Free Health Essays - Cannabinoid Drug Cannabis
Introduction
Cannabis has been used medicinally for thousands of years. It was known to the Sumerians, Assyrians, Chinese and Indians as far back as the second millennium BC and recommended for many ailments including malaria, constipation, rheumatic pains and female disorders.(Grinspoon, 2003, Press) The drug entered mainstream western medicine following the advocacy of O'Shaugnessy,(2003, 35) who had observed its use in India and was impressed by its muscle relaxant, anticonvulsant, analgesic and antiemetic properties.
It was extensively prescribed in the nineteenth century but its status waned as more reliable drugs became accessible. However, cannabis could be prescribed (as a tincture) in the United Kingdom until 1971 when it was classified under Schedule 1 of the Misuse of Drugs Act as having no therapeutic benefit. The synthetic cannabinoids nabilone in the United Kingdom, and dronabinol in the United States, remained licensed for the specific indication of vomiting due to chemotherapy.
Interest in the biomedical benefits of cannabis has been renewed recently following anecdotal reports of efficacy in a wide variety of disorders from multiple sclerosis to glaucoma.(Grinspoon, 2003, Press) These reports, backed by an extremely limited amount of scientific evidence (see Table 1), have led to recommendations that clinical research should be implemented on the therapeutic uses of cannabinoids. A Clinical Cannabinoid Group has been set up to develop guidelines for such research. (British Medical Association, 1997)
This review is based on a Medline search of all papers on the pharmacology, clinical and therapeutic effects of cannabis and cannabinoids 1980-98, supplemented by comprehensive books and compendia and standard books and papers from the older literature. Relevant books and papers were hand-searched for additional references.
Further information was supplied from the Department of Health, particularly a report on therapeutic aspects of cannabinoids by Dr P. Robson (1998) and from colleagues. The search was originally conducted for reports commissioned by the Department of Health (Ashton, 1998) and the British Medical Association, (1997) but has been updated.
The papers quoted in the present review were selected from a very large bibliography as having direct clinical relevance. The review is not claimed to be comprehensive: it is largely confined to papers in the English language and where possible to clinical rather than preclinical or animal studies. Nevertheless, it is hoped that a balanced overall picture of the area is provided.
Pharmacology
The medicinal properties of cannabis are due to its content of cannabinoids, which are unique to the plant species Cannabis sativa. Over 60 cannabinoids, chemically aryl-substituted meroterpenes, (Evans, 2001, 561) have been identified. The pharmacology of most of these is unknown but the most potent psychoactive agent is Delta9-tetrahydrocannabinol (THC).
Some plant cannabinoids are shown in Fig. 1. Not all are psychoactive but some have additive, synergistic or inhibitory interactions with THC. In addition, several synthetic cannabinoids are available for medical use and research purposes (Table 2).
Cannabinoids interact with specific cannabinoid receptors in the body. Two types have been identified: CB1 receptors in the brain and peripheral nerves(Matsuda, 1997, 143) and CB2 receptors in macrophages in the spleen and immune cells in other tissues.(Munro, 1993, 366) Both CB1 and CB2 receptors belong to the class of G-protein coupled receptors which act on second messenger systems affecting cyclic AMP formation and Ca++ and K+ ion transport.
(Musty, 1995, 1935) Natural ligands for these receptors appear to be a family of anandamides (named after the Sanskrit word for bliss, ananda).(Devane, 1992, 1947) Anandamides are arachidonyl acid derivatives related to prostaglandins. The normal physiological functions of the cannabinoid/anandamide system are not known but may include modulating effects on mood, memory and cognition, sensory perception and pain, sleep, appetite, temperature control and immune responses. Pharmacological, physiological and clinical implications are reviewed by Pertwee. (1995, 25)
Medicinal Uses
Medicinal uses of cannabis and cannabinoids have recently been reviewed by the British Medical Association (1997) and by several other authors. (Voth, 1997, 795) Cannabinoids appear to be of therapeutic value as antiemetics, antispasmodics, analgesics and appetite stimulants and may have potential use in epilepsy, glaucoma and asthma.
