Medicinal cannabis: is delta9-tetrahydrocannabinol necessary for all its effects?

Cannabis is under clinical investigation to assess its potential for medicinal use, but the question arises as to whether there is any advantage in using cannabis extracts compared with isolated Delta9-trans-tetrahydrocannabinol (Delta9THC), the major psychoactive component. We have compared the effect of a standardized cannabis extract (SCE) with pure Delta9THC, at matched concentrations of Delta9THC, and also with a Delta9THC-free extract (Delta9THC-free SCE), using two cannabinoid-sensitive models, a mouse model of multiple sclerosis (MS), and an in-vitro rat brain slice model of epilepsy. Whilst SCE inhibited spasticity in the mouse model of MS to a comparable level, it caused a more rapid onset of muscle relaxation, and a reduction in the time to maximum effect compared with Delta9THC alone. The Delta9THC-free extract or cannabidiol (CBD) caused no inhibition of spasticity. However, in the in-vitro epilepsy model, in which sustained epileptiform seizures were induced by the muscarinic receptor agonist oxotremorine-M in immature rat piriform cortical brain slices, SCE was a more potent and again more rapidly-acting anticonvulsant than isolated Delta9THC, but in this model, the Delta9THC-free extract also exhibited anticonvulsant activity. Cannabidiol did not inhibit seizures, nor did it modulate the activity of Delta9THC in this model. Therefore, as far as some actions of cannabis were concerned (e.g. antispasticity), Delta9THC was the active constituent, which might be modified by the presence of other components. However, for other effects (e.g. anticonvulsant properties) Delta9THC, although active, might not be necessary for the observed effect. Above all, these results demonstrated that not all of the therapeutic actions of cannabis herb might be due to the Delta9THC content

Cannabis constituents modulate ∆9-tetrahydrocannabinol-induced hyperphagia in rats

Rationale The hyperphagic effect of ∆9-tetrahydrocannabinol (∆9THC) in humans and rodents is well known. However, no studies have investigated the importance of ∆9THC composition and any influence other non-∆9THC cannabinoids present in Cannabis sativa may have. We therefore compared the effects of purified ∆9THC, synthetic ∆9THC (dronabinol), and ∆9THC botanical drug substance (∆9THC-BDS), a ∆9THC-rich standardized extract comparable in composition to recreationally used cannabis. Methods Adult male rats were orally dosed with purified ∆9THC, synthetic ∆9THC, or ∆9THC-BDS, matched for ∆9THC content (0.34–2.68 mg/kg). Prior to dosing, subjects were satiated, and food intake was recorded following ∆9THC administration. Data were then analyzed in terms of hourly intake and meal patterns. Results All three ∆9THC substances tested induced significant hyperphagic effects at doses ≥0.67 mg/kg. These effects included increased intake during hour one, a shorter latency to onset of feeding and a greater duration and consumption in the first meal. However, while some differences in vehicle control intakes were observed, there were significant, albeit subtle, differences in pattern of effects between the purified ∆9THC and ∆9THC-BDS. Conclusion All ∆9THC compounds displayed classical ∆9THC effects on feeding, significantly increasing short-term intake whilst decreasing latency to the first meal. We propose that the subtle adjustment to the meal patterns seen between the purified ∆9THC and ∆9THC-BDS are due to non-∆9THC cannabinoids present in ∆9THC-BDS. These compounds and other non-cannabinoids have an emerging and diverse pharmacology and can modulate ∆9THC-induced hyperphagia, making them worth further investigation for their therapeutic potential.

Cannabinoid influences on palatability: microstructural analysis of sucrose drinking after Delta(9)-tetrahydrocannabinol, anandamide, 2-arachidonoyl glycerol and SR141716

