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Effect of cannabidiolic acid and ∆9-tetrahydrocannabinol on carrageenan-induced hyperalgesia and edema in a rodent model of inflammatory pain

DOI:10.1007/s00213-018-5034-1
Authors:
Erin M Rock at University of Guelph
Erin M Rock
Cheryl L. Limebeer
Cheryl L. Limebeer
Cheryl L. Limebeer
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Linda A. Parker
Linda A. Parker
Linda A. Parker
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Abstract and Figures

Rationale Cannabidiol (CBD), a non-intoxicating component of cannabis, or the psychoactive Δ⁹-tetrahydrocannabiol (THC), shows anti-hyperalgesia and anti-inflammatory properties. Objectives The present study evaluates the anti-inflammatory and anti-hyperalgesia effects of CBD’s potent acidic precursor, cannabidiolic acid (CBDA), in a rodent model of carrageenan-induced acute inflammation in the rat hind paw, when administered systemically (intraperitoneal, i.p.) or orally before and/or after carrageenan. In addition, we assess the effects of oral administration of THC or CBDA, their mechanism of action, and the efficacy of combined ineffective doses of THC and CBDA in this model. Finally, we compare the efficacy of CBD and CBDA. Results CBDA given i.p. 60 min prior to carrageenan (but not 60 min after carrageenan) produced dose-dependent anti-hyperalgesia and anti-inflammatory effects. In addition, THC or CBDA given by oral gavage 60 min prior to carrageenan produced anti-hyperalgesia effects, and THC reduced inflammation. The anti-hyperalgesia effects of THC were blocked by SR141716 (a cannabinoid 1 receptor antagonist), while CBDA’s effects were blocked by AMG9810 (a transient receptor potential cation channel subfamily V member 1 antagonist). In comparison to CBDA, an equivalent low dose of CBD did not reduce hyperalgesia, suggesting that CBDA is more potent than CBD for this indication. Interestingly, when ineffective doses of CBDA or THC alone were combined, this combination produced an anti-hyperalgesia effect and reduced inflammation. Conclusion CBDA or THC alone, as well as very low doses of combined CBDA and THC, has anti-inflammatory and anti-hyperalgesia effects in this animal model of acute inflammation.
Effect of VEH or CBDA (10, 1000 μg/kg, i.p.) on paw withdrawal latency (s) at 180 (a) or 360 min (b) after carrageenan and paw thickness at 360 min after carrageenan (c), when administered 60 min pre-carrageenan (n = 8/group). The mean (± S.E.M.) difference in paw withdrawal latency from baseline for each paw treatment was measured. The mean (± S.E.M.) difference in paw thickness (mm; ipsilateral paw thickness at each time interval minus baseline paw thickness) for each paw treatment was measured. The asterisks indicate a significant difference from the VEH-I group (**p < 0.01; *p < 0.05)
Effect of VEH or CBDA (10, 1000 μg/kg, i.p.) on paw withdrawal latency (s) at 180 (a) or 360 min (b) after carrageenan and paw thickness at 360 min after carrageenan (c), when administered 60 min pre-carrageenan (n = 8/group). The mean (± S.E.M.) difference in paw withdrawal latency from baseline for each paw treatment was measured. The mean (± S.E.M.) difference in paw thickness (mm; ipsilateral paw thickness at each time interval minus baseline paw thickness) for each paw treatment was measured. The asterisks indicate a significant difference from the VEH-I group (**p < 0.01; *p < 0.05)
… 
Effect of VEH or CBDA (10, 1000 μg/kg, i.p.) on paw withdrawal latency (s) at 180 (a) or 360 min (b) after carrageenan and paw thickness at 360 min after carrageenan (c) when administered 60 min post-carrageenan (n = 8/group). The mean (± S.E.M.) difference in paw withdrawal latencies from baseline for each paw treatment was measured. The mean (± S.E.M.) difference in paw thickness (mm; ipsilateral paw thickness at each time interval minus baseline paw thickness) for each paw treatment was measured