However, for most of these indications (apart from antiemetic effects) the scientific evidence is extremely sparse; there have been few if any large scale controlled trials and claims for clinical utility are based largely on anecdotal reports.
Clinical trials that have been undertaken are limited by small sample size, lack of statistical power, use of different cannabis or cannabinoid preparations and heterogeneous patient groups. Furthermore, the mechanisms of action of any of the medicinal effects are not understood.
Cannabinoids as Anti-Emetics
Nausea and vomiting caused by antineoplastic chemotherapy "is at best miserable and at worst so disabling and demoralising as to lead to refusal of treatment". (Dalzell,1986, 1317) With some agents (including mustine, dacarbazine, cisplatin, cyclophosphamide, doxorubicin and high dose methotrexate) these symptoms are so common that anti-emetic drugs are routinely given before and after treatment, often with the addition of dexamethasone and lorazepam.
Standard anti-emetic treatment has been with dopamine receptor antagonists such as phenothiazines, metoclopramide and domperidone. These drugs are moderately although not completely effective and may produce dystonic reactions and other adverse effects.
Selective serotonin 5-HT3 receptor antagonists have been introduced relatively recently but are expensive, may have to be administered intravenously, and can cause constipation, headache, hypersensitivity reactions, altered liver function and dysrthythmias.
Cannabinoids in Spastic Disorders
Many of the most distressing symptoms associated with spastic disorders such as multiple sclerosis, spinal cord injury and cerebral palsy are not well controlled with existing drugs. Such symptoms include recurrent painful muscle spasms, various combinations of weakness, tremor, dystonia and ataxia, acute and chronic pain syndromes and impaired bladder and bowel control.
Muscle relaxants, analgesics and cholinergic or anticholinergic agents often give only partial relief or unacceptable side effects. Furthermore, many patients do not receive specialized treatment or adequate trials of various drug combinations. Anecdotally,(Meinck, 1999, 122) cannabis relieves many of these intractable symptoms and it is perhaps not surprising that the commonest neurological causes of taking illicit cannabis are multiple sclerosis and spinal cord injury.(Consroe, 2002, 4616)
Despite its reputation among patients, there are only five published reports of double or single blind placebo controlled studies of cannabis or cannabinoids in multiple sclerosis, involving a total of only 41 patients world-wide. Petro & Ellenberger (2001, 413) gave single oral doses of 5 or 10 mg THC to nine patients and noted a significant reduction in objectively rated spasticity scores compared with placebo.
Clifford (2003, 670) studied eight patients who received 5-15mg THC orally 6 hourly for up to 18 hours. Five patients showed mild subjective but not objective improvement in tremor and well-being after THC and two showed subjective and objective improvement in tremor but not ataxia or other symptoms. Ungerleider et al. (1998, 40) gave 13 patients (who had proved refractory to baclofen, dantrolene and diazepam) oral THC 2.5-15mg daily or b.d. for 5 days and found significant subjective improvement overall in spasticity at doses of 7.5mg THC or greater, compared with placebo, but some patients got worse.
There was no change in objective measures of weakness, spasticity, coordination, gait or reflexes. Martyn et al. (1995, 350) studied a single patient who received oral nabilone (1 mg on alternate days) or placebo for two periods of 4 weeks each. The patient noted improvement in general wellbeing, muscle spasms and frequency of nocturia during the periods on nabilone (Fig. 2).
Less encouraging results were reported by Greenberg et al.,(2004, 326) who observed the effects of smoking cannabis in a cigarette containing 1.54% THC in 10 patients with multiple sclerosis and 10 normal subjects. Cannabis impaired posture and balance in all subjects, causing greater impairment in the patients, although some reported subjective improvement.
Patients with spasticity due to spinal cord injuries or cerebral palsy often have painful muscle cramps and impaired bladder control. There appear to have been no controlled trials of cannabis or cannabinoids in these disorders, but a few questionnaire surveys suggest that cannabis may be helpful for some but not all patients. Dunn & Davies (2004, 12) questioned 10 patients with spinal cord injury, of whom five noted that cannabis improved spasticity but three reported worsening of bladder symptoms.