Rationale: Central cannabinoid systems have been implicated in appetite control through the respective hyperphagic and anorectic actions of CB1 agonists and antagonists. The motivational changes underlying these actions remain to be determined, but may involve alterations to food palatability. Objectives: The mode of action of cannabinoids on ingestion was investigated by examining the effects of exogenous and endogenous agonists, and a selective CB1 receptor antagonist, on licking microstructure in rats ingesting a palatable sucrose solution. Methods: Microstructural analyses of licking for a 10% sucrose solution was performed over a range of agonist and antagonist doses administered to non-deprived, male Lister hooded rats. Results: Delta(9)-tetrahydrocannabinol (0.5, 1 and 3 mg/kg) and anandamide (1 mg/kg and 3 mg/kg) significantly increased total number of licks. This was primarily due to an increase in bout duration rather than bout number. There was a nonsignificant increase in total licks following administration of 2-arachidonoyl glycerol (0.2, 1.0 and 2.0 mg/kg), whereas administration of the CB1 antagonist SR141716 (1 mg/kg and 3 mg/kg) significantly decreased total licks. All drugs, with the exception of anandamide, significantly decreased the intra-bout lick rate. An exponential function fitted to the cumulative lick rate curves for each drug revealed that all compounds altered the asymptote of this function without having any marked effects on the exponent. Conclusions: These data are consistent with endocannabinoid involvement in the mediation of food palatability.

A low delta-9-tetrahydrocannabinol cannabis extract induces hyperphagia in rats

Appetite stimulation via partial agonism of cannabinoid type 1 receptors by Δ9tetrahydrocannabinol (Δ9THC) is well documented and can be modulated by non-Δ9THC phytocannabinoids. Δ9THC concentrations sufficient to elicit hyperphagia induce changes to both appetitive (reduced latency to feed) and consummatory (increased meal one size and duration) behaviours. Here, we show that a cannabis extract containing too little Δ9THC to stimulate appetite can induce hyperphagia solely by increasing appetitive behaviours. Twelve, male Lister hooded rats were presatiated before treatment with a low-Δ9THC cannabis extract (0.5, 1.0, 2.0 and 4.0 mg/kg). Hourly intake and meal pattern data were recorded and analyzed using one-way analyses of variance followed by Bonferroni post-hoc tests. The cannabis extract significantly increased food intake during the first hour of testing (at 4.0 mg/kg) and significantly reduced the latency to feed versus vehicle treatments (at doses ≥1.0 mg/kg). Meal size and duration were unaffected. These results show only the increase in appetitive behaviours, which could be attributed to non-Δ9THC phytocannabinoids in the extract rather than Δ9THC. Although further study is required to determine the constituents responsible for these effects, these results support the presence of non-Δ9THC cannabis constituent(s) that exert a stimulatory effect on appetite and likely lack the detrimental psychoactive effects of Δ9THC.

Non-D9-tetrahydrocannabinol phytocannabinoids stimulate feeding in rats

Cannabinoid type 1 receptor-mediated appetite stimulation by D9tetrahydrocannabinol (D9THC) is well understood. Recently, it has become apparent that non-D9THC phytocannabinoids could also alter feeding patterns. Here, we show definitively that non-D9THC phytocannabinoids stimulate feeding. Twelve male, Lister-Hooded rats were prefed to satiety prior to administration of a standardized cannabis extract or to either of two mixtures of pure phytocannabinoids (extract analogues) comprising the phytocannabinoids present in the same proportions as the standardized extract (one with and one without D9THC). Hourly intake and meal pattern data were recorded and analysed using two-way analysis of variance followed by one-way analysis of variance and Bonferroni post-hoc tests. Administration of both extract analogues significantly increased feeding behaviours over the period of the test. All three agents increased hour-one intake and meal-one size and decreased the latency to feed, although the zero-D9THC extract analogue did so to a lesser degree than the high-D9THC analogue. Furthermore, only the analogue containing D9THC significantly increased meal duration. The data confirm that at least one non-D9THC phytocannabinoid induces feeding pattern changes in rats, although further trials using individual phytocannabinoids are required to fully understand the observed effects.

