Cannabinoid drugs: will they relieve or exacerbate tinnitus?

PURPOSE OF REVIEW: Recent enthusiasm for cannabinoid drugs for the treatment of chronic pain and some forms of epilepsy, raises the question of whether they could be useful for other disorders associated with abnormal neuronal activity in the brain, such as subjective tinnitus. Indeed, there is evidence to indicate that some tinnitus sufferers self-medicate using Cannabis. The aim of this review is to critically evaluate the available evidence relating to the effects of cannabinoids on tinnitus. RECENT FINDINGS: Despite the fact that cannabinoids have been shown to decrease neuronal hyperactivity in many parts of the brain, the current evidence suggests that in auditory brain regions such as the dorsal cochlear nucleus, they have the potential to facilitate neuronal hyperactivity and exacerbate tinnitus. All of the available experimental evidence from animal studies suggests that cannabinoid CB1 receptor agonists will either have no effect on tinnitus or will worsen it. SUMMARY: In our opinion, the use of the available cannabinoid drugs to alleviate tinnitus, based on their alleged efficacy for neuropathic pain conditions and some forms of epilepsy, is premature and not supported by the available evidence.

The effects of electrical stimulation of the peripheral vestibular system on neurochemical release in the rat striatum.

For over a century, it has been speculated that the vestibular system transmits information about self-motion to the striatum. There have been inconsistent reports of such a connection, and interest in the subject has been increased by the experimental use of galvanic vestibular stimulation in the treatment of Parkinson's Disease patients. Nonetheless, there are few data available on the effects of vestibular stimulation on neurochemical changes in the striatum. We used in vivo microdialysis to analyse changes in the extracellular levels of amino acids and monoamines in the rat striatum, following electrical vestibular stimulation. Stimulation caused a significant decrease in serine and threonine, compared to the no-stimulation controls (P ≤ 0.005 and P ≤ 0.01, respectively). The ratio of DOPAC:dopamine, decreased on the ipsilateral side following stimulation (P ≤ 0.005). There was a significant treatment x side x intensity interaction for taurine levels (P ≤ 0.002), due to a decrease on the contralateral side in stimulated animals, which varied as a function of current. These results show that peripheral vestibular stimulation causes some neurochemical changes in the striatum and support the view that activaton of the vestibular system exerts effects on the function of the striatum.

The vestibular-basal ganglia connection: balancing motor control.

Connections between the vestibular system and the basal ganglia have been sporadically studied over the last century. Electrophysiological studies of field potentials in animals have shown that most areas of the striatum respond to electrical vestibular stimulation while human studies isolated responses to vestibular stimulation to the putamen of the striatum. Protein studies have shown inconsistent results regarding changes in receptor levels of a number of receptor types. Recent tracer studies identified a pathway between the vestibular nucleus and the striatum via the thalamus, completely bypassing the cortex. Vestibular sensory input is represented in the part of the striatum - the dorsolateral striatum - where fibres from the sensorimotor areas terminate. It is therefore possible that vestibular signals are used together with other sensorimotor inputs in the striatum for body and limb control. The combination of electrophysiological results, changes in protein levels and tracer studies have led to the idea that the dorsolateral striatum is likely to be the main input area for vestibular signals in the basal ganglia and these will have an influence on motor control. This may have clinical implications in the treatment of basal ganglia disorders and other movement disorders.

The effects of the Chinese herbal medicine EMF01 on salicylate-induced tinnitus in rats.

AIM OF THE STUDY: Traditional Chinese medicine (TCM) has been reported to successfully alleviate tinnitus, although well-controlled studies have not been conducted. In this study, we attempted to test a TCM, Er Ming Fang (EMF01) containing Rehmannia glutinosa, Cornus officinalis, Salvia mittiorrhiza, Pueraria, Schisandra chinensis, Poria cocos and Platycodon grandiflorum, on salicylate-induced tinnitus in rats, using a conditioned lick suppression paradigm. MATERIALS AND METHODS: A pilot study examined the effect of 8.75 g/kg and 17.5 g/kg EMF01 (delivered by oral gavage for 20 days) and showed a slight decrease in the suppression ratio (SR) in the 8.75 g/kg group. In order to confirm the possible effect of EMF01 on tinnitus at 8.75 g/kg, a further study was carried out with a larger sample size. RESULTS: While there were statistically significant differences between the treatment groups, post hoc tests revealed that EMF01 did not have any significant effect on salicylate-induced tinnitus. CONCLUSIONS: While this study does not support the efficacy of EMF01 in the treatment of salicylate-induced tinnitus, further studies should be conducted to determine if it alleviates tinnitus associated with acoustic trauma.

Cannabinoids in the treatment of cancer.

