bluuebunny/crossref_metadata_2025 huggingface dataset:
Mechanism for National Distribution of Δ9‐Tetrahydrocannabinol (NSC‐134454)
Authors: ABRAHAM DAVID , PINA KENNETH R. , DAVIGNON J. PAUL
Published: March 2013

Abstract: The National Cancer Institute (NCI) is initiating a national THC distribution program by applying to the FDA for its classification as a Group C investigational agent. Since THC is also a Schedule I drug, the distribution system requires strict adherence to Drug Enforcement Agency (DEA) security and safety regulations. Contrary to the usual distribution of Group C drugs, THC will not be available directly to physicians. THC will be made available to hospital pharmacies which are: (1) an NCI recognized Cancer Center (P‐30 grant supported), (2) an NCI designated New Drug Study Group, (3) a memberof the Council of Teaching Hospitals. Hospital pharmacies that are located in inadequately represented geographic areas when certain criteria are met by them will also be considered. Physicians desiring to prescribe THC need not have Schedule I registration, but should (1) have experience in cancer chemotherapy, (2) have a current DEA registration number, (3) agree to abide by the Guidelines for Use of THC, and (4) be registered with a participating pharmacy. A registered physician may prescribe THC by writing a Research Order for Medication on a usual prescription blank, including, in addition to normal required information, confirmation that patient consent has been obtained and the name of the hospital at which the physician is registered to prescribe THC.
The California Program for the Investigational Use of THC and Marihuana in Heterogeneous Populations Experiencing Nausea and Vomiting from Anticancer Therapy
Authors: DOW GORDON J. , MEYERS FREDERICK H.
Published: March 2013

Abstract: Published studies of Δ9‐tetrahydrocannabinol (THC) and marihuana in the control of nausea and vomiting in cancer patients leave many unanswered questions about dosage, time of administration, technique of use, use in pediatric and geriatric patients, and continuous use for extended periods. Four separate protocols are described which will determine optimal dosage of oral THC in adults and children receiving cyclic chemotherapy and adults receiving chronic chemotherapy or radiotherapy, and the optimal dose for smoked marihuana. Side effects and efficacy will be assessed by chemotherapeutic agent or combination, type of cancer, age, sex, etc. How well THC is tolerated in the elderly and very ill are important questions to be answered. Research goals are combined with widespread therapeutic access of cancer patients to marihuana and THC. The problems of designing and sponsoring a very large‐scale Phase III collaborative study involving community practitioners are outlined. The design stresses uniformity and simplicity to obtain compliance by the more than 200 investigators.
The Controlled Substances Therapeutic Research Act in the State of Washington
Authors: ROFFMAN R. A.
Published: March 2013

Abstract: In March 1979, the Governor of the State of Washington signed legislation establishing a THC/marihuana research program within the Washington State Board of Pharmacy. By November 1980, approximately 80 physicians had enrolled more than 400 patients on the chemotherapy protocol which randomly assigned subjects to receive either THC and prochlorperazine or THC and placebo. This report describes the process of implementing the legislation, the administrative and clinical roles of project personnel, and the design of three currently operating protocols.
Clinical Relevance of Cannabis Tolerance and Dependence
Authors: JONES REESE T. , BENOWITZ NEAL L. , HERNING RONALD I.
Published: March 2013

Abstract: Psychoactive drugs are often widely used before tolerance and dependence is fully appreciated. Tolerance to cannabis‐induced cardiovascular and autonomic changes, decreased intraocular pressure, sleep and sleep EEG, mood and behavioral changes is acquired and, to a great degree, lost rapidly with optimal conditions. Mechanisms appear more functional than metabolic. Acquisition rate depends on dose and dose schedule. Dependence, manifested by withdrawal symptoms after as little as 7 days of THC administration, is characterized by irritability, restlessness, insomnia, anorexia, nausea, sweating, salivation, increased body temperature, altered sleep and waking EEG, tremor, and weight loss. Mild and transient in the 120 subjects studied, the syndrome was similar to sedative drug withdrawal. Tolerance to drug side effects can be useful. Tolerance to therapeutic effects or target symptoms poses problems. Clinical significance of dependence is difficult to assess since drug‐seeking behavior has many determinants. Cannabis‐induced super sensitivity should be considered wherever chronic drug administration is anticipated in conditions like epilepsy, glaucoma or chronic pain. Cannabis pharmacology suggests ways of minimizing tolerance and dependence problems.
Bias and the Cannabis Researcher
Authors: UNGERLEIDER J. THOMAS , ANDRYSIAK THERESE
Published: March 2013