Induction of Psychosis by Delta 9-Tetrahydrocannabinol Reflects Modulation of Prefrontal and Striatal Function During Attentional Salience Processing

Context: The aberrant processing of salience is thought to be a fundamental factor underlying psychosis. Cannabis can induce acute psychotic symptoms, and its chronic use may increase the risk of schizophrenia. We investigated whether its psychotic effects are mediated through an influence on attentional salience processing. Objective: To examine the effects of Delta 9-tetrahydrocannabinol (Delta 9-THC) and cannabidiol (CBD) on regional brain function during salience processing. Design: Volunteers were studied using event-related functional magnetic resonance imaging on 3 occasions after administration of Delta 9-THC, CBD, or placebo while performing a visual oddball detection paradigm that involved allocation of attention to infrequent (oddball) stimuli within a string of frequent (standard) stimuli. Setting: University center. Participants: Fifteen healthy men with minimal previous cannabis use. Main Outcome Measures: Symptom ratings, task performance, and regional brain activation. Results: During the processing of oddball stimuli, relative to placebo, Delta 9-THC attenuated activation in the right caudate but augmented it in the right prefrontal cortex. Delta 9-Tetrahydrocannabinol also reduced the response latency to standard relative to oddball stimuli. The effect of Delta 9-THC in the right caudate was negatively correlated with the severity of the psychotic symptoms it induced and its effect on response latency. The effects of CBD on task-related activation were in the opposite direction of those of Delta 9-THC; relative to placebo, CBD augmented left caudate and hippocampal activation but attenuated right prefrontal activation. Conclusions: Delta 9-Tetrahydrocannabinol and CBD differentially modulate prefrontal, striatal, and hippocampal function during attentional salience processing. These effects may contribute to the effects of cannabis on psychotic symptoms and on the risk of psychotic disorders.

Does intravenous Δ9-tetrahydrocannabinol increase dopamine release? A SPET study

Intravenous (IV) Δ9-tetrahydrocannabinol (THC) induces transient psychotic symptoms in healthy subjects and in schizophrenic patients, but the psychotomimetic mechanism is unknown. One possibility is that THC stimulates dopamine (DA) release in the striatum. In this study we tested whether IV THC led to an increase in striatal DA release compared to placebo. We also investigated whether DA release and positive psychotic symptoms were related. Eleven healthy male volunteers completed two 123I-iodobenzamide ([123I]IBZM) single photon emission tomography (SPET) sessions and received IV THC (2.5 mg) or placebo in a randomized counterbalanced order, under double-blind conditions. Analysable data were obtained from nine participants. The Positive and Negative Syndrome Scale (PANSS) was used to rate psychotomimetic effects. Striatal binding index values were calculated using the occipital cortex as a reference region. Both the PANSS positive and general symptoms increased significantly at 30 min following IV THC. There were no significant differences in binding index in the caudate or putamen under THC compared to placebo conditions. Positive psychotic symptoms and DA release were unrelated. THC did not lead to a significant increase in DA release even though the dose was sufficient for participants to have psychotic symptoms. These findings do not support a central role for striatal DA in THC-elicited psychosis.

On-line SPE LC-MS/MS for the quantification of Δ9-tetrahydrocannabinol (THC) and its two major metabolites in human peripheral blood by liquid chromatography tandem mass spectrometry

A universal and robust analytical method for the determination of Δ9-tetrahydrocannabinol (THC) and two of its metabolites Δ9-(11-OH)-tetrahydrocannabinol (11-OH-THC) and 11-nor-Δ9-carboxy-tetrahydrocannabinol (THC-COOH) in human whole blood was developed and validated for use in forensic toxicology. Protein precipitation, integrated solid phase extraction and on-line enrichment followed by high-performance liquid chromatography separation and detection with a triple quadrupole mass spectrometer were combined. The linear ranges used for the three cannabinoids were from 0.5 to 20 ng/mL for THC and 11-OH-THC and from 2.5 to 100 ng/mL for THC-COOH, therefore covering the requirements for forensic use. Correlation coefficients of 0.9980 or better were achieved for all three analytes. No relevant hydrolysis was observed for THC-COOH glucuronide with this procedure--in contrast to our previous GC-MS procedure, which obviously lead to an artificial increase of the THC-COOH concentration due to the hydrolysis of the glucuronide-conjugate occurring at high pH during the phase-transfer catalyzed methylation step.

Single-dose pharmacokinetics and tolerability of oral delta-9- tetrahydrocannabinol in patients with amyotrophic lateral sclerosis

Cannabinoids exert neuroprotective and symptomatic effects in amyotrophic lateral sclerosis (ALS). We assessed the pharmacokinetics (PK) and tolerability of delta-9-tetrahydrocannabinol (THC) in ALS patients.

