed irritative activity with temporal projection. They had
at least one generalized convulsive crisis weekly.
Clinical and laboratory
examinations showed no signs of renal, cardiovascular or hepatic disease.
The experiment was performed in the Neurology Out-Patient Clinics of the
Hospital Sao Paulo (8 patients) and the Hospital da Santa Case (t
patients). Each patient was followed by the same investigator, beginning 2
weeks before first drug administration and then throughout the whole period
of drug administration.
In the 2 weeks before CBD or placebo
administration, the number of focal and generalized convulsive crises was
recorded and considered as the baseline to evaluate treatment. On the
first day of the experiment, the patients were submitted to the
examinations described in experiment 1. They were randomly divided into
one group of 8 (control group) and another group of 7 (CBD group) and
returned to the hospital for 2 more days. After 1 week each group received
placebo or CBD capsules in a double-blind procedure in addition to the
antiepileptic drugs they were already receiving (see table 1). 1 placebo
patient (Z.S.M.) was transferred to the CBD group after 1 month. Half of
each group of patients was treated in each hospital. The patients were
instructed to take 2 or 3 capsules daily (containing 100 mg of CBD or
glucose) and to return to the hospital every week for clinical and / or
Clinical evaluation of drug treatment was made weekly using a scale
with score 0-3, which took into consideration absence of convulsive crises
or absence of generalization and self-reported subjective improvement (see
tableII). According to this criterion all patients were scored 3 during
the predrug phase (baseline).
During the curse of the experiment none of the 8 patients receiving
CBD showed evidence of behavioral alterations which could be suggestive of
a psychotropic effect. The minimum and maximum times of drug
administration were 8 and 18 weeks for most patients (control and CBD
groups). 2 of the placebo patients did not return after the end of the 4th
week and 1 CBD patient after the 6th week. 1 placebo patient (Z.S.M.)
whose condition remained unaltered during 4 weeks, wanted to give up the
experiment, but remained in it after crossing over to the CBD group.
4 patients under CBD and 1 receiving placebo complained of
somnolence during the experiment. Another CBD patient (M.C.P.)
complained of painful gastric sensations after drug ingestion at the 6th
week. These symptoms disappeared after prescription of an antacid and did
not return throughout the experiment.
Table II. Criteria used to evaluate clinical efficacy of cannabidiol in
Score 0......complete improvement
Score 1......partial improvement
Score 2......small improvement
Score 3......without improvement
0 = Total absence of convulsive crises and self-reported subjective
1 = Absence of generalization of crises and self-reported subjective
2 = Only self-reported subjective improvement.
3 = No reduction in crises and no self-reported improvement.
Neurological Examination and EEG
Before drug treatment 1 CBD patient (N.D.) showed paresthetic
walking towards the right, with spastic hypomotility of the right arm and
leg, mainly of the right hand. He also presented a decrease in psychomotor
functions. 2 other patients in the CBD group (A.A.S. and Z.S.M.) showed
in examinations prior to the experiment some mental underdevelopment.
Neurological examinations of all other patients were within normal limits.
Table III shows the results of the EEG analysis in a condensed
form. Of the patients receiving CBD, 3 showed improvement in EEG pattern
with signs of decrease in frequency of crises throughout the experiment. 2
placebo patients also had improved EEG patterns (J.O.R., and J.S.V.) on
one occasion, with a return to their previous condition on subsequent
Clinical Evaluation of Treatment
Clinical evaluation was performed weekly, scoring 0 - 3 points to
each patient compared to its own baseline (see table II and 'methods' for
details). At the end of the treatment, the median of weekly score for each
patient was calculated. The results are presented in table IV. During the
first week of treatment there was general improvement in almost all
patients (placebo and CBD groups), but from the second week, all placebo
patients with one exception (M.D.M.S.) returned to their previous clinical
state. At the end of the placebo treatment, 7 patients had a median of 3
(i.e. no improvement) whereas patient M.D.M.S. showed complete
improvement (median 0). 2 placebo patients (J.S. and M.G.S.) with no
improvement received the capsules for the 4th week of treatment but did not
return. 3 other placebo patients (J.O.R.; J.S.V.; M.L.M.) remained under
treatment for the period stated in table IV, after which it was decided to
withdraw them from the experiment and to change the antiepileptic drugs
they were receiving (see table I) in an attempt to improve their
condition. Patient R.C. remained in the placebo group for 18 weeks and
received all known antiepileptic drugs without success. Patient Z.S.M. was
on placebo for 4 weeks without improvement and was subsequently transferred
to 200 mg of CBD daily for 6 weeks (without her knowledge) with a small
improvement (median 2).
Of the 8 patients receiving CBD, 4 showed considerable improvement
in their clinical condition (median 0). However, in 1 case (M.C.P.) this
was achieved by increasing the dosage to 300 mg daily. Patient A.A.S., who
showed much improvement from the first week, unfortunately moved to another
city after completing 6 weeks of treatment with CBD. The 5th patient
(F.R.F.) improved only partially (median 1) although he attained score 0
in clinical evaluation (no convulsive crisis and subjective improvement)
in 7 out of the 16 weeks of treatment. 2 of the 3 remaining patients
showed improvement (score 2) whereas the last patient (N.D.) did not
improve at all in spite of increasing CBD to 300 mg daily for the last 2
weeks of treatment.
JOR placebo 3
JS placebo 3
MGS Placebo 3
JSV placebo 3
MLM placebo 3
RC placebo 3
ZSM placebo 3
ZSM CBD200 2
FRF CBD200 1
AAS CBD200 0
ASR CBD200 2
0 = complete improvement
3 = no improvement
Treatment of epilepsy is based mainly on anticonvulsant drugs.
However, even when properly administered in well-diagnosed cases, these
drugs succeed in helping only about 70-75% of the epileptic patients,
whereas about 30% of the patients do not benefit at all (Robb, 1975).
Furthermore, all clinically effective antiepileptic drugs induce
undesirable side effects at normal dosage (osteomalacia, megaloblastic
anemia; gingival hyperplasia) or due to overdose (nystagmus, motor
incoordination, coma and death) or to idiosyncratic reactions (Kutt and
As already stated in the introduction, many ancient reports mention
the antiepileptic properties of cannabis. More recently Consroe et al.
(1975) described an epileptic patient receiving phenobarbital and phenytoin
without good results, who benefited by smoking marihuana. These accounts
indicate that marihuana contains chemical entities which may possess
According to the present data, CBD may turn out to be a useful
drug for the treatment of some cases of epilepsy. There is hardly any
toxicity as shown in our phase 1 study; there were no changes in EEG, ECG,
blood and urine analyses and neurological and clinical examinations were
normal in 8 healthy volunteers receiving 3 mg / kg of CBD daily for 30
days. A similar absence of toxicity was also noted in our phase 2 study in
which 8 epileptic patients received 200 or 300 mg for up to 4 1/2 months.
Furthermore, none of the 16 subjects receiving CBD showed any psychic
delta-1-THC-type effects. The present data obtained after long-term
administration also confirm previous reports showing the absence of
toxicity in acute studies (Hollister, 1973; Carlini et al, 1979).
Somnolence reported by 3 healthy volunteers and 4 epileptic
patients (43% of the subjects receiving the drug) was the only CBD side
effect noted. A certain hypnotic effect is frequently observed with drugs
which possess antiepileptic properties. We have in fact recently
demonstrated that CBD does induce better sleep in human volunteers
(Carlini et al., 1979). On the other hand, CBD induced a remarkable
improvement (median 0) in 4 of 8 epileptic patients who remained almost
free of convulsive crises during the entire period of the experiment. In a
5th patient (median 1), the crises were absent in 7 of the 16 weeks of
treatment. All of these patients (as well as their relatives) reported
subjective improvement. A similar subjective effect was also reported by 2
more patients and only in 1 patient CBD failed to induce any form of
clinical benefit. This is in striking contrast to the results obtained
with the 8 patients receiving placebo of whom 7 showed no improvement in
their clinical condition.
However, EEG results were not as consistent as the clinical
evaluation. As seen in table III, clinical improvement was not always
followed by positive changes in the tracings. As the International League
against Epilepsy (Commission on Antiepileptic Drugs) does not consider
EEG mandatory in this type of research (Penry, 1973), EEG data were not
included in the overall clinical evaluation of CBD effects. It should also
be emphasized that the abnormal EEGs were present from the beginning of the
experiment even though all patients were receiving known antiepileptic
drugs. Furthermore, phenytoin and barbiturates fail to control the EEG
abnormalities of epileptics in spite of being able to abolish their
behavioral convulsions; phenytoin may even increase the prominence of
focal spikes (Morrel et al., 1959; Millichap, 1969).
Wall et al. (1976) have reported pharmacokinetic studies in man
with 3H-CBD injected intravenously into 5 healthy volunteers. They
observed that 8% of the total initial dose (20 mg of CBD) was present in
plasma 30 min after injection, to fall to 3% after 60 minutes. 3 days
later, 33% was excreted in the feces and 16% in the urine, with 50%
remaining in tissues and organs. Therefore, CBD seems to have a relatively
long half-life, which favors its use as a drug in epileptics.
However, in spite of the large number of reports showing beneficial
effects of cannabis and its preparations in many forms of experimental
convulsions and in human epilepsy, a few reports claim the contrary.
Feeney et al. (1976) showed that delta-1-THC in cats induced EEG changes
resembling those observed in convulsions, and Perez-Reyes and Wingfield
(1974) described a similar effect of CBD in man. In neither case,
however, were behavioral convulsions observed. It is interesting in this
context that phenytoin may increase activity of focal spikes (Millichap,
1969). To the best of our knowledge there is only one report attributing a
worsening of an epileptic convulsive crisis (grand mal) following use of
marihuana smoking (Keeler and Reifler, 1967), and we do not know of any
cases described for CBD. Furthermore, in none of our 8 epileptic patients
did we observe deterioration of clinical symptomatology or of EEG, but
rather the opposite effect was true.
The mechanism by which CBD benefited our epileptic patients is not
known. All 8 patients were also receiving known antiepileptic drugs which
were by themselves, however, ineffective. One possibility is that CBD
potentiated their action since enhancement by CBD of anticonvulsant
activity of phenobarbital and phenytoin in animals has been demonstrated
(Consroe and Wolkin, 1977; Chesher and Jackson, 1974; Chesher et al.,
1975). In man, however, 50--500 mcg / kg CBD given in cigarette form is
not able to alter plasma concentrations of secobarbital (Dalton et al.,
1976b). The possibility that CBD acts per se should also be taken into
consideration, as shown by several reports describing its direct
anticonvulsant effects in animals.
In conclusion, we have found that CBD had a beneficial effect in
patients suffering from secondary generalized epilepsy with temporal foci,
who did not benefit from know anti-epileptic drugs. Further research with
more patients and other forms of epilepsy is needed to establish the scope
of the antiepileptic effects of CBD in humans.
Adams, R.,; Hunt, M., and Clark, J.H.: Structure of cannabidiol, a product
isolated from the marihuana extract of Minnesota wild hemp. J. Am. chem.
Soc. 62: 196-200 (1940).
Carlini, E.A.; Leite, J.R.; Tannhauser,M., and Berardi, A.C.: Cannabidiol
and Cannabis sativa extract protect mice and rats against convulsive
agents. J. Pharm. Pharmac. 25: 664-665 (1973).
Carlini, E.A.; Masur, J., and Magalhaes, C.C.P.B.: Possible hypnotic
effect of cannabidiol on human beings. Preliminary study. Cienci Cult., S
Paulo 31: 315-322 (1979).
Carlini, E.A.; Mechoulam, R., and Lander, N.: Anticonvulsant activity of
four oxygenated cannabidiol derivates. Res. Commun. chem. Pathol.
Pharmacol. 12: 1-15 (1975).
Chesher, G.B. and Jackson, D.M.: Anticonvulsant effects of cannabinoids in
mice. Drug interactions within cannabinoids and cannabinoid interactions
with phenytoin. Psychopharmacology 37: 255-264 (1974).
Chesher, G.B.; Jackson, D.M., and Malor, R.M.: Interaction of
delta-9-tetrahydrocannabinol and cannabidiol with phenobarbitone in
protecting mice from electrically induced convulsions. J. Pharm. Pharmac.
27: 608-609 (1975).