Abstract: This report focuses on several aspects of the “drug” cannabis in our society: the historical notion of a chemical as a moral issue (i.e., good and evil) rather than a pharmacological one; the scientist as a human being as well as a witting or unwitting influencer of social policy; the statistical design and manipulation of research consciously or unconsciously for fame and fortune (grants); the research treatment “connection” as part of our drug abuse industrial complex, a billion dollar a year industry; and the covert governmental manipulation and distortion of cannabis (and other drug) data.
On the Definition of Cannabinoids: Botanical? Chemical? Pharmacological?
Authors: WEISSMAN ALBERT
Published: March 2013

Abstract: Cannabinoids (or presumed synonyms such as cannabinols or cannabis‐like agents) have been variously defined in botanical, chemical, or pharmacological terms, with unfortunate consequences. Botanical definitions include inactive substances such as cannabigerol, as well as alkaloids and other secondary constituents of Cannabis sativa, but exclude synthetics such as levonantradol and nabilone. Chemical definitions include inactive close analogs of THC but exclude a growing number of substances structurally remote from THC that share its actions. Pharmacological definitions have depended on relatively nonspecific or vague behavioral endpoints. However, animal testing methodology has recently been developed that can identify and quantify agents that share THC's unique subjective effects. To avoid preexisting ambiguity in the word cannabinoids, the term cannabimimetics has been coined to include all such agents, regardless of origin or structure. Such a classification emphasizes research toward improved biological selectivity and therapeutic advance. While no totally noncannabimimetic agents with potent analgesic effects have yet been identified among derivatives of THC, selectivity has been uncovered for levonantradol, HHC (racemic‐9‐nor, 9‐β‐OH‐hexahydrocannabinol) and several structurally related compounds.
Quality of Life: Some Theoretical Issues
Authors: van DAM F. S. A. M. , SOMERS R. , van BEEK‐COUZIJN A. L.
Published: March 2013

Abstract: The concept “quality of life” is becoming increasingly popular in both the medical and general press. However, from a literature survey of approximately 100 scientific publications in which this concept was used, it appeared that rarely is a definition of this term given. Therefore, it seems useful to formulate several guiding principles: (1) “Quality of life” apparently is too vague a concept. It seems more sensible to isolate a number of relevant factors and to choose the best operational definition possible. The following factors may be considered: daily activity, pattern of complaints, subjective feeling of well‐being, and sexual behavior. Based upon these factors one composite score of psychological and social consequences should be developed, analogous to an IQ test. (2) The patient is the sole authority concerning questions on “quality of life.” (3) The concept “quality of life” should indicate more than a person's momentary well being, since this is dependent on mood, physiologic state, accidental events, etc. It is not the situation at one specific point which should be considered but the situation over a certain period. (4) Questions concerning “quality of life” should be put relatively. For example, does a person have more or less complaints during one period as compared to another? A second possibility is to compare a person's answers to those of a carefully chosen control group. It is essential to keep in mind that these psychologic measures are descriptive; they indicate how patients feel during a certain period concerning the above‐mentioned areas and are definitely nor normative in the sense of stating what is or is not desirable.
Do Plasma Concentrations of Δ9‐Tetrahydrocannabinol Reflect the Degree of Intoxication?
Authors: HOLLISTER L. E. , GILLESPIE H. K. , OHLSSON A. , LINDGREN J‐E. , WAHLEN A. , AGURELL S.
Published: March 2013

Abstract: Plasma concentrations of THC were measured by gas‐liquid chromatography and mass spectrometry following three routes of administration and correlated with clinical effects. Plasma concentrations peaked at 3 minutes after intravenous injection and then sharply declined. The peak “high” occurred at 30 minutes while plasma concentrations were declining. This lag between plasma concentration and “high” continued during most of the span of the drug's effects. The situation was quite similar following smoking, except that peak plasma concentrations were lower. After oral administration of THC, absorption was slow, with peak concentration occurring at 1 to 2 hours. Plasma concentrations were much lower. Correlations between plasma concentrations of drug and “high” were significant but not impressive. The degree of “high” was quite variable in relation to the prevailing plasma concentration. Conjunctival injection was found so long as plasma concentration of THC could be measured. Pulse rate increases occurred at lower concentration after oral administration than after the other two routes. It is unlikely that a range of plasma concentrations can be reliably equated with impaired performance. The mode of administration will become important should THC or some homolog become a therapeutic agent.
The Metabolism of Δ9‐Tetrahydrocannabinol and Related Cannabinoids in Man
Authors: WALL MONROE E. , PEREZ‐REYES MARIO
Published: March 2013