Cannabinoids, the active components of the hemp plant Cannabis sativa, along with their endogenous counterparts and synthetic derivatives, have elicited anti-cancer effects in many different in vitro and in vivo models of cancer. While the various cannabinoids have been examined in a variety of cancer models, recent studies have focused on the role of cannabinoid receptor agonists (both CB(1) and CB(2)) in the treatment of estrogen receptor-negative breast cancer. This review will summarize the anti-cancer properties of the cannabinoids, discuss their potential mechanisms of action, as well as explore controversies surrounding the results.

Inflammation in Parkinson's disease: an update.

Parkinson's disease (PD) is a degenerative neurological disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) of the brain. The loss of the dopaminergic projection from the SNpc deprives the striatum of dopamine and results in a myriad of motor signs, including tremor, rigidity and ataxia. Although the stimulus for the initiation of the degenerative process is not understood, 80% of the dopaminergic neurons in the SNpc must be lost before the clinical symptoms of the disease are observed. This suggests that the degenerative process is initiated many years before clinical presentation of the disease. The neurodegeneration observed in PD is accompanied by inflammatory processes, and it has been suggested that anti-inflammatory drugs may be useful in slowing disease progression once the clinical signs of PD have been observed. This review summarizes and evaluates the progress that has been made in this area of research since 2006.

Symptomatic treatment of multiple sclerosis using cannabinoids: recent advances.

Recent years have seen a dramatic increase in the number of clinical trials investigating the potential efficacy of medicinal cannabinoids for the symptomatic treatment of chronic pain and spasticity in multiple sclerosis (MS). A number of different cannabinoids have been used, including: delta9-tetrahydrocannabinol (THC) itself; the synthetic delta9-THC, dronabinol; a 1:1 ratio of delta9-THC:cannabidiol (Sativex); and the synthetic delta9-THC metabolites CT-3 and nabilone. Other Cannabis extracts have also been tested. While 2-3 years ago there was little consensus in the literature, now the majority of studies are beginning to suggest that cannabinoids are useful in the treatment of MS in at least a subset of individuals. Their adverse side-effect profile has generally been mild compared with other drugs used for pain and spasticity; nonetheless, there is still concern about potential long-term side effects, particularly psychiatric side effects and effects on fetal development.

Ginkgo biloba extracts for tinnitus: More hype than hope?

The investigation into the effects of Ginkgo biloba extracts on tinnitus has suffered from a dearth of effective animal models as well as systematic clinical trials employing double-blind and placebo-controlled designs. Some clinical trials have yielded positive results, however, these studies are few and have been limited either by design flaws, the small size of the significant effects, or else the results have not been published in peer-reviewed journals and therefore the quality of the research is not assured. By contrast, the two most systematic clinical trials, both double-blind and placebo controlled, and published in respected peer-reviewed journals, have yielded negative results and suggest that Ginkgo biloba extracts are of little more use in the treatment of tinnitus than a placebo. Treatments for tinnitus that do not have therapeutic efficacy not only waste money but can potentially prevent patients from seeking therapy that is efficacious. Furthermore, the unsupervised use of Ginkgo biloba extracts with other medications could lead to adverse side effects which are unnecessary and not justified in terms of therapeutic benefit.

The safety of cannabinoids for the treatment of multiple sclerosis.

The evidence for the therapeutic efficacy of cannabinoids in the treatment of multiple sclerosis (MS) is increasing but is not as yet convincing. Although several trials have reported no significant effect, the majority of the evidence which supports a beneficial effect on spasticity and pain is based on subjective measurements in trials where unblinding was likely to be a problem. The available clinical trial data suggest that the adverse side effects associated with using cannabis-based medicinal extracts (CBMEs) are generally mild, such as dry mouth, dizziness, somnolence, nausea and intoxication, and in no case did toxicity develop. However, most of these trials were run over a period of months and it is possible that other adverse side effects, not seen in these short-term studies, could develop with long-term use. Despite the evidence that cannabinoids can disrupt cognitive function and promote depression, on the basis of current data, such adverse effects seem unlikely to be associated with the use of CBMEs. Likewise, there is no evidence to suggest that their effects on balance and motor control, or immune function, may be clinically significant. There is, however, reason to be concerned about the use of therapeutic cannabinoids by people predisposed to psychosis and by pregnant women, given the increasing evidence of their adverse effects on the fetus. In conclusion, given the modest therapeutic effects of cannabinoids demonstrated so far, and the risk of long-term adverse side effects, there is reason to be cautious about their use in the treatment of MS.

Medicinal cannabis extracts for the treatment of multiple sclerosis.