Consroe, P.F.; Carlini, E.A.; Zwicker, A.P., and Lacerda, L.A.: Human
interaction effects of cannabidiol and alcohol. Psychopharmacology 66:
Consroe, P.F. and Man, D.P.: Effects of delta-8- and
delta-9-tetrahydrocannabinol on experimentally induced seizures. Life Sci.
13: 429-439 (1973).
Consroe, P.F. and Wolkin, A.: Cannabidiol-antiepileptic drug comparisons
and interactions in experimentally induced seizures in rats. J. Pharmac.
exp. Ther. 201: 26-32 (1977).
Consroe, P.F.; Wood, G.C., and Buchsbaum, H.: Anticonvulsive nature of
marihuana smoking. J. Am. med. Ass. 234: 306-307 (1975).
Dalton, W.S.; Martz, R.; Lemberger, L.; Rodda, B.E., and Forney, R.B.:
Influence of cannabidiol on delta-9-tetrahydrocannabinol effects. Clin.
Pharmacol. Ther. 19: 300-309 (1976a).
Dalton, W.S.; Martz, R.; Rodda, B.E.; Lemberger, L., and Forney, R.B.:
Influence of cannabidiol on secobarbital effects and plasma kinetics.
Clin. Pharmacol. Ther. 20: 695-700 (1976b).
Davis, J.P. and Ramsey, H.H.: Antiepileptic actions of marihuana active
substances. Abstract. Fed. Proc. 8: 284 (1949).
Feeney, D.M.; Spiker, M.D., and Weiss, G.K.: Marihuana and epilepsy:
Activation of symptoms by delta-9-THC; in Cohen and Stillman, The
therapeutic potential of marijuana (Plenum Press, New York 1976).
Gaoni, Y. and Mechoulam, R.: Isolation, structure and partial synthesis of
an active constituent of hashish. J. Am. chem. Soc. 86: 1646-1647
Gaoni, Y. and Mechoulam, R.: The isolation and structure of delta-1-THC
and other neutral cannabinoids from hashish. J. Am. chem. Soc. 93:
Garriott, J.C.; Forney, R.B.; Hughes, F.W., and Richards, A.B.:
Pharmacologic properties of some cannabis related compounds. Archs int.
Pharmacodyn. Ther. 171: 425-434 (1968).
Hepler, R.S. and Frank, I.R.: Marihuana smoking and intraocular pressure.
J. Am. med. Ass. 217: 1392 (1971).
Hollister, L.E.: Cannabidiol and cannabinol in man. Experientia 29:
Isbell, H.; Gorodetzsky, C.W.; Jasinski, D.; Claussen, U.; Spulak, F.V.,
and Korte, F.: Effects of (-) delta-9-transtetrahydrocannabinol in man.
Psychopharmacologia 11: 184-188 (1967).
Izquierdo, I.; Orsingher, O.A., and Berardi, A.C.: Effect of cannabidiol
and of other Cannabis sativa compounds on hippocampal seizure discharges.
Psychopharmacologia 28: 95-102 (1973).
Karler, R.; Cely, W., and Turkanis, S.A.: The anticonvulsant activity of
cannabidiol and cannabinol. Life Sci. 13: 1527-1531 (1973).
Karler, R.; Cely, W., and Turkanis, S.A.: Anticonvulsant of
delta-9-tetrahydrocannabinol and its 11-hydroxy and
8-a-11-dihydroxymetabolites in the frog. Res. Commun. chem Pathol.
Pharmacol. 9: 441-452 (1974).
Karler, R. and Turkanis, S.A.:The antiepileptic potential of the
cannabinoids; in Cohen and Stilman, The therapeutic potential of marijuana
(Plenum Press, New York 1976).
Karniol, I.G.; Shirakawa, I; Kasinsky, N.; Pfeferman, A., and Carlini,
E.A.: Cannabidiol interferes with the effects of
delta-9-tetrahydrocannabinol in man. Eur. J. Pharmacol. 28: 172-177
Karniol, I.G.; Shirakawa, I.; Takahashi, R.N.; Knoebel, E., and Musty,
R.E.: Effects of delta-9-tetrahydrocannabinol and cannabinol in man.
Pharmacology 13: 502-512 (1975).
Keeler, M.H. and Reifler, C.B.: Grand mal convulsion subsequent to
marijuana use. Dis. nerv. Syst. 28: 474-475 (1967).
Kiplinger, G.F.; Manno, J.E.; Rodda, B.E., and Forney, R.B.: Dose-response
analysis of the effects of tetrahydrocannabinol in man. Clin. Pharmacol.
Ther. 12: 650-657 (1971).
Kutt, H. and Louis, S.: Untoward effects of anticonvulsants. New Engl. J.
Med. 826: 1316-1317 (1972).
Li, H.L.: An archeological and historical account of cannabis in China.
J. econ. Bot. 28: 437-448 (1974).
Loewe, S. and Goodman, L.S.: Anticonvulsant action of marihuana-active
substances. Abstract. Fed. Proc. 6: 352 (1947).
Mechoulam, R.: Marijuana. Chemistry, metabolism, pharmacology and
clinical effects (Academic Press, New York 1973).
Mechoulam, R. and Carlini, E.A.: Toward drugs derived from cannabis.
Naturwissenschaften 65: 174-179 (1978).
Mechoulam, R.; McCallum, N.K., and Burstein, S.: Recent advances in the
chemistry and biochemistry of cannabis. Chem. Rev. 76: 75-112 (1976).
Mechoulam, R. and Shvo, Y.: The structure of cannabidiol. Tetrahedron
19: 2073-2078 (1963).
Millichap, J.G.: Relation of laboratory evaluation to clinical
effectiveness of antiepileptic drugs. Epilepsia 10: 315-328 (1969).
Mincis, M.; Pfeferman, A.; Guimaraes, R.X.; Ramos, O.L.; Zukerman, E.;
Karnio, I.G. Carlini, E.A.: Administracao cronica de canabidiol em seres
humanos. Revta Asoc. med. Brasil 19: 185-190 (1973).
Morrel, F.; Bradley, W., and Ptashne, M.: Effects of drugs on discharge
characteristics of chronic epileptogenic lesions. Neurology 9: 492-498
O'Shaughnessy, W.B.: On the preparations of the Indian hemp or gunjah.
Trans. med. Phys. Soc. Bombay 8: 421-461 (1842).
Penry, J.K.: Principles for clinical testing of antiepileptic drugs.
Epilepsia 14: 451-458 (1973).
Perez-Reyes, M.; Timmons, M.C.; Davis, K.H., and Wall, M.E.: A comparison
of the pharmacological activity in man of intravenously administered
delta-9-tetrahydrocannabinol, cannabinol and cannabidiol. Experientia 29:
Perez-Reyes, M. and Wingfield, M.: Cannabidiol and electroencephalographic
epileptic activity. J. Am. med. Ass. 230: 1635 (1974).
Plotnikoff, N.P.: New benzopyrans: anticonvulsant activities; in Cohen
and Stillman, the therapeutic potential of marijuana (Plenum Press, New
Regelson, W.; Butler, J.R.; Schultz, J.; Kirt, T.; Peek, L., and Green,
M.L.: delta-9-THC as an effective antidepressant and appetite stimulating
agent in advanced cancer patients; in Braude and Szara, International
conference on the pharmacology of cannabis (Raven Press, New York 1975).
Reynolds, J.R.: Therapeutic uses and toxic effects of Cannabis indica.
Lancet i: 637-638 (1890).
Robb, P.: Focal epilepsy: the problem, prevalence and contributing
factors. Adv. Neurol. 8: 11-22 (1975).
Rosenthal, F.: The herb hashish versus medieval Muslim society (Brill,
Shaw, J.: On the use of Cannabis indica in tetanus hydrophobia, and in
cholera with remarks on its effects. Madras med. J. 5: 74-80 (1843).
Sofia, R.D.; Solomon, T.A., and Barry, H., III: The anticonvulsant
activity of delta-1-tetrahydrocannabinol in mice. Abstract.
Pharmacologist 13: 246 (1971).
Tashkin, D.P.; Shapiro, B.J., and Frank, I.M.: Acute pulmonary
physiological effects of smoked marijuana and oral
delta-9-tetrahydrocannabinol in healthy young men. New Engl. J. Med. 289:
Turkanis, S.A.; Cely, W.; Olsen, D.M., and Karler, R.: Anticonvulsant
properties of cannabidiol. Res. Commun. chem. Pathol. Pharmacol. 8:
Wall,, M.E.; Brine, D.R., and Perez-Reyes, M.: Metabolism of cannabinoids
in man; in Braude and Szara, The pharmacology of marihuana (Raven Press,
New York 1976).
Jomar M. Cunha, Departamento de psicobiologia, Escola Paulista de Medicina,
Rua Botucatu 862, 04023 Sao Paulo (Brasil)
El-Remessy AB, Khalil IE, Matragoon S, Abou-Mohamed G, Tsai NJ, Roon P, Caldwell RB, Caldwell RW, Green K, Liou GI
Neuroprotective effect of (-)Delta9-tetrahydrocannabinol and cannabidiol in N-methyl-D-aspartate-induced retinal neurotoxicity: involvement of peroxynitrite. [Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.]
Am J Pathol 2003 Nov; 163(5):1997-2008.
In glaucoma, the increased release of glutamate is the major cause of retinal ganglion cell death. Cannabinoids have been demonstrated to protect neuron cultures from glutamate-induced death. In this study, we test the hypothesis that glutamate causes apoptosis of retinal neurons via the excessive formation of peroxynitrite, and that the neuroprotective effect of the psychotropic Delta9-tetrahydroxycannabinol (THC) or nonpsychotropic cannabidiol (CBD) is via the attenuation of this formation.
Excitotoxicity of the retina was induced by intravitreal injection of N-methyl-D-aspartate (NMDA) in rats, which also received 4-hydroxy-2,2,6,6-tetramethylpiperidine-n-oxyl (TEMPOL,a superoxide dismutase-mimetic), N-omega-nitro-L-arginine methyl ester (L-NAME, a nitric oxide synthase inhibitor), THC, or CBD. Retinal neuron loss was determined by TDT-mediated dUTP nick-end labeling assay, inner retinal thickness, and quantification of the mRNAs of ganglion cell markers.
NMDA induced a dose- and time-dependent accumulation of nitrite/nitrate, lipid peroxidation, and nitrotyrosine (foot print of peroxynitrite), and a dose-dependent apoptosis and loss of inner retinal neurons. Treatment with L-NAME or TEMPOL protected retinal neurons and confirmed the involvement of peroxynitrite in retinal neurotoxicity.
The neuroprotection by THC and CBD was because of attenuation of peroxynitrite. The effect of THC was in part mediated by the cannabinoid receptor CB1.
These results suggest the potential use of CBD as a novel topical therapy for the treatment of glaucoma.
In glaucoma, the increased release of glutamate is the major cause of retinal ganglion cell death. Cannabinoids have been demonstrated to protect neuron cultures from glutamate-induced death. In this study, we test the hypothesis that glutamate causes apoptosis of retinal neurons via the excessive formation of peroxynitrite, and that the neuroprotective effect of the psychotropic Delta9-tetrahydroxycannabinol (THC) or nonpsychotropic cannabidiol (CBD) is via the attenuation of this formation. Excitotoxicity of the retina was induced by intravitreal injection of N-methyl-D-aspartate (NMDA) in rats, which also received 4-hydroxy-2,2,6,6-tetramethylpiperidine-n-oxyl (TEMPOL,a superoxide dismutase-mimetic), N-omega-nitro-L-arginine methyl ester (L-NAME, a nitric oxide synthase inhibitor), THC, or CBD.
Retinal neuron loss was determined by TDT-mediated dUTP nick-end labeling assay, inner retinal thickness, and quantification of the mRNAs of ganglion cell markers. NMDA induced a dose- and time-dependent accumulation of nitrite/nitrate, lipid peroxidation, and nitrotyrosine (foot print of peroxynitrite), and a dose-dependent apoptosis and loss of inner retinal neurons.
Treatment with L-NAME or TEMPOL protected retinal neurons and confirmed the involvement of peroxynitrite in retinal neurotoxicity. The neuroprotection by THC and CBD was because of attenuation of peroxynitrite. The effect of THC was in part mediated by the cannabinoid receptor CB1. These results suggest the potential use of CBD as a novel topical therapy for the treatment of glaucoma.