Effect of VEH or CBDA (10, 1000 μg/kg, i.p.) on paw withdrawal latency (s) at 180 (a) or 360 min (b) after carrageenan and paw thickness at 360 min after carrageenan (c) when administered 60 min post-carrageenan (n = 8/group). The mean (± S.E.M.) difference in paw withdrawal latencies from baseline for each paw treatment was measured. The mean (± S.E.M.) difference in paw thickness (mm; ipsilateral paw thickness at each time interval minus baseline paw thickness) for each paw treatment was measured
… 
Effect of CBDA (1, 10, 100, 1000 μg/kg, oral gavage), THC (1000 μg/kg, oral gavage) or VEH on paw withdrawal latency (s) at 180 (a) 360 min (b) after carrageenan and paw thickness at 180 (c) and 360 min (d) after carrageenan, when administered 60 min pre-carrageenan (n = 8/group). The mean (± S.E.M.) difference in paw withdrawal latencies from baseline for each paw treatment was measured at 30, 60, 180, and 360 min following carrageenan treatment. The mean (± S.E.M.) difference in paw thickness (mm; ipsilateral paw thickness at each time interval minus baseline paw thickness) for each paw treatment was measured. The asterisks indicate a significant difference from the VEH-I group (**p < 0.01; *p < 0.05)
Effect of CBDA (1, 10, 100, 1000 μg/kg, oral gavage), THC (1000 μg/kg, oral gavage) or VEH on paw withdrawal latency (s) at 180 (a) 360 min (b) after carrageenan and paw thickness at 180 (c) and 360 min (d) after carrageenan, when administered 60 min pre-carrageenan (n = 8/group). The mean (± S.E.M.) difference in paw withdrawal latencies from baseline for each paw treatment was measured at 30, 60, 180, and 360 min following carrageenan treatment. The mean (± S.E.M.) difference in paw thickness (mm; ipsilateral paw thickness at each time interval minus baseline paw thickness) for each paw treatment was measured. The asterisks indicate a significant difference from the VEH-I group (**p < 0.01; *p < 0.05)
… 
Effect of CBDA (0.1 μg/kg, oral gavage), THC (100 μg/kg, oral gavage), their combination, or VEH on paw withdrawal latency (s) at 30 (a), 60 (b), 180 (c), or 360 min (d) after carrageenan and paw thickness at 0 (e), 180 (f), or 360 min (g) after carrageenan, when administered 60 min pre-carrageenan (n = 8/group). The mean (± S.E.M.) difference in paw withdrawal latencies from baseline for each paw treatment was measured. The mean (± S.E.M.) difference in paw thickness (mm; ipsilateral paw thickness at each time interval minus baseline paw thickness) for each paw treatment was measured. The asterisks indicate a significant difference from the VEH-I group (***p ≤ 0.001; **p < 0.01; *p < 0.05)
Effect of CBDA (0.1 μg/kg, oral gavage), THC (100 μg/kg, oral gavage), their combination, or VEH on paw withdrawal latency (s) at 30 (a), 60 (b), 180 (c), or 360 min (d) after carrageenan and paw thickness at 0 (e), 180 (f), or 360 min (g) after carrageenan, when administered 60 min pre-carrageenan (n = 8/group). The mean (± S.E.M.) difference in paw withdrawal latencies from baseline for each paw treatment was measured. The mean (± S.E.M.) difference in paw thickness (mm; ipsilateral paw thickness at each time interval minus baseline paw thickness) for each paw treatment was measured. The asterisks indicate a significant difference from the VEH-I group (***p ≤ 0.001; **p < 0.01; *p < 0.05)
… 
Effect of CBDA (100 μg/kg, oral gavage) alone and in combination with AMG (1 mg/kg, i.p.), and THC (1000 μg/kg, oral gavage) alone and in combination with SR (1 mg/kg, i.p.) on paw withdrawal latency (s) at 360 (a) after carrageenan and paw thickness at 360 min (b) after carrageenan (n = 8/group). The mean (± S.E.M.) difference in paw withdrawal latencies from baseline for each paw treatment was measured. The mean (± S.E.M.) difference in paw thickness (mm; ipsilateral paw thickness at each time interval minus baseline paw thickness) for each paw treatment was measured. The asterisks indicate a significant difference from the VEH-I group (**p < 0.01; *p < 0.05). The pound sign indicates a significant difference from the 100 CBDA-I group (p < 0.05). The ampersand indicates a significant difference from the 1000 THC-I group (p < 0.05)
+1