Twenty-one of 24 patients who replied to a questionnaire sent to 48 patients reported that cannabis decreased spasticity. Isolated case reports record that cannabis relieved pain and muscle spasms in two patients with spinal cord injury and that oral THC (5 mg) had a beneficial effect on pain and spasticity in one.
With regard to movement disorders, cannabis appeared to be of no benefit to patients with Parkinson's disease or parkinsonism co-existing with dystonia in whom tremor and hypokinaesia were aggravated. Oral cannabidiol ( 100-600mg daily for 6 weeks) improved dystonia in five patients with various dystonias but had no effect in 15 patients with Huntington's disease.
Patients who take cannabis illicitly and report beneficial effects are clearly a self-selected group. The results of controlled studies, few though they are, are equivocal. Some patients appear to benefit but in others there is no effect and some symptoms, such as ataxia and muscle weakness, may be worsened. Ungerleider et al. (1998, 51) reported a high incidence of adverse reactions to THC at doses that were adequate to relieve spasticity, affecting all but one patient at the 7.5 mg dose.
Side effects consisted of weakness, dry mouth, dysphoria, mental clouding and other psychological effects. Clifford (2003, 671) and Greenberg et al. (2004, 328) also reported psychological effects, including a "high" or dysphoria in patients with multiple sclerosis receiving cannabinoids.
Nevertheless, the available evidence indicates a need for further investigations into the value of cannabinoids (nabilone, THC and perhaps more selective synthetic cannabinoids (Consroe, 2002, 463) in spastic disorders, particularly as present drugs are often unsatisfactory. Cannabinoids seem most promising for muscle spasms and possibly tremor and bladder control, and they may find a place as adjuvant drugs in selected patients.
Large controlled trials with carefully recruited patients and accurate subjective and objective measurements of efficacy are required. Treatment would need to be long-term and a further problem which requires study in chronic illness is the development of tolerance to cannabinoids.
Cannabinoids in Pain Conditions
Pain, particularly neuropathic pain, is often poorly controlled by available analgesics, antiinflammatory agents, anticonvulsants or antidepressants and the use of these drugs is sometimes limited by adverse effects. New drugs with analgesic efficacy and minimal toxicity are needed, and some claims have been made for cannabinoids in this context.
In animal models many cannabinoids have anti-inflammatory and analgesic properties which appear to be mediated by non-opioid mechanisms. (Consroe, 2002, 466) There is some anecdotal evidence that cannabis alleviates various types of pain in man but very few controlled trials.
Noyes et al. (1995, 140) carried out two double-blind placebo-controlled trials in patients with cancer pain. In the first, (Maurer, 2000, 240) 10 patients received oral THC in a range of doses. Significant pain relief compared with placebo was obtained with doses of 15 mg and 20 mg THC; the analgesic effect peaked at 3 hours and lasted over 6 hours. In the second study (Noyes, 1995, 86) the effect of oral THC (10 mg and 20mg) was compared with oral codeine 60mg and 120 mg. THC 20 mg and codeine 120 mg gave significant and equivalent pain relief.
In a single patient with spinal cord injury 5 mg THC and codeine 50mg similarly gave equal pain relief. (Maurer, 2000, 4) In a controlled study of postoperative or trauma pain in 56 patients, levonantradol given intramuscularly provided significant pain relief lasting over 6 hours after doses of 2.5mg or 3mg (Consroe, 1996, 280) A few reports have described relief of phantom limb pain after cannabis.( Finnegan-Ling, 2004, 53)
In contrast, no significant analgesic effect was found with intravenous THC in 10 patients undergoing dental surgery (Raft, 1997, 30) and oral cannabidiol provided no pain relief in 10 patients with chronic neuropathic pain.(Lindstrom, 2002) Marked sedation was a common side effect of cannabinoids in all the pain studies but other psychological effects were minimal.
Cannabinoids thus appear to have a potential for pain relief with a potency similar to that of codeine. Further research is needed, but they may prove to be helpful, probably as adjuvant drugs, in chronic and terminal pain and for various neuropathic pains, such as phantom limb pain, not well-controlled by standard analgesics. It is permissible at present to prescribe nabilone and THC for intractable pain.