Neurology 36 (Suppl 1) April 1986 p. 342
Reuven Sandyk, Paul Consroe, Lawrence Z. Stern, and Stuart R. Snider, Tucson, AZ
Cannabidiol (CBD) is a major nonpsychoactive cannabinoid of marijuana. Based on reports indicating possible efficacy of CBD in dystonic movements (Neurology 1984; 34 [Suppl 1]: 147 and 1985; 35 [Suppl 1]: 201), we tried CBD in three patients with Huntington's disease (HD).
The patients;, aged 30 to 56, had HD of 7 to 12 years' duration. Their condition has been slowly progressive and unresponsive to prior therapy with neuroleptics. Orally administered CBD was initiated at 300 mg/d and increased 1 week later to 600 mg/d for the next 3 weeks.
Mild improvement ( 5 to 15%) in the choreic movements was documented using the tongueprotrusion test (Neurology [Minneap} 1972; 22: 929-33) and a chorea severity evaluation scale (Br J Clin Pharmacol 1981; 11: 129-51) after the first week. Further improvement (20 to 40%) was noticed after the second week of CBD, and this remained stable for the following 2 weeks.
Except for transient, mild hypotension, no side effects were recorded, and laboratory tests were normal. Withdrawal of CBD after 48 hours resulted in return of choreic movements to the pre-CBD state.
(Supported in part by NINCDS grant #NS15441)
Russo E; Guy GW
GW Pharmaceuticals, Porton Down Science Park, Salisbury, Wiltshire SP4 0JQ, UK. firstname.lastname@example.org
This study examines the current knowledge of physiological and clinical effects of tetrahydrocannabinol (THC) and cannabidiol (CBD) and presents a rationale for their combination in pharmaceutical preparations. Cannabinoid and vanilloid receptor effects as well as non-receptor mechanisms are explored, such as the capability of THC and CBD to act as anti-inflammatory substances independent of cyclo-oxygenase (COX) inhibition.
CBD is demonstrated to antagonise some undesirable effects of THC including intoxication, sedation and tachycardia, while contributing analgesic, anti-emetic, and anti-carcinogenic properties in its own right.
In modern clinical trials, this has permitted the administration of higher doses of THC, providing evidence for clinical efficacy and safety for cannabis based extracts in treatment of spasticity, central pain and lower urinary tract symptoms in multiple sclerosis, as well as sleep disturbances, peripheral neuropathic pain, brachial plexus avulsion symptoms, rheumatoid arthritis and intractable cancer pain. Prospects for future application of whole cannabis extracts in neuroprotection, drug dependency, and neoplastic disorders are further examined.
The hypothesis that the combination of THC and CBD increases clinical efficacy while reducing adverse events is supported.
|Major Subject Heading(s)||Minor Subject Heading(s)||CAS Registry / EC Numbers|
- Author Affiliations
In the current study, we examined the effects of the nonpsychoactive cannabinoid, cannabidiol, on the induction of apoptosis in leukemia cells.
Exposure of leukemia cells to cannabidiol led to cannabinoid receptor 2 (CB2)-mediated reduction in cell viability and induction in apoptosis.
Furthermore, cannabidiol treatment led to a significant decrease in tumor burden and an increase in apoptotic tumors in vivo. From a mechanistic standpoint, cannabidiol exposure resulted in activation of caspase-8, caspase-9, and caspase-3, cleavage of poly(ADP-ribose) polymerase, and a decrease in full-length Bid, suggesting possible cross-talk between the intrinsic and extrinsic apoptotic pathways. The role of the mitochondria was further suggested as exposure to cannabidiol led to loss of mitochondrial membrane potential and release of cytochrome c.
It is noteworthy that cannabidiol exposure led to an increase in reactive oxygen species (ROS) production as well as an increase in the expression of the NAD(P)H oxidases Nox4 and p22phox. Furthermore, cannabidiol-induced apoptosis and reactive oxygen species (ROS) levels could be blocked by treatment with the ROS scavengers or the NAD(P)H oxidase inhibitors.
Finally, cannabidiol exposure led to a decrease in the levels of p-p38 mitogen-activated protein kinase, which could be blocked by treatment with a CB2-selective antagonist or ROS scavenger. Together, the results from this study reveal that cannabidiol, acting through CB2 and regulation of Nox4 and p22phox expression, may be a novel and highly selective treatment for leukemia.
This work was supported in part by grants from National Institutes of Health (R01-DA016545, R21-DA014885, K12-DA14041, and P50-DA05274), The American Cancer Society (IRG-100036) and The Jeffress Memorial Trust Fund (J-741).
ABBREVIATIONS: THC, Δ9-tetrahydrocannabinol; CBD, cannabidiol; ROS, reactive oxygen species; PBS, phosphate-buffered saline; SR141716A; CB1, cannabinoid receptor 1; CB2, cannabinoid receptor 2; DPI, diphenylene iodinium; CPZ, capsazepine; VR1, vanilloid receptor 1; NAC, N-acetylcysteine; TUNEL, terminal deoxynucleotidyl transferase dUTP nick-end labeling; DiOC6, 3,3′-dihexylcarbocyanine iodide; ERK, extracellular signal-regulated kinase; JNK, c-Jun NH2-terminal kinase; MAPK, mitogen-activated protein kinase.
Murillo-Rodríguez E ; Millán-Aldaco D ; Palomero-Rivero M ; Mechoulam R ; Drucker-Colín R
Depto de Neurociencias, Instituto de Fisiología Celular, Ciudad Universitaria, Circuito Interior, Universidad Nacional Autónoma de México, México DF, CP 04510, Mexico. email@example.com
Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and cannabidiol (CBD) are two major constituents of Cannabis sativa. Delta(9)-THC modulates sleep, but no clear evidence on the role of CBD is available. In order to determine the effects of CBD on sleep, it was administered intracerebroventricular (icv) in a dose of 10 microg/5 microl at the beginning of either the lights-on or the lights-off period.
We found that CBD administered during the lights-on period increased wakefulness (W) and decreased rapid eye movement sleep (REMS).
No changes on sleep were observed during the dark phase. Icv injections of CBD (10 microg/5microl) induced an enhancement of c-Fos expression in waking-related brain areas such as hypothalamus and dorsal raphe nucleus (DRD). Microdialysis in unanesthetized rats was carried out to characterize the effects of icv administration of CBD (10 microg/5 microl) on extracellular levels of dopamine (DA) within the nucleus accumbens. CBD induced an increase in DA release.
Finally, in order to test if the waking properties of CBD could be blocked by the sleep-inducing endocannabinoid anandamide (ANA), animals received ANA (10 microg/2.5 microl, icv) followed 15 min later by CBD (10 microg/2.5 microl).
Results showed that the waking properties of CBD were not blocked by ANA. In conclusion, we found that CBD modulates waking via activation of neurons in the hypothalamus and DRD.
Both regions are apparently involved in the generation of alertness. Also, CBD increases DA levels as measured by microdialysis and HPLC procedures. Since CBD induces alertness, it might be of therapeutic value in sleep disorders such as excessive somnolence.
1Cardiology Department and 4Pathology Department, Hadassah Hebrew University Medical Center, 2Lautenberg Center for General and Tumor Immunology, and 3Department of Medicinal Chemistry and Natural Products, Pharmacy School, Hebrew University Medical School, Jerusalem, Israel
Submitted 24 January 2007 ; accepted in final form 19 September 2007
Cannabidiol (CBD) is a major, nonpsychoactive Cannabis constituent with anti-inflammatory activity mediated by enhancing adenosine signaling. Inasmuch as adenosine receptors are promising pharmaceutical targets for ischemic heart diseases, we tested the effect of CBD on ischemic rat hearts. For the in vivo studies, the left anterior descending coronary artery was transiently ligated for 30 min, and the rats were treated for 7 days with CBD (5 mg/kg ip) or vehicle. Cardiac function was studied by echocardiography.
Infarcts were examined morphometrically and histologically. For ex vivo evaluation, CBD was administered 24 and 1 h before the animals were killed, and hearts were harvested for physiological measurements.
In vivo studies showed preservation of shortening fraction in CBD-treated animals: from 48 ± 8 to 39 ± 8% and from 44 ± 5 to 32 ± 9% in CBD-treated and control rats, respectively (n = 14, P < 0.05). Infarct size was reduced by 66% in CBD-treated animals, despite nearly identical areas at risk (9.6 ± 3.9 and 28.2 ± 7.0% in CBD and controls, respectively, P < 0.001) and granulation tissue proportion as assessed qualitatively.
Infarcts in CBD-treated animals were associated with reduced myocardial inflammation and reduced IL-6 levels (254 ± 22 and 2,812 ± 500 pg/ml in CBD and control rats, respectively, P < 0.01). In isolated hearts, no significant difference in infarct size, left ventricular developed pressures during ischemia and reperfusion, or coronary flow could be detected between CBD-treated and control hearts.
Our study shows that CBD induces a substantial in vivo cardioprotective effect from ischemia that is not observed ex vivo. Inasmuch as CBD has previously been administered to humans without causing side effects, it may represent a promising novel treatment for myocardial ischemia....read more
J Neurosci 2007;27
Cannabidiol (CBD) may prevent the development of prion diseases, the most known being BSE (bovine spongiforme enzephalopathy), which is often called mad cow disease. It is believed that the BSE may be transmitted to human beings. In humans, it is known as Creutzfeldt-Jakob disease.
Capasso R, Borrelli F, Aviello G, Romano B, Scalisi C, Capasso F, Izzo AA
1Department of Experimental Pharmacology, University of Naples Federico II and Endocannabinoid Research Group, Naples, Italy.
Background and purpose:Cannabidiol is a Cannabis-derived non-psychotropic compound that exerts a plethora of pharmacological actions, including anti-inflammatory, neuroprotective and antitumour effects, with potential therapeutic interest. However, the actions of cannabidiol in the digestive tract are largely unexplored. In the present study, we investigated the effect of cannabidiol on intestinal motility in normal (control) mice and in mice with intestinal inflammation.
Motility in vivo was measured by evaluating the distribution of an orally administered fluorescent marker along the small intestine; intestinal inflammation was induced by the irritant croton oil; contractility in vitro was evaluated by stimulating the isolated ileum, in an organ bath, with ACh.Key results:In vivo, cannabidiol did not affect motility in control mice, but normalized croton oil-induced hypermotility. The inhibitory effect of cannabidiol was counteracted by the cannabinoid CB(1) receptor antagonist rimonabant, but not by the cannabinoid CB(2) receptor antagonist SR144528 (N-[-1S-endo-1,3,3-trimethyl bicyclo [2.2.1] heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide), by the opioid receptor antagonist naloxone or by the alpha(2)-adrenergic antagonist yohimbine.
Cannabidiol did not reduce motility in animals treated with the fatty acid amide hydrolase (FAAH) inhibitor N-arachidonoyl-5-hydroxytryptamine, whereas loperamide was still effective. In vitro, cannabidiol inhibited ACh-induced contractions in the isolated ileum from both control and croton oil-treated mice.Conclusions and implications:Cannabidiol selectively reduces croton oil-induced hypermotility in mice in vivo and this effect involves cannabinoid CB(1) receptors and FAAH. In view of its low toxicity in humans, cannabidiol may represent a good candidate to normalize motility in patients with inflammatory bowel disease.British Journal of Pharmacology (2008) 154, 1001-1008; doi:10.1038/bjp.2008.177; published online 12 May 2008.
Published 30 June 2008 in Br J Pharmacol, 154(5): 1001-8.
Full-text of this article is available online (may require subscription).
A.W. Zuardi, J.A.S. Crippa, J.E.C. Hallak, F.A. Moreira and F.S. Guimarães
Braz J Med Biol Res, April 2006, Volume 39(4) 421-429 (Review)
A high dose of D9-tetrahydrocannabinol, the main Cannabis sativa (cannabis) component, induces anxiety and psychotic-like symptoms in healthy volunteers. These effects of D9-tetrahydrocannabinol are significantly reduced by cannabidiol (CBD), a cannabis constituent which is devoid of the typical effects of the plant.