Effect of CBDA (100 μg/kg, oral gavage) alone and in combination with AMG (1 mg/kg, i.p.), and THC (1000 μg/kg, oral gavage) alone and in combination with SR (1 mg/kg, i.p.) on paw withdrawal latency (s) at 360 (a) after carrageenan and paw thickness at 360 min (b) after carrageenan (n = 8/group). The mean (± S.E.M.) difference in paw withdrawal latencies from baseline for each paw treatment was measured. The mean (± S.E.M.) difference in paw thickness (mm; ipsilateral paw thickness at each time interval minus baseline paw thickness) for each paw treatment was measured. The asterisks indicate a significant difference from the VEH-I group (**p < 0.01; *p < 0.05). The pound sign indicates a significant difference from the 100 CBDA-I group (p < 0.05). The ampersand indicates a significant difference from the 1000 THC-I group (p < 0.05)
… 
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ORIGINAL INVESTIGATION
Effect of cannabidiolic acid and Δ
9
-tetrahydrocannabinol
on carrageenan-induced hyperalgesia and edema in a rodent model
of inflammatory pain
Erin M. Rock
1
&Cheryl L. Limebeer
1
&Linda A. Parker
1
Received: 16 January 2018 /Accepted: 7 September 2018 /Published online: 17 September 2018
#Springer-Verlag GmbH Germany, part of Springer Nature 2018
Abstract
Rationale
Cannabidiol (CBD), a non-intoxicating component of cannabis, or the psychoactive Δ
9
-tetrahydrocannabiol (THC), shows anti-
hyperalgesia and anti-inflammatory properties.
Objectives
The present study evaluates the anti-inflammatory and anti-hyperalgesia effects of CBD’s potent acidic precursor, cannabidiolic
acid (CBDA), in a rodent model of carrageenan-induced acute inflammation in the rat hind paw, when administered systemically
(intraperitoneal, i.p.) or orally before and/or after carrageenan. In addition, we assess the effects of oral administration of THC or
CBDA, their mechanism of action, and the efficacy of combined ineffective doses of THC and CBDA in this model. Finally, we
compare the efficacy of CBD and CBDA.
Results
CBDA given i.p. 60 min prior to carrageenan (but not 60 min after carrageenan) produced dose-dependent anti-hyperalgesia and
anti-inflammatory effects. In addition, THC or CBDA given by oral gavage 60 min prior to carrageenan produced anti-
hyperalgesia effects, and THC reduced inflammation. The anti-hyperalgesia effects of THC were blocked by SR141716 (a
cannabinoid 1 receptor antagonist), while CBDA’s effects were blocked by AMG9810 (a transient receptor potential cation
channel subfamily V member 1 antagonist). In comparison to CBDA, an equivalent low dose of CBD did not reduce
hyperalgesia, suggesting that CBDA is more potent than CBD for this indication. Interestingly, when ineffective doses of
CBDA or THC alone were combined, this combination produced an anti-hyperalgesia effect and reduced inflammation.
Conclusion
CBDA or THC alone, as well as very low doses of combined CBDA and THC, has anti-inflammatory and anti-hyperalgesia
effects in this animal model of acute inflammation.
Keywords Inflammation .Hyperalgesia .Δ
9
-Tetrahydrocannabiol .Cannabidiolic acid .Cannabidiol .Rat .Carrageenan .
SR141716 .AMG9810
Introduction
Cannabis sativa has been used medicinally for centuries. The
cannabis plant consists of over 100 cannabinoid compounds,
the primary ones being the psychoactive component Δ
9
-tetra-
hydrocannabinol (THC), and the non-intoxicating component
cannabidiol (CBD). The most frequently reported use of med-
ical cannabis is for pain relief (e.g., Ogborne et al. 2000;
*Linda A. Parker
parkerl@uoguelph.ca
1
Department of Psychology and Collaborative Neuroscience
Program, University of Guelph, Guelph, ON N1G2W1, Canada
Psychopharmacology (2018) 235:3259–3271
https://doi.org/10.1007/s00213-018-5034-1
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
... Carrageenan is used in the induction of inflammation due to its ability to cause the release of inflammatory mediators (Solanki et al., 2015). Carrageenan-induced inflammation is manifested in three phases (Rock et al., 2018). In the first phase (the first 90 minutes), histamine and serotonin are released, in the second phase (the first 90-150 minutes), kinins are released, while in the third phase (after 180 minutes), prostaglandins are released after the intraperitoneal administration of carrageenan (Rock et al., 2018). ...