Cannabinoids as Appetite Stimulants
Acute doses of cannabis stimulate appetite, although with chronic use the effect disappears. The anti-emetic effects may allow eating and prevent weight loss in patients undergoing cancer chemotherapy and these effects combined with appetite stimulation may benefit patients with AIDS-related diseases, many of whom are receiving antiviral drugs or have other illnesses which cause anorexia, nausea and vomiting.
Cannabinoids in Epilepsy
Existing anticonvulsant drugs fail to provide total protection from fits in a third of epileptic patients and all have adverse effects which can be severe. Animal work shows that cannabinoids have complex actions on seizure activity and that they can exert both convulsant and anticonvulsant effects. Cannabidiol appears to hold promise in human epilepsy since it has an anticonvulsant spectrum different from standard drugs. It is virtually devoid of psychoactivity since it does not react with cannabinoid receptors.
Cannabinoids in Glaucoma
Glaucoma is the commonest cause of blindness in the western world and many cases are associated with raised intraocular pressure for which treatment with miotics, adrenergic agents, beta-blockers or carbonic anhydrase inhibitors is not always satisfactory. Several investigations have shown that oral or smoked cannabis or THC, THC eye drops and some other psychoactive cannabinoids (but not the non-psychoactive cannabidiol) can reduce intraocular pressure in normal human subjects.
Cannabinoids in Asthma
Acute doses of cannabis exert a bronchodilator action on the small airways (Hollister, 1996, 15) by a mechanism that appears to be different from that of betaadrenoceptor agonists and other bronchodilators used at present for asthma.( Graham, 1996, 150) Concern over risks of long-term use of potent betaadrenoceptor stimulants has renewed interest in earlier studies,(Tashkin, 1996, 787) suggesting a possible benefit of cannabinoids in asthma. Such studies have been limited to acute administration in a small number of asthmatic patients and a few normal volunteers.
Advantages and Disadvantages of Clinical use of Cannabinoids
The major advantage of cannabinoids is that they are extremely non-toxic: no deaths have resulted from their use and their side-effects profile compares favourably with that of many drugs used for conditions in which cannabinoids have a therapeutic potential. However, for all their promise, there may be limitations to the clinical use of cannabinoids.
Psychological Effects
The second most common effects in clinical trials are psychological, including euphoria, dysphoria, anxiety, depersonalization, hallucinations, paranoia and depression. Certain individuals may be particularly sensitive to these effects, and cannabis can aggravate psychosis in patients with schizophrenia, lead to loss of control with anti-psychotic drugs and possibly precipitate schizophrenia in vulnerable subjects.(Hollister, 1995, 110)
Physical Effects
Also common are physical side-effects of cannabinoids. These include dry mouth, ataxia (incidence over 50%), general inco-ordination, muscle weakness and tremor. Tachycardia and hypotension may make cannabinoids unsuitable for patients with cardiovascular disease. Endocrine effects may preclude their use in children and in pregnancy, and immunosuppressant effects may be of importance in immunocompromised individuals. (Chesher, 1995, 14)
Tolerance, Dependence, Withdrawal Effects
Tolerance develops rapidly, although incompletely and unevenly, to many of the effects of cannabis including those on mood, heart rate, blood pressure, intraocular pressure and psychomotor performance.(Jones, 1996, 225) Such tolerance may be an advantage in overcoming unwanted effects but a disadvantage if it develops to therapeutic effects. In recreational settings cannabis can cause dependence and an abstinence syndrome on withdrawal.
However, by analogy with opioids used in pain relief (Twycross, 1999, 689) abuse or addiction are unlikely to become problems with prescribed dosage of cannabinoids in therapeutic settings. Nevertheless, precautions may be necessary to prevent prescribed cannabinoids being subverted like benzodiazepines, other hypnotics and amphetamines) into illicit "street" use.
Research Study
Cannabinoids are a group of compounds first found in marijuana (Cannabis sativa). Among them, Δ9-tetrahydrocannabinol (THC) was established as the main psychoactive constituent (Gaoni & Mechoulam, 2004, 1647). Marijuana's cognition-altering properties have long been known, and one of the most intriguing and widely reported is a change of time perception (Hicks, Gualtieri, Mayo, & Perez-Reyes, 2004, 229; Mathew, Wilson, Turkington, & Coleman, 1998, 183).