Delta-9-tetrahydrocannabinol for nighttime agitation in severe dementia

RATIONALE: Nighttime agitation occurs frequently in patients with dementia and represents the number one burden on caregivers today. Current treatment options are few and limited due to substantial side effects. OBJECTIVES: The aim of the study was to measure the effect of the cannabinoid dronabinol on nocturnal motor activity. METHODS: In an open-label pilot study, six consecutive patients in the late stages of dementia and suffering from circadian and behavioral disturbances-five patients with Alzheimer's disease and one patient with vascular dementia-were treated with 2.5 mg dronabinol daily for 2 weeks. Motor activity was measured objectively using actigraphy. RESULTS: Compared to baseline, dronabinol led to a reduction in nocturnal motor activity (P=0.028). These findings were corroborated by improvements in Neuropsychiatric Inventory total score (P=0.027) as well as in subscores for agitation, aberrant motor, and nighttime behaviors (P<0.05). No side effects were observed. CONCLUSIONS: The study suggests that dronabinol was able to reduce nocturnal motor activity and agitation in severely demented patients. Thus, it appears that dronabinol may be a safe new treatment option for behavioral and circadian disturbances in dementia.

The treatment of spasticity with Delta9-tetrahydrocannabinol in persons with spinal cord injury

STUDY DESIGN: Open label study to determine drug dose for a randomized double-blind placebo-controlled parallel study. OBJECTIVES: To assess the efficacy and side effects of oral Delta(9)-tetrahydrocannabinol (THC) and rectal THC-hemisuccinate (THC-HS) in SCI patients. SETTING: REHAB Basel, Switzerland. METHOD: Twenty-five patients with SCI were included in this three-phase study with individual dose adjustment, each consisting of 6 weeks. Twenty-two participants received oral THC open label starting with a single dose of 10 mg (Phase 1, completed by 15 patients). Eight subjects received rectal THC-HS (Phase 2, completed by seven patients). In Phase 3, six patients were treated with oral THC and seven with placebo. Major outcome parameters were the spasticity sum score (SSS) using the Modified Ashworth Scale (MAS) and self-ratings of spasticity. RESULTS: Mean daily doses were 31 mg with THC and 43 mg with THC-HS. Mean SSS for THC decreased significantly from 16.72 (+/-7.60) at baseline to 8.92 (+/-7.14) on day 43. Similar improvement was seen with THC-HS. We observed a significant improvement of SSS with active drug (P=0.001) in the seven subjects who received oral THC in Phase 1 and placebo in Phase 3. Major reasons for drop out were increase of pain and psychological side effects. CONCLUSION: THC is an effective and safe drug in the treatment of spasticity. At least 15-20 mg per day were needed to achieve a therapeutic effect.

Development and pharmacokinetic characterization of pulmonal and intravenous delta-9-tetrahydrocannabinol (THC) in humans

The aim of the present study was to develop a physiologically compatible inhalation solution of delta-9-tetrahydrocannabinol (THC), and to compare the pharmacokinetic and analgesic properties of pulmonal THC versus pulmonal placebo and intravenous (iv) THC, respectively. Eight healthy volunteers were included in this randomized, double-blind, crossover study. The aqueous THC formulations were prepared by using a solubilization technique. iv THC (0.053 mg/kg body weight), pulmonal THC (0.053 mg/kg), or a placebo inhalation solution was administered as single dose. At defined time points, blood samples were collected, and somatic and psychotropic side effects as well as vital functions monitored. An ice water immersion test was performed to measure analgesia. Using a pressure-driven nebulizer, the pulmonal administration of the THC liquid aerosol resulted in high THC peak plasma levels within minutes. The bioavailability of the pulmonal THC was 28.7 +/- 8.2% (mean +/- SEM). The side effects observed after pulmonal THC were coughing and slight irritation of the upper respiratory tract, very mild psychotropic symptoms, and headache. The side effects after iv THC were much more prominent. Neither pulmonal nor iv THC significantly reduced experimentally induced pain.