Abstract: The metabolism of Δ9‐tetrahydrocannabinol (THC) and related cannabinoids in man has been studied in detail utilizing intravenous, oral, and smoking routes of administration. The general pattern of metabolism was the same in all studies involving THC and related cannabinoids. Microsomal hydroxylation allylic to the Δ9‐THC double bond occurs, the major product resulting in formation of an 11‐CH2OH moiety; minor hydroxylation occurs on the C‐8 carbon. Nonmicrosomal oxidation of the resultant 11‐OH‐Δ9‐THC to 11‐nor‐Δ9‐THC‐9‐carboxylic acid and to other more polar acids generates the major terminal metabolic products. After oral administration, approximately equal quantities of THC and its highly active 11‐hydroxy metabolite were formed, whereasthe latter metabolite is a minor constituent after administration by intravenous or smoking routes. Initial pharmacokinetic analyses of the data show that the mean terminal‐phase (β‐phase) plasma half‐life after intravenous administration of THC was about 30 hours; after oral administration, it was 23 hours. No significant statistical difference was noted between men and women as to metabolic routes or plasma terminal‐phase half‐lives.
Pharmacokinetics of Levonantradol in Laboratory Animals and Man
Authors: SHEPARD RICHARD M.
Published: March 2013

Abstract: Levonantradol exhibits potent analgetic activity in standard animal tests and appears not to act directly at opiate receptors. It is currently in clinical trials as an analgesic and antiemetic. The pharmacokinetic behavior of levonantradol, administered orally or intramuscularly, has been investigated in man at dose levels of 0.25 to 3.0 mg and in animals at 0.03 to 10 mg/kg, using a specific HPLC/electrochemical assay. Only desacetyllevonantradol is detected in plasma, due to rapid in vivo deacetylation of levonantradol. In man, at the various doses tested, plasma concentrations of desacetyllevonantradol range from < 5 to 51 ng/ml. Comparable plasma levels and clinical activity occur at nearly identical doses after oral and intramuscular dosing, suggesting good oral absorption in man. In animals, desacetyllevonantradol has a time of peak concentration of 1 to 2 hours and an elimination half‐life of 1 to 2 hours. In animals, a tenfold higher oral dose is needed to achieve the same plasma drug levels as that afteran intramuscular dose, suggesting extensive first‐pass metabolism following oral admininstration. Little or no evidence for drug accumulation and sex differences in plasma concentrations of desacetyllevonantradol is noted during chronic intramuscular dosing in laboratory animals.
The Clinical Pharmacology and Dynamics of Marihuana Cigarette Smoking
Authors: PEREZ‐REYES MARIO , OWENS S. MICHAEL , DI GUISEPPI STEPHANIE
Published: March 2013

Abstract: We have studied the dynamics of marihuana smoking, the plasma concentration of Δ9‐tetrahydrocannabinol (THC), and the pharmacologic effects produced by the sequential smoking of two 1% marihuana cigarettes at a 2‐hour interval. Three males and three females, experienced marihuana smokers, participated in the study. The results indicate that each subject smoked his or her two cigarettes at a similar rate. The THC plasma concentrations produced by the smoking of the second cigarette were slightly lower than those produced by the first cigarette. The levels of the psychologic “high” caused by the two cigarettes were similar. However, the first cigarette accelerated the heart twice as much as the second cigarette. Between males and females there were marked differences in the rate at which the cigarettes were smoked. In particular, males took more puffs, took them more often, and consumed the cigarettes more rapidly than females. The plasma concentrations of THC, the self‐reported psychologic effects, and the heart rate acceleration produced by the smoking of the two cigarettes were identical between the sexes.
The Kinetics of Cannabinoid Distribution and Storage With Special Reference to the Brain and Testis
Authors: NAHAS GABRIEL , LEGER COLETTE , TOCQUE BRUNO , HOELLINGER HENRI
Published: March 2013