Smokers have consistently reported a subjective feeling that time passes more slowly when they are intoxicated, a feeling that would be reflected in an underestimation of the duration of time intervals (Hicks et al., 2004, 235; Mathew et al., 1998, 185).
In contrast to the considerable evidence from human studies of cannabinoid effects on time estimation, demonstrated effects of cannabinoid compounds in rodent models of timing are almost completely lacking. In one previous rodent study, it was reported that THC shortened interresponse times on a differential-reinforcement of low rate (10 to 13 s) schedule, suggesting that the subjects underestimated the 10- to 13-s time interval (McClure & McMillan, 1997, 1369).
The successful demonstration of the effects of cannabinoids in rodent timing paradigms is a first step to using those models to study the underlying neural processes mediating cannabinoid modulation of time perception.
Another thoroughly validated procedure for studying time perception in rodents is a variant of a simple fixed-interval schedule, also known as the peak procedure (Catania, 2000, 32). There are two types of trials in this procedure. In the fixed-interval trial (FIT), the reinforcer is delivered upon the first lever press by the subject after a fixed time period has elapsed. A well-trained subject accelerates responding as the end of the interval approaches, as this is the time when the press is most likely to be rewarded.
When the subject has mastered the task, some trials are replaced randomly by probe trials (PTs), which are different from FITs only in that the interval is longer and no reinforcement is given after any lever press. During the PT, the subject produces a response rate-versus-time bell curve that peaks near the end of the fixed interval. The time at which the response rate is highest, the peak, is thought to represent the subject's estimate of the fixed interval (Catania, 2000, 34; Roberts, 2001, 244).
This study is the first to systematically examine the effects of cannabinoids on interval estimation in the peak procedure. The effects of exogenous activation of cannabinoid receptors were studied by using cannabinoid receptor agonists WIN 55,212-2 and THC. The effects of the antagonism of endogenous cannabinoids were studied by using the antagonist SR 141716A.
To produce effects similar to those reported for humans, cannabinoid agonists would produce a decrease in the modal response time in rats. Alternatively, one might expect cannabinoid receptor antagonist SR 141716A to increase the modal response time in rats.
Subjects
The subjects initially trained were 15 male Sprague-Dawley rats (Taconic Farms, Germantown, NY), approximately 120 days old at the beginning of behavioral training. They were housed individually in plastic tub cages with bedding of wood shavings in humidity- and temperature-controlled conditions and were maintained on a 12-hr light–dark cycle. The experiments were conducted 7 days per week, during which rats were maintained on a 23.5-hr water restriction schedule.
Food was continuously available in the home cages. Body weights were measured daily to ensure that they remained above 85% ad-lib weights. All procedures were conducted in accordance with the Guide for the Care and Use of Laboratory Animals (National Institutes of Health, 1996) and with the approval of the State University of New York Stony Brook Institutional Animal Care and Use Committee.
Apparatus
The subjects were tested in six identical computer-controlled operant test chambers (MED Associates, East Fairfield, VT), equipped with one rear-mounted and two front-mounted response levers. The operant chambers were placed in sound-attenuating enclosures. The interior space was 60 cm long × 40 cm wide × 47 cm high. The floor consisted of stainless steel bars 0.4 cm in diameter and spaced 1.7 cm apart. A ventilation fan exchanged air and reduced extraneous noise.
Water reinforcement was delivered into a water aperture measuring 5 cm × 5 cm and centered on the front panel. Two response levers were mounted 4 cm above the cage floor on either side of the water aperture. A single response lever was similarly mounted on the rear panel.
A white cue lamp was mounted above each lever, and a house light was mounted above the rear cue lamp. In this study, only the left front cue lamp and lever were used. Experimental events and data recording were controlled by a Micron PC computer with MEDstate Notation programming language (MED Associates).
Behavioral Training
Pretraining
All subjects were trained for basic operant response for 3 days. The training included drinking water from the water aperture, associating lever pressing with the water reward, and associating the lamp cue with the start of the trial.