... Carrageenan-induced inflammation is manifested in three phases (Rock et al., 2018). In the first phase (the first 90 minutes), histamine and serotonin are released, in the second phase (the first 90-150 minutes), kinins are released, while in the third phase (after 180 minutes), prostaglandins are released after the intraperitoneal administration of carrageenan (Rock et al., 2018). Both steroidal and non-steroidal anti-inflammatory drugs show greater effect on the second phase than first phase since prostaglandins are the most suspected chemicals for inflammation (Patil et al., 2012 andKumari et al., 2013). ...
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Patterns of medicinal cannabis use, strain analysis, and substitution effect among patients with migraine, headache, arthritis, and chronic pain in a medicinal cannabis cohort
Article
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Background Medicinal cannabis registries typically report pain as the most common reason for use. It would be clinically useful to identify patterns of cannabis treatment in migraine and headache, as compared to arthritis and chronic pain, and to analyze preferred cannabis strains, biochemical profiles, and prescription medication substitutions with cannabis. Methods Via electronic survey in medicinal cannabis patients with headache, arthritis, and chronic pain, demographics and patterns of cannabis use including methods, frequency, quantity, preferred strains, cannabinoid and terpene profiles, and prescription substitutions were recorded. Cannabis use for migraine among headache patients was assessed via the ID Migraine™ questionnaire, a validated screen used to predict the probability of migraine. Results Of 2032 patients, 21 illnesses were treated with cannabis. Pain syndromes accounted for 42.4% (n = 861) overall; chronic pain 29.4% (n = 598;), arthritis 9.3% (n = 188), and headache 3.7% (n = 75;). Across all 21 illnesses, headache was a symptom treated with cannabis in 24.9% (n = 505). These patients were given the ID Migraine™ questionnaire, with 68% (n = 343) giving 3 “Yes” responses, 20% (n = 102) giving 2 “Yes” responses (97% and 93% probability of migraine, respectively). Therefore, 88% (n = 445) of headache patients were treating probable migraine with cannabis. Hybrid strains were most preferred across all pain subtypes, with “OG Shark” the most preferred strain in the ID Migraine™ and headache groups. Many pain patients substituted prescription medications with cannabis (41.2–59.5%), most commonly opiates/opioids (40.5–72.8%). Prescription substitution in headache patients included opiates/opioids (43.4%), anti-depressant/anti-anxiety (39%), NSAIDs (21%), triptans (8.1%), anti-convulsants (7.7%), muscle relaxers (7%), ergots (0.4%). Conclusions Chronic pain was the most common reason for cannabis use, consistent with most registries. The majority of headache patients treating with cannabis were positive for migraine. Hybrid strains were preferred in ID Migraine™, headache, and most pain groups, with “OG Shark”, a high THC (Δ9-tetrahydrocannabinol)/THCA (tetrahydrocannabinolic acid), low CBD (cannabidiol)/CBDA (cannabidiolic acid), strain with predominant terpenes β-caryophyllene and β-myrcene, most preferred in the headache and ID Migraine™ groups. This could reflect the potent analgesic, anti-inflammatory, and anti-emetic properties of THC, with anti-inflammatory and analgesic properties of β-caryophyllene and β-myrcene. Opiates/opioids were most commonly substituted with cannabis. Prospective studies are needed, but results may provide early insight into optimizing crossbred cannabis strains, synergistic biochemical profiles, dosing, and patterns of use in the treatment of headache, migraine, and chronic pain syndromes.