This observation led us to suspect that CBD could have anxiolytic and/or antipsychotic actions. Studies in animal models and in healthy volunteers clearly suggest an anxiolytic-like effect of CBD. The antipsychotic-like properties of CBD have been investigated in animal models using behavioral and neurochemical techniques which suggested that CBD has a pharmacological profile similar to that of atypical antipsychotic drugs.
The results of two studies on healthy volunteers using perception of binocular depth inversion and ketamine-induced psychotic symptoms supported the proposal of the antipsychotic-like properties of CBD. In addition, open case reports of schizophrenic patients treated with CBD and a preliminary report of a controlled clinical trial comparing CBD with an atypical antipsychotic drug have confirmed that this cannabinoid can be a safe and well-tolerated alternative treatment for schizophrenia.
Future studies of CBD in other psychotic conditions such as bipolar disorder and comparative studies of its antipsychotic effects with those produced by clozapine in schizophrenic patients are clearly indicated.
Key words: Cannabidiol, D9-Tetrahydrocannabinol, Cannabinoid, Anxiety, Antipsychotic, Schizophrenia
The use Cannabis sativa (cannabis) extracts as medicine was described in China and India before the birth of Christ.
The therapeutic use of cannabis was introduced in Western medicine in the first half of the 19th century and reached its climax in the last two decades of the same century.
At the turn of the century, several pharmaceutical companies were marketing cannabis extracts and tinctures which were prescribed by doctors for many different complaints including pain, whooping cough and asthma, and as a sedative/hypnotic agent.
However, the use of cannabis as a medicine almost completely disappeared at about the middle of the 20th century.
The main reasons for this disappearance were the variable potency of cannabis extracts, the erratic and unpredictable individual responses, the introduction of synthetic and more stable pharmaceutical substitutes such as aspirin, chloral hydrate and barbiturates, the recognition of important adverse effects such as anxiety and cognitive impairment, and the legal restrictions to the use of cannabis-derived medicines .
Today this situation has changed considerably. The main active psychotropic constituent of cannabis, D9-tetrahydrocannabinol (D9-THC), was isolated, identified and synthesized in the 1960's. Almost three decades later, cannabinoid receptors in the brain were described and cloned and the endogenous cannabinoids were isolated and identified.
As a result of these discoveries the interest in cannabis research has remarkably increased. For instance, the number of publications using the key word "brain", compiled by the ISI Web of Knowledge, increased 26 times from 1960-1964 to 2000-2004, while the number of publications about `cannabis' increased 78.5 times during the same period.
As a consequence, the research on the use of cannabis as medicine has been renewed.
Although D9-THC is commonly accepted as the main factor responsible for the effects of cannabis, several reports have demonstrated that other components of the plant influence its pharmacological activity.
One of these components is cannabidiol (CBD), which may constitute up to 40% of cannabis extracts and is devoid of the typical psychological effects of cannabis in humans.
Studies on the interaction between D9-THC and CBD have produced apparently contradictory results (7). Although potentiation of the effects of D9-THC has been observed (8,9), this phenomenon probably involves pharmacokinetic interactions since CBD is a potent inhibitor of hepatic drug metabolism (10) and increases D9-THC concentrations in the brain.
Several studies, however, have reported antagonism of the effects of D9-THC when both compounds are administered simultaneously to animals or humans.
CBD (1 mg/kg) co-administered with D9-THC (0.5 mg/kg) significantly reduced the anxiety and the psychotomimetic symptoms induced by the latter drug in healthy volunteers.
Since the dose of CBD used in that study did not change D9-THC levels in blood, it was suggested that CBD blocked the effects of D9-THC by some intrinsic pharmacological properties.
Actually, when administered alone CBD produced its own effects, including hypnotic, anticonvulsive, neuroprotective, and hormonal (increased corticosterone and cortisol levels) effects (19,20).
These effects led to the hypothesis that CBD could have anxiolytic and/or antipsychotic effects.
Anxiolytic effect of cannabidiol
The anxiolytic properties of CBD has been demonstrated by several pre-clinical studies that employed different paradigms such as the conditioned emotional response, the Vogel conflict test and the elevated plus-maze.
In the later study, the effective doses of CBD ranged from 2.5 to 10 mg/kg, and the drug produced an inverted U-shaped dose-response curve, the higher doses being no longer effective in rats. This could explain the negative results obtained with high doses of CBD (above 100 mg/kg) in a previous study employing the Geller-Seifter conflict test.
To evaluate a possible anxiolytic effect of CBD in humans, a double-blind study was conducted on healthy volunteers submitted to a simulation of the public speaking test. CBD (300 mg, po) was compared to ipsapirone (5 mg), diazepam (10 mg) or placebo. The results showed that both CBD and the two other anxiolytic compounds attenuated the anxiety induced by the test.
The anxiolytic-like effect of CBD in healthy volunteers was also observed in a more recent double-blind study that investigated its effects on regional cerebral blood flow by single-photon emission computed tomography.
Because the procedure, by itself, can be interpreted as an anxiogenic situation, it permits the evaluation of anxiolytic drugs. CBD induced a clear anxiolytic effect and a pattern of cerebral activity compatible with an anxiolytic activity.
Therefore, similar to the data obtained in animal models, results from studies on healthy volunteers have strongly suggested an anxiolytic-like effect of CBD.
Studies employing animal models
Animal models used for screening antipsychotic drugs are based on the neurochemical hypothesis of schizophrenia, involving mainly the neurotransmitters dopamine and glutamate.
Antagonism of dopamine D2 receptors may be a common feature of most clinically effective antipsychotic drugs, especially those active against hallucinations and delusions.
The dopamine-based models usually employ apomorphine, a direct agonist, or amphetamine, a drug that increases the release of this neurotransmitter and blocks its re-uptake.
Another common effect of antipsychotic drugs is hyperprolactinemia that results from the antagonism of D2 receptors on anterior-pituitary mammotrophic cells. These cells are tonically inhibited by dopamine produced in the hypothalamic arcuate nucleus.
Conventional or typical antipsychotic drugs, especially those with high affinity for D2 receptors (haloperidol being the standard compound), induce motor side effects characterized by a Parkinson-like syndrome.
On the contrary, atypical antipsychotic drugs, of which clozapine is the prototype, are therapeutically effective at doses that induce fewer or no Parkinson-like effects.
The probability of an antipsychotic agent to induce Parkinson-like symptoms may be evaluated in the catalepsy test.
Atypical antipsychotics inhibit the stereotypies and hyperlocomotion induced by dopamine agonists at lower doses than those that produce catalepsy.
As a first step in the investigation of possible antipsychotic-like properties of CBD, the drug was compared to haloperidol in rats submitted to dopamine-based models.
However, blocking D2 receptors is not necessarily the only mechanism for the antipsychotic activity. Several lines of evidence suggest that the glutamatergic N-methyl-D-aspartate (NMDA) receptor is involved in the mechanism of action of clozapine.
The glutamate-based models of schizophrenia employ sub-anesthetic doses of ketamine, a glutamate NMDA receptor antagonist, or its related compound phencyclidine, to induce psychotic symptoms. A more recent study investigated the effects of CBD in both dopamine and glutamate-based models predictive of antipsychotic activity.
The study compared the ability of CBD, haloperidol and clozapine to prevent the hyperlocomotion induced by amphetamine or ketamine in mice (34). The results of these two studies are summarized in Table 1.
|Table 1. Summary of two studies employing animal models for the screening of antipsychotic drugs, which compared cannabidiol, haloperidol and clozapine in rats and mice.|
[View larger version of this table (87 K JPG file)]
CBD (15-60 mg/kg), like haloperidol (0.25-0.5 mg/kg), reduced the apomorphine-induced stereotyped behavior in rats in a dose-related manner. These drugs also increased the plasma levels of prolactin.
However, higher doses of CBD were needed (120 and 240 mg/kg) to obtain such effects. Moreover, in contrast to haloperidol, CBD did not induce catalepsy, even at doses as high as 480 mg/kg.
In agreement with the results obtained in rats, CBD (15-60 mg/kg) inhibited the hyperlocomotion induced by amphetamine in mice in a dose-related manner.
In addition, the drug also attenuated the hyperlocomotion induced by ketamine, expanding its antipsychotic-like effects to a glutamate-based model.
As expected, while both haloperidol (0.15-0.6 mg/kg) and clozapine (1.25-5.0 mg/kg) inhibited hyperlocomotion, only haloperidol induced catalepsy in this dose range. Therefore, similar to clozapine, CBD did not induce catalepsy at doses that inhibited hyperlocomotion in mice.
These results support the view that CBD exhibits a profile similar to that of atypical antipsychotic drugs.
In addition to being tested on behavioral models, typical and atypical antipsychotics may also be distinguished according to their pattern of neural activation.
This may be detected by the expression of the proto-oncogene c-Fos. For example, haloperidol induces Fos immunoreactivity in the dorsal striatum, probably reflecting its motor side effects, while clozapine induces Fos immunoreactivity in the prefrontal cortex but not in the dorsal striatum.
The Fos immunoreactivity pattern induced by CBD (120 mg/kg) was compared to that of haloperidol (1 mg/kg) and clozapine (20 mg/kg) in rats. Only haloperidol increased Fos immunoreactivity in the dorsal striatum, while both CBD and clozapine, but not haloperidol, induced Fos immunoreactivity in the prefrontal cortex (36,37).
These results are consistent with the behavioral data obtained when comparing CBD with these prototype antipsychotics.
In conclusion, animal models employing behavioral as well as neurochemical techniques suggest that CBD has a pharmacological profile similar to that of an atypical antipsychotic drug.
Safety studies of CBD were required before human tests. CBD was extensively investigated in laboratory animals to detect possible side or toxic effects.
Acute CBD administration by the oral, inhalatory or intravenous route did not induce any significant toxic effect in humans. In addition, chronic administration of CBD for 30 days to healthy volunteers, at daily doses ranging from 10 to 400 mg, failed to induce any significant alteration in neurological, psychiatric or clinical exams.
Finally, in patients suffering from Huntington's disease, daily doses of CBD (700 mg) for 6 weeks did not induce any toxicity.
Therefore, confirming results from animal studies, the available clinical data suggest that CBD can be safely administered over a wide dose range.
In 1848 the French psychiatrist Jacques-Joseph Moreau de Tour began to investigate the effects of cannabis. He proposed for the first time the use of the plant as an experimental psychotomimetic.
Results from a recent study, obtained with more appropriate measurements and scales, agreed with Moreau's observation that D9-THC administration induces subjective, cognitive and behavioral changes that resemble endogenous psychosis, suggesting that D9-THC can, indeed, be used as an experimental psychotomimetic drug.
In 1982, a study investigating a possible interaction between D9-THC and CBD in healthy volunteers demonstrated that the latter drug could inhibit D9-THC-induced subjective changes that resembled symptoms of psychotic diseases (Figure 1).
In the same year, it was observed that patients admitted to a psychiatric hospital in South Africa, after the use of a variety of cannabis virtually devoid of CBD, showed much higher frequency of acute psychotic episodes than in other countries.
These lines of evidence led to several investigations of a possible antipsychotic effect of CBD.
Figure 1. Percentage of healthy volunteers who exhibited psychotic-like effects after the ingestion of 0.5 mg/kg D9-tetrahydrocannabinol (D9-THC; lozenges) and a combination of 0.5 mg/kg D9-THC + 1 mg/kg cannabidiol (circles).
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In order to evaluate the antipsychotic effects of new drugs in healthy volunteers, a useful model is the perception of binocular depth inversion. When a picture is presented separately to each eye, with a slight difference in the angle, it induces a three-dimensional perception.
The inversion of this picture from one eye to the other normally induces a change in convexity. This change may not be perceived if familiar objects (faces, for example) are presented, with the expected image predominating, which is illusory. Schizophrenic patients have difficulty in perceiving this illusory image, reporting a more veridical judgment.
During antipsychotic treatment, the inverted faces were seen as more illusionary.
This veridical judgment may also be obtained by the administration of psychotomimetic drugs such as nabilone, a D9-THC analogue. In this model, impairment of the perception of the illusory image induced by nabilone was attenuated by CBD, suggesting an antipsychotic-like effect of this compound.
Another important model used to evaluate antipsychotic-like activity in healthy volunteers is the administration of sub-anesthetic doses of ketamine. This glutamate-based model induces a psychotic reaction that mimics both positive and negative symptoms of schizophrenia.