FI-30s
The subjects were then trained to respond to FI-30s in a 60-min session daily. The left cue lamp was turned on to signal the start of each trial. The first lever press after the 30-s fixed interval and before 36 s resulted in the reinforcement delivery of water (approximately 0.5 ml). A 10-s to 50-s variable intertrial interval (ITI) followed each trial. The exact duration of the ITI was determined by the computer program. The chamber was completely dark during the ITI.
PT-60s
Fifty percent of the trials were randomly replaced by PT-60s after 120 days of training. PT-60s was different from FI-30s in that no reinforcement was given upon any lever press, and the trial lasted 60 s. The number of responses of each subject was collected throughout the 60-s interval. The training was completed when the subjects produced a stable response distribution, peaking at about 33 s. The training took 150 days, on average.
Drug Preparation and Administration
WIN 55,212-2 was purchased from RBI, St. Louis, MO. SR 141716A and THC were provided by the National Institute on Drug Abuse, Bethesda, MD. THC was supplied dissolved in ethanol; we added Emulphor (GAF, Rochester, NY). SR 141716A was initially dissolved in a 1:1 mixture of ethanol and Emulphor. The ethanol for both was later evaporated under a stream of nitrogen. WIN 55,212-2 was initially dissolved in dimethyl sulfoxide (to 100 mg WIN 55,212-2/ml dimethyl sulfoxide); we then added a drop of Emulphor.
The injection doses (THC–vehicle, 0.50, 1.00, 2.00, and 4.00 mg/kg; WIN 55,212-2–vehicle, 0.25, 0.50, and 1.00 mg/kg; and SR 141716A–vehicle, 0.50, 1.00, and 2.00 mg/kg) were made by serially diluting the stock solution by adding saline. All drugs were injected intraperitoneally in a volume of 1 ml/kg. All subjects received the THC drug series first, then the SR 141716A series, and finally the WIN 55,212-2 series.
The sequence by which any particular subject received the doses of a drug was in accordance with a Latin square design. Vehicle injections were given on drug injection days as part of the Latin square sequence.
Each drug injection day was preceded by a no-injection training day as the baseline. On the drug administration day, the subjects received an intraperitoneal injection of one of the drug doses described above or an equivalent amount of vehicle. The subjects were returned to the home cages for 40 min before behavioral testing began.
Data Collection and Analysis
For each subject, the responses within each PT-60s trial were collected in consecutive 1-s bins. Each bin was summed over trials for each session to produce the response rate-versus-time curve. A moving average based on consecutive 3-s epochs was used to smooth the distribution. The peak time measure was defined as the middle of the epoch containing the maximum number of responses.
When more than one epoch contained the maximum number of responses, the peak time was determined as the median of those epochs. The total responses measure was the sum of all responses in all PT-60s epochs over an entire session divided by the number of trials completed. This measure gives an indication of the overall rate of lever pressing.
The peak responses measure was calculated by first determining the peak time interval, summing over the entire session all the responses at that 3-s epoch, and dividing the result by the number of trials per session. This measure gives an indication of the response rate at the peak.
The standard deviation, skewness, and kurtosis measures assessed spread, symmetry, and how peaked or flat the distributions were. A positive value for skewness indicated that the tail of the distribution tended toward the right, positive side, and a negative value for skewness indicated that the tail of the distribution tended toward the left, negative side.
A positive value for kurtosis indicated a curve flatter than a normal distribution, and a negative value represented a curve sharper than normal. All of the above measures were tested by single-factor repeated measures analysis of variance. Dunnett's test was used for post hoc analyses when a significant F test value was found.
Behavioral Criteria, Missing Values, and Processing of Data
After training, rats whose peak time deviated less than 15% from 33 s on 4 consecutive days were injected. The numbers of rats treated with WIN 55,212-2, THC, and SR 141716A were 10, 10, and 9, respectively. One rat in the SR 141716A study was further excluded because the peak time was greater than 60 s after saline injection. A few values for the peak time, kurtosis, and skewness were not entered or calculated when the response rate was so low that the response distribution was not discernible.