Pharmacokinetic and behavioural profile of THC, CBD, and THC+CBD combination after pulmonary, oral, and subcutaneous administration in rats and confirmation of conversion in vivo of CBD to THC
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Metabolic and behavioural effects of, and interactions between Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are influenced by dose and administration route. Therefore we investigated, in Wistar rats, effects of pulmonary, oral and subcutaneous (sc.) THC, CBD and THC+CBD. Concentrations of THC, its metabolites 11-OH-THC and THC-COOH, and CBD in serum and brain were determined over 24 h, locomotor activity (open field) and sensorimotor gating (prepulse inhibition, PPI) were also evaluated. In line with recent knowledge we expected metabolic and behavioural interactions between THC and CBD. While cannabinoid serum and brain levels rapidly peaked and diminished after pulmonary administration, sc. and oral administration produced long-lasting levels of cannabinoids with oral reaching the highest brain levels. Except pulmonary administration, CBD inhibited THC metabolism resulting in higher serum/brain levels of THC. Importantly, following sc. and oral CBD alone treatments, THC was also detected in serum and brain. S.c. cannabinoids caused hypolocomotion, oral treatments containing THC almost complete immobility. In contrast, oral CBD produced mild hyperlocomotion. CBD disrupted, and THC tended to disrupt PPI, however their combination did not. In conclusion, oral administration yielded the most pronounced behavioural effects which corresponded to the highest brain levels of cannabinoids. Even though CBD potently inhibited THC metabolism after oral and sc. administration, unexpectedly it had minimal impact on THC-induced behaviour. Of central importance was the novel finding that THC can be detected in serum and brain after administration of CBD alone which, given the increasing medical use of CBD-only products, has important legal and forensic ramifications.
Cannabis constituent synergy in a mouse neuropathic pain model
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Cannabis and its psychoactive constituent Δ9-tetrahydrocannabinol (THC) have efficacy against neuropathic pain however, this is hampered by their side-effects. It has been suggested that co-administration with another major constituent cannabidiol (CBD) might enhance the analgesic actions of THC and minimise its deleterious side-effects. We examined the basis for this phytocannabinoid interaction in a mouse chronic constriction injury (CCI) model of neuropathic pain. Acute systemic administration of THC dose-dependently reduced CCI-induced mechanical and cold allodynia, but also produced motor incoordination, catalepsy and sedation. CBD produced a lesser dose-dependent reduction in allodynia, but did not produce the cannabinoid side-effects. When co-administered in a fixed ratio, THC and CBD produced a biphasic dose-dependent reduction in allodynia. At low doses, the THC:CBD combination displayed a 200-fold increase in anti-allodynic potency, but had lower efficacy compared to that predicted for an additive drug interaction. By contrast, high THC:CBD doses had lower potency, but greater anti-allodynic efficacy compared to that predicted for an additive interaction. Only the high dose THC:CBD anti-allodynia was associated with cannabinoid side-effects and these were similar to those of THC alone. Unlike THC, the low dose THC:CBD anti-allodynia was not cannabinoid receptor mediated. These findings demonstrate that CBD synergistically enhances the pain relieving actions of THC in an animal neuropathic pain model, but has little impact on the THC-induced side-effects. This suggests that low dose THC:CBD combination treatment has potential in the treatment of neuropathic pain.
Quantitative Determination of Δ9-THC, CBG, CBD, Their Acid Precursors and Five Other Neutral Cannabinoids by UHPLC-UV-MS
Article
  • Dec 2017
Cannabinoids are a group of terpenophenolic compounds in the medicinal plant Cannabis sativa (Cannabaceae family). Cannabigerolic acid, Δ9-tetrahydrocannabinolic acid A, cannabidiolic acid, Δ9-tetrahydrocannabinol, cannabigerol, cannabidiol, cannabichromene, and tetrahydrocannabivarin are major metabolites in the classification of different strains of C. sativa. Degradation or artifact cannabinoids cannabinol, cannabicyclol, and Δ8-tetrahydrocannabinol are formed under the influence of heat and light during processing and storage of the plant sample. An ultrahigh-performance liquid chromatographic method coupled with photodiode array and single quadruple mass spectrometry detectors was developed and validated for quantitative determination of 11 cannabinoids in different C. sativa samples. Compounds 1 – 11 were baseline separated with an acetonitrile (with 0.05% formic acid) and water (with 0.05% formic acid) gradient at a flow rate of 0.25 mL/min on a Waters Cortec UPLC C18 column (100 mm × 2.1 mm I. D., 1.6 µm). The limits of detection and limits of quantitation of the 11 cannabinoids were below 0.2 and 0.5 µg/mL, respectively. The relative standard deviation for the precision test was below 2.4%. A mixture of acetonitrile and methanol (80 : 20, v/v) was proven to be the best solvent system for the sample preparation. The recovery of all analytes was in the range of 97 – 105%. A total of 32 Cannabis samples including hashish, leaves, and flower buds were analyzed.