A double-blind crossover procedure was performed to study the effect of CBD in this model. Nine healthy volunteers were assigned randomly to the placebo or CBD (600 mg) groups in two experimental sessions separated by a 1-week interval.
After being submitted to psychiatric assessment scales, the volunteers received placebo orally or the drug and rested for 65 min.
An infusion pump was then installed and an intravenous bolus of S-ketamine (0.26 mg/kg) was administered during 1 min followed by a maintenance dose of 0.25 mg/kg for 30 min.
A Clinician-Administered Dissociative States Scale (CADSS) was applied at the beginning of the sessions and 90 min after the bolus injection.
The volunteers were asked to respond the scale according to the period during which they felt most symptomatic. CBD attenuated the effects of ketamine on the total score of the CADSS and also on each of its factors separately. This effect was significant for the depersonalization factor, further reinforcing the antipsychotic-like properties of CBD (Figure 2).
Figure 2. Depersonalization factor scores of the Clinician-Administered Dissociative States Scale for each healthy volunteer (lines) during intravenous ketamine infusion, after oral placebo or cannabidiol (CBD) (600 mg) administration. Bars indicate the mean ± SEM. *P < 0.05 compared to placebo (paired t-test) for 9 volunteers.
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In view of the safe profile of CBD administration in humans and in laboratory animals, we decided to perform open-label clinical trials in a reduced number of patients. In 1995, CBD was tested in a case study with a 19-year-old schizophrenic female patient who presented serious side effects after treatment with conventional antipsychotics.
Following a wash-out period of 4 days this patient received increasing oral doses of CBD dissolved in oil, reaching 1500 mg/day, for 4 weeks. After this period, CBD administration was interrupted and placebo was administered for 4 days.
Finally, the treatment was shifted to increasing doses of haloperidol that reached 12.5 mg/day. The psychiatric interviews were video-recorded and the symptoms were assessed by a blinded-psychiatrist using the Brief Psychiatric Rating Scale (BPRS).
A significant improvement was observed during CBD treatment, while a worsening was observed when the administration was interrupted. The improvement obtained with CBD was not increased by haloperidol (Figure 3, patient A).
Further supporting the safe profile of CBD, no side effects were observed, as assessed by the Ugvalg for Kliniske Undersgelser (UKU) scale.
Figure 3. Brief Psychiatric Rating Scale (BPRS) scores for 4 schizophrenic patients treated with cannabidiol (CBD). Patient A received up to 1500 mg/day CBD and patients B, C, and D received up to 1280 mg/day. Bars indicate BPRS scores for each schizophrenic patient at the end point after the oral administration of placebo, CBD and a control antipsychotic drug (haloperidol for patient A and olanzapine for patients B, C and D).
Placebo was administered before and after CBD treatment. Patient A is a woman who presented serious side effects with typical antipsychotics. Patients B, C, and D are men previously treated with typical antipsychotics with no response.
[View larger version of this image (41 K JPG file)]
More recently, CBD was administered to three 22- or 23-year-old male patients with a diagnosis of schizophrenia who had not responded to typical antipsychotic drugs (48). They received placebo for 5 days in the hospital followed by CBD from the 6th to the 35th day. After this period, they received placebo for an additional 5 days, followed by olanzapine for at least 15 days.
The dose of CBD was increased from 40 up to 1280 mg/day. The patients were assessed by two psychiatrists, who were blind to the doses administered, using the BPRS and UKU scales. No side effects were observed during CBD treatment, even at the higher dose of 1280 mg/day. A partial improvement was observed in one patient (Figure 3, patient B) while slight or no improvement was observed in the other two (Figure 3, patients C and D).
However, the patients (C and D) were considered to be refractory, since they did not even respond to clozapine, a fact that may explain the lack of CBD effectiveness (48). Figure 3 shows the results obtained with the 4 schizophrenic patients treated so far with CBD. These studies suggest, therefore, that CBD has an antipsychotic-like profile in healthy volunteers and may possess antipsychotic properties in schizophrenic patients, but not in the resistant ones.
Confirming this suggestion, a preliminary report from a 4-week, double-blind controlled clinical trial, using an adequate number of patients and comparing the effects of CBD with amisulpride in acute schizophrenic and schizophreniform psychosis, showed that CBD significantly reduced acute psychotic symptoms after 2 and 4 weeks of treatment when compared to baseline. In this trial CBD did not differ from amisulpride except for a lower incidence of side effects.
In conclusion, results from pre-clinical and clinical studies suggest that CBD is an effective, safe and well-tolerated alternative treatment for schizophrenic patients. Future trials of this cannabinoid in other psychotic conditions such as bipolar disorder (50) and comparative studies of its antipsychotic effects with those produced by clozapine in schizophrenic patients are clearly needed.
1. Mikuriya TH (1969). Marijuana in medicine: past, present and future. California Medicine, 110: 34-40. [ Links ]
2. Fankhauser M (2002). History of cannabis in Western Medicine. In: Grotenhermen F & Russo E (Editors), Cannabis and Cannabinoids. The Haworth Integrative Healing Press, New York, 37-51. [ Links ]
3. Martin BR, Mechoulam R & Razdan RK (1999). Discovery and characterization of endogenous cannabinoids. Life Sciences, 65: 573-595. [ Links ]
4. Carlini EA, Santos M, Claussen V et al. (1970). Structure activity relationship of four tetrahydrocannabinols and the pharmacological activity of five semipurified extracts of Cannabis sativa. Psychopharmacologia, 18: 82-93. [ Links ]
5. Grlie L (1976). A comparative study on some chemical and biological characteristics of various samples of cannabis resin. Bulletin on Narcotics 14: 37-46. [ Links ]
6. Zuardi AW, Shirakawa I, Finkelfarb E et al. (1982). Action of cannabidiol on the anxiety and other effects produced by D9-THC in normal subjects. Psychopharmacology, 76: 245-250. [ Links ]
7. Karniol IG & Carlini EA (1973). Pharmacological interaction between cannabidiol and D9-tetrahydrocannabinol. Psychopharmacologia, 33: 53-70. [ Links ]
8. Fernandes M, Schabarek A, Coper H et al. (1974). Modification of D9-THC-actions by cannabinol and cannabidiol in the rats. Psychopharmacologia, 38: 329-338. [ Links ]
9. Hollister LE & Gillespie H (1975). Interactions in man of D9-tetrahydrocannabinol, H-cannabinol and cannabidiol. Clinical Pharmacology and Therapeutics,18: 80-83. [ Links ]
10. Bornhein LM, Borys HK & Karler R (1981). Effect of cannabidiol on cytochrome P-450 and hexobarbital sleep time. Biochemical Pharmacology, 30: 503-507. [ Links ]
11. Jones G & Pertwee RG (1972). A metabolic interaction in vivo between cannabidiol and D9-tetrahydrocannabinol. British Journal of Pharmacology, 45: 375-377. [ Links ]
12. Davis WM & Borgen LA (1974). Effects of cannabidiol and D9-tetrahydrocannabinol on operant behavior. Research Communications in Chemical Pathology and Pharmacology, 9: 453-462. [ Links ]
13. Zuardi AW, Finkelfarb E, Bueno OFA et al. (1981). Characteristics of the stimulus produced by the mixture of cannabidiol with D9-tetrahydrocannabinol. Archives Internationales de Pharmacodynamie et de Therapie, 249: 137-146. [ Links ]
14. Karniol IG, Shirakawa I, Kasinsky N et al. (1974). Cannabidiol interferes with the effect of D9-tetrahydrocannabinol in man. European Journal of Pharmacology, 28: 172-177. [ Links ]
15. Agurell S, Carlsson S, Lindgreen JE et al. (1981). Interactions of D1-tetrahydrocannabinol with cannabinol and cannabidiol following oral administration in man. Assay of cannabinol and cannabidiol by mass fragmentography. Experientia, 37: 1090-1092. [ Links ]
16. Monti JM (1977). Hypnotic-like effects of cannabidiol in the rats. Psychopharmacology, 76: 263-265. [ Links ]
17. Cunha J, Carlini EA, Pereira AE et al. (1980). Chronic administration of cannabidiol to healthy volunteers and epileptic patients. Pharmacology, 21: 175-185. [ Links ]
18. Hampson AJ, Grimaldi M, Axelroad J et al. (1998). Cannabidiol and D9-tetrahydrocannabinol are neuroprotective antioxidants. Proceedings of the National Academy of Sciences, USA, 95: 8268-8273. [ Links ]
19. Zuardi AW, Teixeira NA & Karniol IG (1984). Pharmacological interaction of the effects of D9-tetrahydrocannabinol and cannabidiol on serum corticosterone levels in rats. Archives Internationales de Pharmacodynamie et de Therapie, 269: 12-19. [ Links ]
20. Zuardi AW, Guimarães FS & Moreira AC (1993). Effect of cannabidiol on plasma prolactin, growth hormone and cortisol in human volunteers. Brazilian Journal of Medical and Biological Research, 26: 213-217. [ Links ]
21. Zuardi AW & Karniol IG (1983). Changes in the conditioned emotional response of rats induced by D9-THC, CBD and mixture of the two cannabinoids. Arquivos de Biologia e Tecnologia, 26: 391-397. [ Links ]
22. Musty RE, Conti LH & Mechoulam R (1984). Anxiolytic properties of cannabidiol. In: Harvey DJ (Editor), Marihuana '84. Proceedings of the Oxford Symposium on Cannabis. IRL Press Limited, Oxford, UK, 713-719. [ Links ]
23. Onaivi ES, Green MR & Martin BR (1990). Pharmacological characterization of cannabinoids in the elevated plus maze. Journal of Pharmacology and Experimental Therapeutics, 253: 1002-1009. [ Links ]
24. Guimarães FS, Chiaretti TM, Graeff FG et al. (1990). Antianxiety effect of cannabidiol in the elevated plus-maze. Psychopharmacology, 100: 558-559. [ Links ]
25. Silveira Filho NG & Tufik S (1981). Comparative effects between cannabidiol and diazepam on neophobia, food intake and conflict behavior. Research Communications in Psychology, Psychiatry and Behavior, 6: 25-26. [ Links ]
26. Zuardi AW, Cosme RA, Graeff FG et al. (1993). Effects of ipsapirone and cannabidiol on human experimental anxiety. Journal of Psychopharmacoly, 7: 82-88. [ Links ]
27. Crippa JAS, Zuardi AW, Garrido GE et al. (2004). Effects of cannabidiol (CBD) on regional cerebral blood flow. Neuropsychopharmacology, 29: 417-426. [ Links ]
28. Lipska BK & Weinberger DR (2000). To model a psychiatric disorder in animals: schizophrenia as a reality test. Neuropsychopharmacology, 23: 223-239. [ Links ]
29. Gardner DM, Baldessarini RJ & Waraich P (2005). Modern antipsychotic drugs: a critical overview. Canadian Medical Association Journal, 172: 1703-1711. [ Links ]
30. Baldessarini RJ & Tarazi FI (1996). Brain dopamine receptors: a primer on their current status, basic and clinical. Harvard Review of Psychiatry, 3: 301-325. [ Links ]
31. Hoffman DC & Donovan H (1995). Catalepsy as a rodent model for detecting antipsychotic drugs with extrapyramidal side effects. Psychopharmacology, 120: 128-133. [ Links ]
32. Zuardi AW, Rodrigues JA & Cunha JM (1991). Effects of cannabidiol in animal models predictive of antipsychotic activity. Psychopharmacology, 104: 260-264. [ Links ]
33. Malhotra AK, Adler CM, Kennison SD et al. (1997). Clozapine blunts N-methyl-D-aspartate antagonist-induced psychosis: a study with ketamine. Biological Psychiatry, 42: 664-668. [ Links ]
34. Moreira FA & Guimarães FS (2005). Cannabidiol inhibits the hyperlocomotion induced by psychotomimetic drugs in mice. European Journal of Pharmacology, 512: 199-205. [ Links ]
35. Robertson GS & Fibiger HC (1992). Neuroleptics increase c-Fos expression in the forebrain: contrasting effects of haloperidol and clozapine. Neuroscience, 46: 315-328. [ Links ]
36. Zuardi AW, Guimarães FS, Guimarães VM et al. (2002). Cannabidiol: possible therapeutic application. In: Grotenhermen F, Russo E & Varo RN (Editors), Cannabis and Cannabinoids: Pharmacology, Toxicology and Therapeutic Potential. The Haword Interactive Healing Press, New York, 359-369. [ Links ]
37. Guimarães VMC, Zuardi AW, Del Bel EA et al. (2004). Cannabidiol increases Fos expression in the nucleus accumbens but not in the dorsal striatum. Life Sciences, 75: 633-638. [ Links ]
38. Zuardi AW & Guimarães FS (1997). Cannabidiol as an anxiolytic and antipsychotic. In: Mathre ML (Editor), Cannabis in Medical Practice. McFarland & Company, Inc., Jefferson, NC, USA, 133-141. [ Links ]
39. Consroe P, Laguna J, Allender J et al. (1991). Controlled clinical trial of cannabidiol in Huntington's disease. Pharmacology, Biochemistry, and Behavior, 40: 701-708. [ Links ]
40. Moreau JJ (1845). Du Hachisch et de l'Alienation Mentale: Etudes Psychologiques. Librarie de Fortin Mason, Paris, France (English edition: Raven Press, New York, 1972). [ Links ]
41. D'Souza DC, Perry E, MacDougall L et al. (2004). The psychotomimetic effects of intravenous delta-9-tetrahydrocannabinol in healthy individuals: Implications for psychosis. Neuropsychopharmacology, 29: 1558-1572. [ Links ]
42. Rottanburg D, Robins AH, Ben-Aire O et al. (1982). Cannabis-associated psychosis with hypomaniac feature. Lancet, 2: 1364-1366. [ Links ]
43. Schneider U, Borsutzky M, Seifert J et al. (2002). Reduced binocular depth inversion in schizophrenic patients. Schizophrenia Research, 53: 101-108. [ Links ]
44. Leweke FM, Schneider U, Radwan M et al. (2000). Different effects of nabilone and cannabidiol on binocular depth inversion in man. Pharmacology, Biochemistry, and Behavior, 66: 175-181. [ Links ]
45. Krystal JH, Karper LP, Bremner JD et al. (1994). Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Archives of General Psychiatry, 51: 199-214. [ Links ]
46. Bosi DC, Hallak JEC, Dursun SM et al. (2003). Effects of cannabidiol on (s)-ketamine-induced psychopathology in healthy volunteers. Journal of Psychopharmacology, 17 (Suppl): A55. [ Links ]
47. Zuardi AW, Morais SL, Guimarães FS et al. (1995). Anti-psychotic effect of cannabidiol. Journal of Clinical Psychiatry, 56: 485-486. [ Links ]
48. Zuardi AW, Hallak JEC, Dursun SM et al. (2006). Effect of cannabidiol in non responsive schizophrenia. Journal of Psychopharmacology (in press). [ Links ]
49. Leweke FM, Koethe D, Gerth CW et al. (2005). Cannabidiol as an antipsychotic: a double-blind, controlled clinical trial on cannabidiol vs amisulpride in acute schizophrenics. 2005 Symposium on the Cannabinoids, Burlington, Vermont, International Cannabinoid Research Society. http://CannabinoidSociety.org. [ Links ]
50. Ashton CH, Moore PB, Gallagher P et al. (2005). Cannabinoids in bipolar affective disorder: a review and discussion of their therapeutic potential. Journal of Psychopharmacology, 19: 293-300. [ Links ]
Address for correspondence: A.W. Zuardi, Departamento de Neurologia, Psiquiatria e Psicologia Médica, FMRP, USP, Av. Bandeirantes, 3900, 14049-900 Ribeirão Preto, SP, Brasil. E-mail: firstname.lastname@example.org
Several studies reviewed here were supported by FAPESP and CNPq. Received August 9, 2005. Accepted December 14, 2005.