This happened when the highest response rate per epoch per trial was less than 0.14. This included two such distributions for 0.50 mg/kg WIN 55,212-2 and two for 1.00 mg/kg WIN 55,212-2. Therefore, the within-groups degrees of freedom for the F values for the peak time, kurtosis, and skewness are 2 fewer than for the other F values.
Results
Figure 3 shows the peak time as a function of doses for the three drugs. For WIN 55,212-2, F(3, 32) = 3.41, p < .05, the 0.50- and 1.00-mg/kg doses were significantly different from the vehicle injection, as determined by Dunnett's test, p < .01. For THC, F(4, 40) = 2.82, p < .05, the 0.50-, 1.00-, and 4.00-mg/kg doses were significantly different from the vehicle injection (Dunnett's test), p < .01. For SR 141716A, F(3, 36) = 3.25, p < .05, Dunnett's test revealed that all doses were significantly different from the vehicle injection.
Measures for the responses at the peak, total responses, standard deviation, kurtosis, and skewness as functions of dose of drug are shown in Table 3. No significant differences were found among any drug group for any measure. The results of the analyses of variance also are shown in Table 3. Discussion
The present data strongly argue for an involvement of cannabinoid receptors in time estimation in rats. Cannabinoid agonists WIN 55,212-2 and THC both decreased the peak time, whereas SR 141716A increased the peak time. The secondary measures of response rate - peak response and total responses - showed no significant difference among the drug groups, implying that no significant motor impairment was produced by the doses administered.
In addition, the measures of the shape of the response distribution - kurtosis, skewness, and standard deviation - were also not significantly altered, suggesting that the shift in peak time was not an artifact of flattening or distortion of the response distribution.
The present experiments do not allow a clear differentiation of whether the peak shift reflects a cannabinoid-induced change in the rate of the “internal clock” or the reference memory of the FI. Meck (2003, 172) suggested that immediate changes, such as those observed here, represent an alteration of the internal clock. However, the design does not assess long-term effects, to determine if they too might have been present. Further work that uses experimental designs capable of revealing this perceptual-versus-memory dissociation clearly is needed.
An additional approach to the study of underlying mechanisms would be to use site microinjection techniques to localize the effect of cannabinoids to specific brain structures. Cannabinoid receptors are numerous in the neocortex, especially in the prefrontal cortex (Berrendero et al., 1998, 3179; Glass, Dragunow, & Faull, 1997, 300; Matsuda, 1997, 145; Pettit, Harrison, Olson, Spencer, & Cabral, 1998, 399). The prefrontal cortex is thought to be involved in higher cognitive functions, including temporal integration (Fuster, 1999, Press).
It is possible that cannabinoids exert an effect on higher cognition, including time perception, via binding with cannabinoid receptors in the prefrontal cortex. However, cannabinoid receptors in other structures also may be involved in timing. For example, it was reported that for humans, a decrease in cerebellar–cerebral blood flow was associated with a significant alteration in time estimation (Mathew et al., 1998, 188). Microinjection of cannabinoid drugs into the candidate brain areas related to time perception, such as the prefrontal cortex, hypothalamus, basal ganglia, and cerebellum, can be used to investigate these hypotheses.
Conclusions
The place of cannabinoids in modern medicine remains to be evaluated and the results of clinical and pharmaceutical research will be awaited with interest. Recommendations for such research have been suggested under each indication discussed in this review. It seems that cannabinoids are unlikely to constitute a cure for any illness, but on present evidence it is possible that they could be valuable for symptom control in a selection of conditions for which existing drugs are not fully adequate.
They are mainly probable to find a place as adjuvant to standard agents, and it is possible that the development of novel synthetic agents with more specific actions and fewer side-effects will extend their therapeutic range.
Meanwhile, several authorities (Robson, 1998) have argued for enhanced access to cannabinoids in clinical practice and the British Medical Association report (British Medical Association, 1997) concludes: "While research is underway, police, the courts and other prosecuting authorities should be aware of the medicinal reasons for the unlawful use of cannabis by those suffering from certain medical conditions for whom other drugs have proved ineffective."
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Appendix
Figure 3. Peak time as a function of doses for the three drugs. Error bars indicate SEM. THC = Δ9 -tetrahydrocannabinol