Determination of Acid and Neutral Cannabinoids in Extracts of Different Strains of Cannabis sativa Using GC-FID
Article
  • Dec 2017
Cannabis (Cannabis sativa L.) is an annual herbaceous plant that belongs to the family Cannabaceae. Trans-Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) are the two major phytocannabinoids accounting for over 40% of the cannabis plant extracts, depending on the variety. At the University of Mississippi, different strains of C. sativa, with different concentration ratios of CBD and Δ9-THC, have been tissue cultured via micropropagation and cultivated. A GC-FID method has been developed and validated for the qualitative and quantitative analysis of acid and neutral cannabinoids in C. sativa extracts. The method involves trimethyl silyl derivatization of the extracts. These cannabinoids include tetrahydrocannabivarian, CBD, cannabichromene, trans-Δ8-tetrahydrocannabinol, Δ9-THC, cannabigerol, cannabinol, cannabidiolic acid, cannabigerolic acid, and Δ9-tetrahydrocannabinolic acid-A. The concentration-response relationship of the method indicated a linear relationship between the concentration and peak area ratio with R2 > 0.999 for all 10 cannabinoids. The precision and accuracy of the method were found to be ≤ 15% and ± 5%, respectively. The limit of detection range was 0.11 – 0.19 µg/mL, and the limit of quantitation was 0.34 – 0.56 µg/mL for all 10 cannabinoids. The developed method is simple, sensitive, reproducible, and suitable for the detection and quantitation of acidic and neutral cannabinoids in different extracts of cannabis varieties. The method was applied to the analysis of these cannabinoids in different parts of the micropropagated cannabis plants (buds, leaves, roots, and stems).
Effects of Sex and Stress on Trigeminal Neuropathic Pain-Like Behavior in Rats
Article
  • Oct 2017
Aims: To investigate the effects and interactions of sex and stress (provoked by chronic restraint [RS]) on pain-like behavior in a rat model of trigeminal neuropathic pain. Methods: The effects of sex and RS (carried out for 14 days as a model for stress) on somatosensory measures (reaction to pinprick, von Frey threshold) in a rat model of trigeminal neuropathic pain were examined. The study design was 2 × 4, with surgery (pain) and sham surgery (no pain) interacting with male restrained (RS) and unrestrained (nRS) rats and female RS and nRS rats. A total of 64 Sprague Dawley rats (32 males and 32 females) were used. Half of the animals in each sex group underwent RS, and the remaining half were left unstressed. Following the RS period, trigeminal neuropathic pain was induced by unilateral infraorbital nerve chronic constriction injury (IOCCI). Half of the animals in the RS group and half in the nRS group (both males and females) were exposed to IOCCI, and the remaining halves to sham surgery. Elevated plus maze (EPM) assessment and plasma interferon gamma (IFN-γ) levels were used to measure the effects of RS. Analysis of variance (ANOVA) was used to assess the effects of stress, sex, and their interactions on plasma IFN-γ levels, changes in body weight, EPM parameters, tactile allodynia, and mechanohyperalgesia. Pairwise comparisons were performed by using Tukey post hoc test corrected for multiple comparisons. Results: Both male and female RS rats showed significantly altered exploratory behavior (as measured by EPM) and had significantly lower plasma IFN-γ levels than nRS rats. Rats exposed to RS gained weight significantly slower than the nRS rats, irrespective of sex. Following RS but before surgery, RS rats showed significant bilateral reductions in von Frey thresholds and significantly increased pinprick response difference scores compared to nRS rats, irrespective of sex. From 17 days postsurgery, RSIOCCI rats showed significantly reduced von Frey thresholds and significantly increased pinprick response difference scores compared to nRS-IOCCI rats, and the von Frey thresholds were significantly lower in females than in males. RS-sham females-but not RS-sham males-developed persistently reduced thresholds and increased pinprick response difference scores. Conclusion: RS produced an increased bilateral sensitivity to stimuli applied to the vibrissal pad following infraorbital nerve injury, irrespective of sex. This observed sensitivity subsequently persisted in RS-sham female rats but not in RS-sham male rats. Stress induced a significant but moderate increase in pain-like behavior in female rats compared to male rats. RS had no significant sex effects on IFN-γ levels, EPM parameters, or body weight gain. This suggests that stress may have a selective effect on pain-like behavior in both sexes, but the possible mechanisms are unclear.