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The essential oil and the solvent extract of two populations of Cannabis sativa L. ssp. spontanea growing wild in Austria were analyzed comparatively. In the essential oil, myrcene (31% and 27%, respectively), (E)-beta-ocilnene (13% and 3%, respectively) and beta-caryophyllene (11 % and 16%, respectively) were found, while in the solvent extract the non-hallucinogeneous cannabidiol (77% and 59%, respectively) dominated.
The hallucinogeneous delta-9-tetrahydrocannabinol (THC) was also found in the solvent extract at a level of less than 1%.
In Cannabis sativa L. ssp. spontanea (formerly Cannabis ruderalis) (Cannabaceae) the perianth of the female flowers is in contrast to C. sativa ssp. sativa still present; the fruit is brownish and has a peduncle-like ringbulge. It is a ruderal, but a rare plant in the east of Austria (1).
Two populations of C. sativa L. ssp. spontanea ("Albrechtsfeld" and "Schoschtolacke") from the region of lake Neusiedl, Burgenland, eastern Austria were sampled in June, 1998, at the beginning of seed ripening.
At each population upper parts of approximately 10 plants were sampled. Voucher specimens were deposited in the Herbarium of the Institute for Applied Botany, University of Veterinary Medicine, Vienna.
For distillation and extraction, only fresh material was used, since drying results in a high loss (30-40%) of the essential oil.
Twenty g of fresh plant material (upper plant parts) were distilled in a modified Clevenger apparatus for 3 h. The solvent extracts were prepared by adding CH^sub 2^Cl^sub 2^ to 1 g fresh material of hemp (upper plant parts); extraction was performed in an ultrasonic bath for 15 min.
The essential oil (5 (mu)L) was diluted with CH^sub 2^Cl^sub 2^ (495 (mu)L) prior to analyses. GC/MS-analyses were performed on a HP 6890 coupled with a HP 5972 MSD and fitted with a HP 30 m x 0.25 mm capillary column coated with HP-5MS (0.25 (mu)m film thickness).
The analytical conditions were: carrier gas helium, injector temperature 250 deg C, split ratio 50:1, temperature programme 50 deg -140 deg C at 5 deg C/min and 140-170 deg C at 2 deg C/min. Components were identified by comparing their retention indices (RI) and mass spectra (3-5).
The essential oil of C. sativa has been the subject of previous studies (2, 6-15 and references cited therein).
Mono- and sesquiterpenes: The oil of C. sativa L. ssp. spontanea contains as main compounds alpha-pinene (9% and 6%, respectively), myrcene (32% and 28%, respectively), beta-- caryophyllene (11% and 16%, respectively) and beta-caryophyllene oxide (7% and 8%, respectively) (Table I). However, the main differences between the two populations could be found in the high content of (E)-beta-ocimene with a very high content of 12.6% from "Albrechtsfeld" and a low content of 3% from "Schoschtolacke." Compared to "Schoschtolacke," the content of alpha-humulene was approximately the half at "Albrechtsfeld" (3.2%).
The oil compositions reported here differ very much from Ross et al., Hendriks et al. and Nigam where (E)-beta-ocimene was only found in traces or not at all. Hendriks et al. (8) and Nigam found alpha-pinene, beta-- pinene and myrcene at alevel of less than 1%, beta-caryophyllene instead reached 37% and 45%, respectively. In contrast, Ross et al. noticed beta-caryophyllene to be present at only 1.3%. Myrcene (67%) and limonene (16%) were much higher than reported elsewhere (2). The Austrian populations of this report are within the range ofwhere different cultivars (especially European fiber cultivars) were analyzed.
Composition of cannabinoids: Regarding the cannabinoids in the oil, relatively high percentages of the non-- hallucinogeneous cannabidiol (CBD) (9.8% "Albrechtsfeld" and 10.9% "Schoschtolacke," respectively) could be found. The hallucinogenic delta-9-tetrahydrocannabinol (THC) was only present at "Schoschtolacke," and here only at low amounts (0.7%). CBD in the oil was still very high, but it's content was strictly dependant on the distillation conditions. The presence of cannabinoids in oils at higher amounts (11,17 and this report) as well as the almost absence of cannabinoids (12 and 16) are also dependant on distillation conditions and the state of the plant material being distilled. In the solvent extract, the content of CBD was extremely high (76.6% and 58.8%, respectively), while THC was always (even in the extract) below 1%. These can be regarded as being populations with a low content of THC, while the amount of CBD (especially in the extracts) was very high. So the ratio of CBD/THC, which is used for characterizing and distinguishing "fiber" from "drug" genotypes (18), is very much in favor of the fiber types.
Alkanes: Hendriks et al. (19) found nonacosane as main compound in the alkane-fraction obtained by extraction (55%) and at 11% in the oil. Nonacosane was also detected in the extracts of our study at 9% ("Albrechtsfeld") and 18% ("Schoschtolacke"), while it was absent in the oil
|Title||Treatment with CBD in oily solution of drug-resistant paediatric epilepsies.|
|Author(s)||Pelliccia A, Grassi G, Romano A, Crocchialo P|
|Journal, Volume, Issue||2005 Congress on Cannabis and the Cannabinoids, Leiden, The Netherlands: International Association for Cannabis as Medicine, p. 14.|
|Major outcome(s)||Improvement of EPILEPSY without side effects|
Introduction: As shown by Turkanis et al. (EPILEPSY, 1979), cannabidiol (CBD), similarly to d9- tetrahydrocannabinol (d9-THC) and Phenytoin (PHT) increases the “afterdischarge” and seizures threshold, mainly at the limbic level, without exhibiting the side effects induced by drugs such as PHT. Studies on rats were conducted that confirmed the anticonvulsant effects of both CBD (Chiu et al., 1979) and of d 9-THC (Cosroe and Mechoulam, 1987).
However, in spite of other studies having confirmed the anticonvulsant effect of cannabinoids, up to date no trials were conducted on man and, the less so, on the child.
Methods: We collected data on a population of children who presented with traditional antiepileptic drugs-resistant seizures, treated with a 2.5% corn oily solution of CBD as part of an open study, by modulating administration and titration schedules on a case by case basis, according to clinical response.
Results: On June 2002 we started to treat an eleven year-old girl affected with a
Results have been encouraging: the girl, since she assumes CBD, did not need any longer to be admitted to hospital for her epileptic seizures, while her attacks decreased both in frequency and intensity, in addition her awareness, postural tone and speaking ability improved, as to allow us to gradually decrease her barbiturate intake.
Along the same line, CBD was proposed to another patient, a 17 year-old boy with an equally drug-resistant Lennox-Gastaut syndrome: although he reached the dose of only 30 drops daily, he also exhibited a slight improvement of the crises and, first and foremost, a clear-cut attention-behavioural improvement, and even in his case a suspension of the barbiturate treatment was initiated.
During the last year, 16 more children were started on CBD, all of them affected with symptomatic drug-resistant EPILEPSY; however, only 9 out of these are currently on treatment, since the parents of the remaining children, although appreciating the improvement of their offspring, not only concerning the fits but also the awareness and the muscular tone, preferred to discontinue due to the economic overcharge induced by the treatment (approximately 300 EURos per month).
Conclusions: So far obtained results in our open study appear encouraging for various reasons:
1) no side effects of such a severity were observed as to require CBD discontinuation;
2) in most of the treated children an improvement of the crises was obtained equal to, or higher than, 25% in spite of the low CBD doses administered;
3) in all CBD- treated children a clear improvement of consciousness and spasticity (whenever present) was observed.
All Conditions Benefited by Medical Marijuana
|Participants||18 children with epilepsy|
|Type of publication||Meeting abstract|
|Address of author(s)||II Facoltà di Medicina,Università “La Sapienza”, 00100 Rome, Italy, Istituto Sperimentale Colture Industriali, Sezione di Rovigo, Italy, American University of Rome, 00100, Italy|
Cannabidiol (CBD) is a cannabinoid component from Cannabis sativa that does not induce psychotomimetic effects and possess anti-inflammatory properties. In the present study we tested the effects of CBD in a periodontitis experimental model in rats. We also investigated possible mechanisms underlying these effects.
Periodontal disease was induced by a ligature placed around the mandible first molars of each animal.
Male Wistar rats were divided into 3 groups: control animals; ligature-induced animals treated with vehicle and ligature-induced animals treated with CBD (5 mg/kg, daily).
Thirty days after the induction of periodontal disease the animals were sacrificed and mandibles and gingival tissues removed for further analysis.
Morphometrical analysis of alveolar bone loss demonstrated that CBD-treated animals presented a decreased alveolar bone loss and a lower expression of the activator of nuclear factor-kappaB ligand RANKL/RANK. Moreover, gingival tissues from the CBD-treated group showed decreased neutrophil migration (MPO assay) associated with lower interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha production.