Prior to 2002, few clinical data were available to indicate whether cannabis extracts may be beneficial. However, in the last two years, results of several placebo-controlled clinical trials of orally administered compounds have been published, and these cast doubt on the efficacy of delta9-tetrahydrocannabinol (delta9-THC) in objectively reducing spasticity in MS. By contrast, it has been claimed that sublingually administered cannabis extracts that contain approximately equal concentrations of delta9-THC and cannabidiol, a natural cannabinoid that does not act on the CB1 receptor, can produce a statistically and clinically significant reduction in spasticity, although this claim has yet to be thoroughly validated. Nonetheless, results of preclinical trials also lend support to the hypothesis that the endogenous cannabinoid system may be involved in the regulation of spasticity and pain. A better indication of the clinical potential of the different cannabis extracts will have to await the publication of the most recent clinical trial data. This review critically evaluates the most recent evidence available on the potential use of medicinal extracts of cannabis to relieve pain and spasticity in multiple sclerosis.

GW-1000. GW Pharmaceuticals.

GW Pharmaceuticals is developing GW-1000 (Sativex), a narrow ratio delta9-tetrahydrocannabinol:cannabidiol product for the potential treatment of multiple sclerosis, spinal cord injury, neurogenic pain and peripheral neuropathy. In March 2003, the company filed for approval for the treatment of MS with the UK Medicines Control Agency, and in May 2004, filed for new drug submission with Health Canada.

Adrenalectomy-induced cell death in the dentate gyrus: further characterisation using TUNEL and effects of the Ginkgo biloba extract, EGb 761, and ginkgolide B.

This study investigated the potential neuroprotective effects of the Ginkgo biloba extract, EGb-761, and ginkgolide B, on adrenalectomy (ADX)-induced cell death in the dentate gyrus (DG). Adrenalectomised, sham surgery-treated, and naive controls received either EGb-761 (25, 50, or 100 mg/kg), 0.9% saline vehicle control, ginkgolide B (10 or 25 mg/kg), or a polyethylene glycol vehicle control, i.p, daily for 6 days postsurgery. Cell death in the DG was determined by in situ labelling of DNA fragments, using the TUNEL method; sections were counterstained with hematoxylin. Radioimmunoassay was used to confirm a decrease in plasma corticosterone (CORT) after ADX. TUNEL-positive granule cells were observed in the DG at 1 week, but not at 24 h, post-ADX. The rate of granule cell death at this time was highest in the suprapyramidal blade and increased in a crest tip and a rostrotemporal gradient. Whereas CORT replacement completely prevented the occurrence of TUNEL-positive granule cells, EGb-761 and ginkgolide B did not, at any of the doses used. These results suggest that these drugs may not have substantial neuroprotective effects in the ADX model of neurodegeneration.

The CNS effects of Ginkgo biloba extracts and ginkgolide B.

Ginkgo biloba extracts such as EGb-761 have been suggested to have a multitude of beneficial effects on CNS function, from enhancing cognitive function in dementia to facilitating recovery from acute forms of neural damage such as hypoxia/ischemia. Ginkgolide B, one of the major components of EGb-761, is a potent platelet-activating factor (PAF) receptor antagonist, which is also regarded as having neuroprotective effects in the CNS. The aim of this review is to summarise and to critically evaluate the current evidence on the CNS effects of EGb-761 and ginkgolide B, with particular emphasis on the data relating to their neuroprotective effects.

Cannabinoids in the treatment of pain and spasticity in multiple sclerosis.

There is a large amount of evidence to support the view that the psychoactive ingredient in cannabis, delta9-tetrahydrocannabinol (delta9-THC), and cannabinoids in general, can reduce muscle spasticity and pain under some circumstances. Cannabinoid (CB1) receptors in the CNS appear to mediate both of these effects and endogenous cannabinoids may fulfil these functions to some extent under normal circumstances. However, in the context of multiple sclerosis (MS), it is still questionable whether cannabinoids are superior to existing, conventional medicationsfor the treatment of spasticity and pain. In the case of spasticity, there are too few controlled clinical trials to draw any reliable conclusion at this stage. In the case of pain, most of the available trials suggest that cannabinoids are not superior to existing treatments; however, few trials have examined chronic pain syndromes that are relevant to MS. Whether or not cannabinoids do have therapeutic potential in the treatment of MS, a further issue will be whether synthetic cannabinoids should be used in preference to cannabis itself. Smoking cannabis is associated with significant risks of lung cancer and other respiratory dysfunction. Furthermore, delta9-THC, as a broad-spectrum cannabinoid receptor agonist, will activate both CB1 and CB2 receptors. Synthetic cannabinoids, which target specific cannabinoid receptor subtypes in specific parts of the CNS, are likely to be of more therapeutic use than delta9-THC itself. If rapid absorption is necessary, such synthetic drugs could be delivered via aerosol formulations.