Cannabinoids concentration variability in cannabis olive oil galenic preparations
Article
  • Oct 2017
Objectives: Knowledge of the exact concentration of active compounds in galenic preparations is crucial to be able to ensure their quality and to properly administer the prescribed dose. Currently, the need for titration of extracts is still debated. Considering this, together with the absence of a standard preparation method, the aim of this study was to evaluate cannabinoids concentrations variability in galenic olive oil extracts, to evaluate the interlot and interlaboratory variability in the extraction yield and in the preparation composition. Methods: Two hundred and one extracts (123 (61.2%) from Bedrocan(®) , 54 (26.9%) from Bediol(®) , 11 (5.5%) from Bedrolite(®) , and 13 (6.5%) from mixed preparations) were analysed by liquid chromatography coupled with tandem mass spectrometry, quantifying cannabinoids (THC, CBD, THCA, CBDA and CBN) concentrations. Key findings: The RSD% of THC and CBD concentrations resulted higher than 50%. Specifically for Bedrocan(®) , Bediol(®) , Bedrolite(®) (5 g/50 ml), these were THC 82%, THC 53% and CBD 91%, THC 58% and CBD 59%, respectively. The median extraction yields were greater than 75% for all preparations. Conclusions: Our results highlighted a wide variability in THC and CBD concentrations that justify the need for titration and opens further questions about other pharmaceutical preparations without regulatory indication for this procedure.
Current evidence of cannabinoid-based analgesia obtained in preclinical and human experimental settings
Article
  • Oct 2017
Significance: Cannabinoids consistently produced antinociceptive effects in preclinical models, whereas they heterogeneously influenced the perception of experimentally induced pain in humans and did not provide robust clinical analgesia, which jeopardizes the translation of preclinical research on cannabinoid-mediated antinociception into the human setting.
Clinical and Pre-Clinical Evidence for Functional Interactions of Cannabidiol and Δ(9)-Tetrahydrocannabinol
Article
The plant Cannabis sativa, commonly called cannabis or marijuana, has been used for its psychotropic and mind-altering side effects for millennia. There has been growing attention in recent years on its potential therapeutic efficacy as municipalities and legislative bodies in the United States, Canada, and other countries grapple with enacting policy to facilitate the use of cannabis or its constituents for medical purposes. There are over 550 chemical compounds and over 100 phytocannabinoids isolated from cannabis, including Δ(9)-tetrahydrocannabinol (THC) and Cannabidiol (CBD). THC is thought to produce the main psychoactive effects of cannabis, while CBD does not appear to have similar effects. Studies conflict as to whether CBD attenuates or exacerbates the behavioral and cognitive effects of THC. This includes effects of CBD on THC induced anxiety, psychosis and cognitive deficits. In this article, we review the available evidence on the pharmacology and behavioral interactions of THC and CBD from pre-clinical and human studies particularly with reference to anxiety and psychosis like symptoms. Both THC and CBD, as well as other cannabinoid molecules, are currently being evaluated for medicinal purposes, separately and in combination. Future cannabis-related policy decisions should include consideration of scientific findings including the individual and interactive effects of CBD and THC.Neuropsychopharmacology accepted article preview online, 06 September 2017. doi:10.1038/npp.2017.209.