These results indicate that CBD may be useful to control bone resorption during progression of experimental periodontitis in rats.
Cannabidiol (CBD) is a constituent of Cannabis sativa that induces nonpsychotropic effects, and some of its biological actions in sleep have been described by the authors' group.
Here, the authors report that when administered 10 or 20 microg/1 microl during the lights-on period directly into either lateral hypothalamus (LH) or dorsal raphe nuclei (DRN), which are wake-inducing brain areas, CBD enhanced wakefulness and decreased slow wave sleep and REM sleep.
Furthermore, CBD increased alpha and theta power spectra but diminished delta power spectra.
Additionally, CBD increased c-Fos expression in LH or DRN. These findings suggest that this cannabinoid is a wake-inducing compound that presumably activates neurons in LH and DRN. (PsycINFO Database Record (c) 2008 APA, all rights reserved).
Here, we demonstrate that anandamide, Δ9-tetrahydrocannabinol (THC), HU-210, and Win55,212-2 promote mitogenic kinase signaling in cancer cells. Treatment of the glioblastoma cell line U373-MG and the lung carcinoma cell line NCI-H292 with nanomolar concentrations of THC led to accelerated cell proliferation that was completely dependent on metalloprotease and epidermal growth factor receptor (EGFR) activity.
EGFR signal transactivation was identified as the mechanistic link between cannabinoid receptors and the activation of the mitogen-activated protein kinases extracellular signal-regulated kinase 1/2 as well as prosurvival protein kinase B (Akt/PKB) signaling. Depending on the cellular context, signal cross-communication was mediated by shedding of proAmphiregulin (proAR) and/or proHeparin-binding epidermal growth factor-like growth factor (proHB-EGF) by tumor necrosis factor α converting enzyme (TACE/ADAM17). Taken together, our data show that concentrations of THC comparable with those detected in the serum of patients after THC administration accelerate proliferation of cancer cells instead of apoptosis and thereby contribute to cancer progression in patients.
Am J Physiol Heart Circ Physiol. Author manuscript; available in PMC 2008 February 4.
Published in final edited form as:
Published online 2007 March 23. doi: 10.1152/ajpheart.00236.2007.
Br J Pharmacol. 2
007 August; 151(8): 1272–1279.
Published online 2007 June 25. doi: 10.1038/sj.bjp.0707337.
We examined the neuroprotective mechanism of cannabidiol, non-psychoactive component of marijuana, on the infarction in a 4 h mouse middle cerebral artery (MCA) occlusion model in comparison with Delta(9)-tetrahydrocannabinol (Delta(9)-THC).
Release of glutamate in the cortex was measured at 2 h after MCA occlusion. Myeloperoxidase (MPO) and cerebral blood flow were measured at 1 h after reperfusion. In addition, infarct size and MPO were determined at 24 and 72 h after MCA occlusion.
The neuroprotective effect of cannabidiol was not inhibited by either SR141716 or AM630. Both pre- and post-ischemic treatment with cannabidiol resulted in potent and long-lasting neuroprotection, whereas only pre-ischemic treatment with Delta(9)-THC reduced the infarction. Unlike Delta(9)-THC, cannabidiol did not affect the excess release of glutamate in the cortex after occlusion.
Cannabidiol suppressed the decrease in cerebral blood flow by the failure of cerebral microcirculation after reperfusion and inhibited MPO activity in neutrophils. Furthermore, the number of MPO-immunopositive cells was reduced in the ipsilateral hemisphere in cannabidiol-treated group.
Cannabidiol provides potent and long-lasting neuroprotection through an anti-inflammatory CB(1) receptor-independent mechanism, suggesting that cannabidiol will have a palliative action and open new therapeutic possibilities for treating cerebrovascular disorders.
Takeda S, Usami N, Yamamoto I, Watanabe K
Drug Metab Dispos 2009 Apr 30.
The inhibitory effect of nordihydroguaiaretic acid (NDGA), a non-selective lipoxygenase (LOX) inhibitor, -mediated 15-LOX inhibition has been reported to be affected by modification of its catechol ring such as methylation of the hydroxyl group. Cannabidiol (CBD), one of the major components of marijuana, is known to inhibit LOX activity.
Based on the phenomenon observed in NDGA, we investigated whether or not methylation of CBD affects its inhibitory potential against 15-LOX, since CBD contains a resorcinol ring, which is an isomer of catechol. Although CBD inhibited 15-LOX activity with an IC50 value (50% inhibition concentration) of 2.56 microM, its mono-methylated and di-methylated derivatives, CBD-2'-monomethyl ether (CBDM) and CBD-2',6'-dimethyl ether (CBDD) inhibited 15-LOX activity more strongly than CBD.
The number of methyl groups in the resorcinol moiety of CBD (as a prototype) appears to be a key determinant for potency and selectivity in inhibition of 15-LOX. The IC50 value of 15-LOX inhibition by CBDD is 0.28 microM, and the inhibition selectivity for 15-LOX (i.e., the 5-LOX/15-LOX ratio of IC50 values) is more than 700.
Among LOX isoforms, 15-LOX is known to be able to oxygenate the cholesterol esters in the low density lipoprotein (LDL) particle (i.e., the formation of oxidized LDL).
Thus, 15-LOX is suggested to be involved in developing atherosclerosis, and CBDD may be a useful prototype for producing medicines for atherosclerosis.
Phytother Res 2009 May 13.
Comelli F, Bettoni I, Colleoni M, Giagnoni G, Costa B
Neuropathy is the most common complication of diabetes and it is still considered to be relatively refractory to most of the analgesics.
The aim of the present study was to explore the antinociceptive effect of a controlled cannabis extract (eCBD) in attenuating diabetic neuropathic pain.
Repeated treatment with cannabis extract significantly relieved mechanical allodynia and restored the physiological thermal pain perception in streptozotocin (STZ)-induced diabetic rats without affecting hyperglycemia.
In addition, the results showed that eCBD increased the reduced glutathione (GSH) content in the liver leading to a restoration of the defence mechanism and significantly decreased the liver lipid peroxidation suggesting that eCBD provides protection against oxidative damage in STZ-induced diabetes that also strongly contributes to the development of neuropathy.
Finally, the nerve growth factor content in the sciatic nerve of diabetic rats was restored to normal following the repeated treatment with eCBD, suggesting that the extract was able to prevent the nerve damage caused by the reduced support of this neurotrophin.
These findings highlighted the beneficial effects of cannabis extract treatment in attenuating diabetic neuropathic pain, possibly through a strong antioxidant activity and a specific action upon nerve growth factor. Copyright (c) 2009 John Wiley & Sons, Ltd.
Zuardi AW Rev Bras Psiquiatr 2008 Sep; 30(3):271-80.
The aim of this review is to describe the historical development of research on cannabidiol.
This review was carried out on reports drawn from Medline, Web of Science and SciELO.
After the elucidation of the chemical structure of cannabidiol in 1963, the initial studies showed that cannabidiol was unable to mimic the effects of Cannabis.
In the 1970's the number of publications on cannabidiol reached a first peak, having the research focused mainly on the interaction with delta9-THC and its antiepileptic and sedative effects.
The following two decades showed lower degree of interest, and the potential therapeutic properties of cannabidiol investigated were mainly the anxiolytic, antipsychotic and on motor diseases effects.
The last five years have shown a remarkable increase in publications on cannabidiol mainly stimulated by the discovery of its anti-inflammatory, anti-oxidative and neuroprotective effects. These studies have suggested a wide range of possible therapeutic effects of cannabidiol on several conditions, including Parkinson's disease, Alzheimer's disease, cerebral ischemia, diabetes, rheumatoid arthritis, other inflammatory diseases, nausea and cancer.
In the last 45 years it has been possible to demonstrate that CBD has a wide range of pharmacological effects, many of which being of great therapeutic interest, but still waiting to be confirmed by clinical trials.
Scuderi C, Filippis DD, Iuvone T, Blasio A, Steardo A, Esposito G
Phytother Res 2008 Oct 9.
Cannabidiol (CBD) is the main non-psychotropic component of the glandular hairs of Cannabis sativa. It displays a plethora of actions including anticonvulsive, sedative, hypnotic, antipsychotic, antiinflammatory and neuroprotective properties.
However, it is well established that CBD produces its biological effects without exerting significant intrinsic activity upon cannabinoid receptors.
For this reason, CBD lacks the unwanted psychotropic effects characteristic of marijuana derivatives, so representing one of the bioactive constituents of Cannabis sativa with the highest potential for therapeutic use.
The present review reports the pharmacological profile of CBD and summarizes results from preclinical and clinical studies utilizing CBD, alone or in combination with other phytocannabinoids, for the treatment of a number of CNS disorders.
Copyright (c) 2008 John Wiley & Sons, Ltd.
Iuvone T, Esposito G, De Filippis D, Scuderi C, Steardo L
Cannabidiol: a promising drug for neurodegenerative disorders? [Journal Article, Research Support, Non-U.S. Gov't, Review]
CNS Neurosci Ther 2009; 15(1):65-75.
Neurodegenerative diseases represent, nowadays, one of the main causes of death in the industrialized country. They are characterized by a loss of neurons in particular regions of the nervous system. It is believed that this nerve cell loss underlies the subsequent decline in cognitive and motor function that patients experience in these diseases.
A range of mutant genes and environmental toxins have been implicated in the cause of neurodegenerative disorders but the mechanism remains largely unknown. At present, inflammation, a common denominator among the diverse list of neurodegenerative diseases, has been implicated as a critical mechanism that is responsible for the progressive nature of neurodegeneration.
Since, at present, there are few therapies for the wide range of neurodegenerative diseases, scientists are still in search of new therapeutic approaches to the problem. An early contribution of neuroprotective and antiinflammatory strategies for these disorders seems particularly desirable because isolated treatments cannot be effective.
In this contest, marijuana derivatives have attracted special interest, although these compounds have always raised several practical and ethical problems for their potential abuse.
Nevertheless, among Cannabis compounds, cannabidiol (CBD), which lacks any unwanted psychotropic effect, may represent a very promising agent with the highest prospect for therapeutic use.
Borrelli F, Aviello G, Romano B, Orlando P, Capasso R, Maiello F, Guadagno F, Petrosino S, Capasso F, Di Marzo V, Izzo AA
Cannabidiol, a safe and non-psychotropic ingredient of the marijuana plant Cannabis sativa, is protective in a murine model of colitis. [Journal Article]
J Mol Med 2009 Nov; 87(11):1111-21.
Inflammatory bowel disease affects millions of individuals; nevertheless, pharmacological treatment is disappointingly unsatisfactory. Cannabidiol, a safe and non-psychotropic ingredient of marijuana, exerts pharmacological effects (e.g., antioxidant) and mechanisms (e.g., inhibition of endocannabinoids enzymatic degradation) potentially beneficial for the inflamed gut.
Thus, we investigated the effect of cannabidiol in a murine model of colitis. Colitis was induced in mice by intracolonic administration of dinitrobenzene sulfonic acid. Inflammation was assessed both macroscopically and histologically.
In the inflamed colon, cyclooxygenase-2 and inducible nitric oxide synthase (iNOS) were evaluated by Western blot, interleukin-1beta and interleukin-10 by ELISA, and endocannabinoids by isotope dilution liquid chromatography-mass spectrometry.
Human colon adenocarcinoma (Caco-2) cells were used to evaluate the effect of cannabidiol on oxidative stress. Cannabidiol reduced colon injury, inducible iNOS (but not cyclooxygenase-2) expression, and interleukin-1beta, interleukin-10, and endocannabinoid changes associated with 2,4,6-dinitrobenzene sulfonic acid administration.
In Caco-2 cells, cannabidiol reduced reactive oxygen species production and lipid peroxidation. In conclusion, cannabidiol, a likely safe compound, prevents experimental colitis in mice.
Magen I, Avraham Y, Ackerman Z, Vorobiev L, Mechoulam R, Berry EM
Cannabidiol ameliorates cognitive and motor impairments in mice with bile duct ligation. [Journal Article, Research Support, Non-U.S. Gov't]
J Hepatol 2009 Sep; 51(3):528-34.
The endocannabinoid system in mice plays a role in models of human cirrhosis and hepatic encephalopathy (HE), induced by a hepatotoxin. We report now the therapeutic effects of cannabidiol (CBD), a non-psychoactive constituent of Cannabis sativa, on HE caused by bile duct ligation (BDL), a model of chronic liver disease.
CBD (5mg/kg; i.p.) was administered over 4weeks to mice that had undergone BDL.
Cognitive function in the eight arm maze and the T-maze tests, as well as locomotor function in the open field test were impaired by the ligation and were improved by CBD. BDL raised hippocampal expression of the TNF-alpha-receptor 1 gene, which was reduced by CBD. However, BDL reduced expression of the brain-derived neurotrophic factor (BDNF) gene, which was increased by CBD. The effects of CBD on cognition, locomotion and on TNF-alpha receptor 1 expression were blocked by ZM241385, an A(2)A adenosine receptor antagonist. BDL lowers the expression of this receptor.
CONCLUSIONS: The effects of BDL apparently result in part from down-regulation of A(2)A adenosine receptor. CBD reverses these effects through activation of this receptor, leading to compensation of the ligation effect.
Int J Neuropsychopharmacol. 2010 May;13(4):421-32. Epub 2009 Sep 24
Neuroimaging Section, Division of Psychological Medicine, Institute of Psychiatry, King's College London, UK. email@example.com
Cannabis sativa, the most widely used illicit drug, has profound effects on levels of anxiety in animals and humans.
Although recent studies have helped provide a better understanding of the neurofunctional correlates of these effects, indicating the involvement of the amygdala and cingulate cortex, their reciprocal influence is still mostly unknown.
In this study dynamic causal modelling (DCM) and Bayesian model selection (BMS) were used to explore the effects of pure compounds of C. sativa [600 mg of cannabidiol (CBD) and 10 mg Delta 9-tetrahydrocannabinol (Delta 9-THC)] on prefrontal-subcortical effective connectivity in 15 healthy subjects who underwent a double-blind randomized, placebo-controlled fMRI paradigm while viewing faces which elicited different levels of anxiety.
In the placebo condition, BMS identified a model with driving inputs entering via the anterior cingulate and forward intrinsic connectivity between the amygdala and the anterior cingulate as the best fit. CBD but not Delta 9-THC disrupted forward connectivity between these regions during the neural response to fearful faces.
This is the first study to show that the disruption of prefrontal-subocritical connectivity by CBD may represent neurophysiological correlates of its anxiolytic properties.
Trends Pharmacol Sci. 2009 Oct;30(10):515-27. Epub 2009 Sep 2.
Department of Experimental Pharmacology, University of Naples Federico II, Naples, Italy. firstname.lastname@example.org
Delta(9)-tetrahydrocannabinol binds cannabinoid (CB(1) and CB(2)) receptors, which are activated by endogenous compounds (endocannabinoids) and are involved in a wide range of physiopathological processes (e.g. modulation of neurotransmitter release, regulation of pain perception, and of cardiovascular, gastrointestinal and liver functions).
The well-known psychotropic effects of Delta(9)-tetrahydrocannabinol, which are mediated by activation of brain CB(1) receptors, have greatly limited its clinical use. However, the plant Cannabis contains many cannabinoids with weak or no psychoactivity that, therapeutically, might be more promising than Delta(9)-tetrahydrocannabinol. Here, we provide an overview of the recent pharmacological advances, novel mechanisms of action, and potential therapeutic applications of such non-psychotropic plant-derived cannabinoids.
Special emphasis is given to cannabidiol, the possible applications of which have recently emerged in inflammation, diabetes, cancer, affective and neurodegenerative diseases, and to Delta(9)-tetrahydrocannabivarin, a novel CB(1) antagonist which exerts potentially useful actions in the treatment of epilepsy and obesity.
|Title||Antidepressant-like effects of cannabidiol in mice: possible involvement of 5-HT1A receptors.|
|Author(s)||Zanelati TV, Biojone C, Moreira FA, Guimarães FS, Joca SR|
|Institution||Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.|
|Source||Br J Pharmacol 2010 Jan; 159(1):122-8.|
BACKGROUND AND PURPOSE: Cannabidiol (CBD) is a non-psychotomimetic compound from Cannabis sativa that induces anxiolytic- and antipsychotic-like effects in animal models. Effects of CBD may be mediated by the activation of 5-HT(1A) receptors. As 5-HT(1A) receptor activation may induce antidepressant-like effects, the aim of this work was to test the hypothesis that CBD would have antidepressant-like activity in mice as assessed by the forced swimming test.
We also investigated if these responses depended on the activation of 5-HT(1A) receptors and on hippocampal expression of brain-derived neurotrophic factor (BDNF). EXPERIMENTAL APPROACH: Male Swiss mice were given (i.p.) CBD (3, 10, 30, 100 mg*kg(-1)), imipramine (30 mg*kg(-1)) or vehicle and were submitted to the forced swimming test or to an open field arena, 30 min later.
An additional group received WAY100635 (0.1 mg*kg(-1), i.p.), a 5-HT(1A) receptor antagonist, before CBD (30 mg*kg(-1)) and assessment by the forced swimming test. BDNF protein levels were measured in the hippocampus of another group of mice treated with CBD (30 mg*kg(-1)) and submitted to the forced swimming test.
KEY RESULTS: CBD (30 mg*kg(-1)) treatment reduced immobility time in the forced swimming test, as did the prototype antidepressant imipramine, without changing exploratory behaviour in the open field arena. WAY100635 pretreatment blocked CBD-induced effect in the forced swimming test. CBD (30 mg*kg(-1)) treatment did not change hippocampal BDNF levels.
|Pub Type(s)||Comparative Study|
Research Support, Non-U.S. Gov't
|Title||Effects of cannabidiol on amphetamine-induced oxidative stress generation in an animal model of mania.|
|Author(s)||Valvassori SS, Elias G, de Souza B, Petronilho F, Dal-Pizzol F, Kapczinski F, Trzesniak C, Tumas V, Dursun S, Chagas MH, Hallak JE, Zuardi AW, Quevedo J, Crippa JA|
|Institution||Laboratório de Neurociências, Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense.|
|Source||J Psychopharmacol 2009 Nov 25.|
Cannabidiol (CBD), a Cannabis sativa constituent, may present a pharmacological profile similar to mood stabilizing drugs, in addition to anti-oxidative and neuroprotective properties.
The present study aims to directly investigate the effects of CBD in an animal model of mania induced by D-amphetamine (D-AMPH).
In the first model (reversal treatment), rats received saline or D-AMPH (2 mg/kg) once daily intraperitoneal (i.p.) for 14 days, and from the 8th to the 14th day, they were treated with saline or CBD (15, 30 or 60 mg/kg) i.p. twice a day. In the second model (prevention treatment), rats were pretreated with saline or CBD (15, 30, or 60 mg/kg) regime i.p. twice a day, and from the 8th to the 14th day, they also received saline or D-AMPH i.p. once daily.
In the hippocampus CBD (15 mg/kg) reversed the D-AMPH-induced damage and increased (30 mg/kg) brain-derived neurotrophic factor (BDNF) expression. In the second experiment, CBD (30 or 60 mg/kg) prevented the D-AMPH-induced formation of carbonyl group in the prefrontal cortex. In the hippocampus and striatum the D-AMPH-induced damage was prevented by CBD (15, 30 or 60 mg/kg).
At both treatments CBD did not present any effect against D-AMPH-induced hyperactivity. In conclusion, we could not observe effects on locomotion, but CBD protect against D-AMPH-induced oxidative protein damage and increased BDNF levels in the reversal model and these effects vary depending on the brain regions evaluated and doses of CBD administered.
|Title||Opposite effects of delta-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology.|
|Author(s)||Bhattacharyya S, Morrison PD, Fusar-Poli P, Martin-Santos R, Borgwardt S, Winton-Brown T, Nosarti C, O' Carroll CM, Seal M, Allen P, Mehta MA, Stone JM, Tunstall N, Giampietro V, Kapur S, Murray RM, Zuardi AW, Crippa JA, Atakan Z, McGuire PK|
|Institution||Section of Neuroimaging, Division of Psychological Medicine & Psychiatry, Institute of Psychiatry, King's College London, London, UK. email@example.com|
|Source||Neuropsychopharmacology 2010 Feb; 35(3):764-74.|
Delta-9-tetrahydrocannabinol (Delta-9-THC) and Cannabidiol (CBD), the two main ingredients of the Cannabis sativa plant have distinct symptomatic and behavioral effects.
We used functional magnetic resonance imaging (fMRI) in healthy volunteers to examine whether Delta-9-THC and CBD had opposite effects on regional brain function. We then assessed whether pretreatment with CBD can prevent the acute psychotic symptoms induced by Delta-9-THC.
Fifteen healthy men with minimal earlier exposure to cannabis were scanned while performing a verbal memory task, a response inhibition task, a sensory processing task, and when viewing fearful faces.
Subjects were scanned on three occasions, each preceded by oral administration of Delta-9-THC, CBD, or placebo. BOLD responses were measured using fMRI. In a second experiment, six healthy volunteers were administered Delta-9-THC intravenously on two occasions, after placebo or CBD pretreatment to examine whether CBD could block the psychotic symptoms induced by Delta-9-THC.
Delta-9-THC and CBD had opposite effects on activation relative to placebo in the striatum during verbal recall, in the hippocampus during the response inhibition task, in the amygdala when subjects viewed fearful faces, in the superior temporal cortex when subjects listened to speech, and in the occipital cortex during visual processing.
In the second experiment, pretreatment with CBD prevented the acute induction of psychotic symptoms by Delta-9-tetrahydrocannabinol.
Delta-9-THC and CBD can have opposite effects on regional brain function, which may underlie their different symptomatic and behavioral effects, and CBD's ability to block the psychotogenic effects of Delta-9-THC.
Brazilian researchers from prestigious University of São Paulo (USP) have discovered that marijuana contains substances that can help ease the collateral effects of medicines prescribed to patients suffering from Parkinson disease.
Six patients with Parkinson were given during a whole month small doses of Cannabidiol (CBD) one of the 400 substances in marijuana, following which encouraging results were confirmed according to scientists from the Ribeirão Preto Medicine School from the SP University.
"Patients with Parkinson developed improvements in their sleeping alterations, in their psychotic symptoms and could even reduce their trembling," said psychiatrist Jose Alexander Crippa, Neuro-sciences Department professor.
The paper on the discovery was published last November and an additional paper with test results on the anxiolytic effects of Cannabidiol in patients with obsession and compulsion disorders will be released in 2010.
A group of voluntary patients with obsessive and compulsive conducts were medicated with the substance 70 minutes before facing situations that forced them into anxiety fits, and "improvements were evident."
Crippa underlined the significance of the research which scientifically establishes the positive effects of Cannabidiol but warned that "the non therapeutic use of marijuana was not recommended since it could only lead to worsen the psychotic symptoms and consequences of patients."
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Source: Brazzil Mag
Contact: Brazzil Mag
Copyright: 2010 Brazzil Mag
Website: Brazilian Scientists Show How Marijuana Can Help in Treating Parkinson
Wednesday, December 30th 2009
Brazilian researchers have tested the positive effects of canabiodiol
Researchers from Brazil’s prestigious University of Sao Paulo have discovered that marihuana contains substances which can help ease the collateral effects of medicines prescribed to patients suffering from Parkinson disease.
Six patients with Parkinson were given during a whole month small doses of “canabiodiol” one of the 400 substances in marihuana, following which encouraging results were confirmed according to scientists from the Riberao Preto Medicine School from the SP University.
“Patients with Parkinson developed improvements in their sleeping alterations, in their psychotic symptoms and could even reduce their trembling” said psychiatrist Jose Alexander Crippa, Neuro-sciences Department professor.
The paper on the discovery was published last November and next year an additional paper with test results on the anxiolytic effects of “canabiodiol” in patients with obsession and compulsion disorders will be released.
A group of voluntary patients with obsessive and compulsive conducts were medicated with the substance 70 minutes before facing situations that forced them into anxiety fits, and “improvements were evident”.
Crippa underlined the significance of the research which scientifically establishes the positive effects of “canabiodiol” but warned that “the non therapeutic use of marihuana was not recommended since it could only lead to worsen the psychotic symptoms and consequences of patients”.