Abstract: Male and female rats were given either single or repeated intramuscular injections of 2 μCi of 14C‐Δ8‐tetrahydrocannabinol. They were sacrificed by groups of three at regular intervals 2, 3, 4, 6, or 24 hours after the last injection. Samples of blood, lung, brain and pituitary, spleen, liver, fat, testis, and ovary were removed. Some samples were pyrolysed in an automatic oxygen train system to measure 14C‐CO2, which reflects total cannabinoid concentration; other samples were kept for measurements of individual cannabinoids after extraction. After a single administration of 14C‐Δ8‐THC, maximal concentration of total radioactivity was reached in the brain between 2 and 4 hours amounting to 6 ng/gm tissue, or 0.06 per cent of the administered dose. After two weeks of chronic administration, concentrations of radioactivity progressively increased in liver and neutral fat, while cannabinoid levels in brain and testis remained unchanged. These data illustrate the efficiency of the blood‐brain and blood‐testicular barrier in limiting the access and accumulation of cannabinoids in these tissues.
Cardiovascular and Metabolic Considerations in Prolonged Cannabinoid Administration in Man
Authors: BENOWITZ NEAL L. , JONES REESE T.
Published: March 2013

Abstract: Safe therapeutic use of cannabinoids for prolonged periods of time requires an appreciation of pharmacologic actions with both acute and repetitive administration. Cardiovascular effects of acute Δ9‐tetrahydrocannabinol (THC) administration included increased sympathetic and reduced parasympathetic tone, although sympathetic reflex responses were impaired. Thus, supine tachycardia and increased blood pressure with upright hypotension are observed. With repetitive dosing, there is a transition from increased to decreased sympathetic activity and from decreased to increased parasympathetic activity, and blood volume substantially increases. As a result, supine bradycardia and decreased blood pressure with tolerance to orthostatic hypotension are observed. Relevance of these observations to management of patients with THC, including considerations of potential drug interactions, is discussed. In other experiments, THC and cannabidiol were found to inhibit metabolism of other drugs (antipyrine and barbiturates) metabolized by liver mixed‐function oxidase enzymes. Potential inhibition of drug metabolism must be considered in evaluating responses to chemotherapeutic agents in cancer patients receiving THC and responses to coadministered anticonvulsants in epileptic patients receiving cannabidiol.
Discriminative Stimulus Properties of Δ9‐Tetrahydrocannabinol: Mechanistic Studies
Authors: BROWNE RONALD Q. , WEISSMAN ALBERT
Published: March 2013

Abstract: Δ9‐Tetrahydrocannabinol (THC) produces a multiplicity of pharmacologic effects including analgesic, antiinflammatory, anticonvulsant, antidiarrheal, antiglaucoma, antihypertensive, and sedative effects. Efforts to elucidate the neurochemical systems mediating the THC effects have used these and related endpoints. However, animal models useful for evaluating the mechanisms by which THC produces its unique subjective effects have only recently been established. The use of drugs as discriminative stimuli provides a means for studying such mechanisms, since generalization data from this test closely correlate with subjective properties observed in clinical studies. The present study examined the ability of various drugs to mimic or block the cue produced by THC In rats. In animals trained to discriminate 3.2 mg/kg THC from vehicle, generalization occurred consistently with cannabinoids such as 11‐OH‐THC, HHC, and nabilone. Stereoselective generalization was also obtained with isomers of a potent analgesic, nantradol; potencies were consistent with results from other endpoints. In contrast, THC cueing was not produced by agents acting on adrenergic, cholinergic, serotonergic, GABAergic, or opiate systems. Similarly, a number of drugs previously reported to antagonize various nonunique effects of THC uniformly failed to block its subjective properties. These results indicate that the subjective properties of THC are mediated through as yet unidentified neurochemical systems.
Effects of Levonantradol on Habituation of Startle in Rats
Authors: GEYER MARK A.
Published: March 2013

Abstract: Levonantradol, a nonopioid analgetic related to cannabinoids, produced a dose‐dependent impairment of the habituation of startle response in rats. Startle was elicited by air‐puff stimuli and monitored in stabilimeters by a computer. Habituation was assessed by presenting the same tactile stimulus repeatedly at 15‐second intervals. While a dose of 0.1 mg/kg reduced startle on all trials, doses ranging from 0.01 to 0.03 mg/kg had no effect on the initial level of reactivity to the first several stimuli but did impair the habituation of startle. This effect was not attributable to the time course of the drug's action and was also found with acoustic stimuli. The relatively inactive enantiomer of levonantradol was ineffective at 0.1 mg/kg. Thus, startle appears to be a sensitive measure of the effects of levonantradol in animals. Since comparable phenomena can be demonstrated in humans by measuring the blink reflex component of startle, direct comparisons can potentially be made across species.
Prostaglandins and Cannabis—VIII. Elevation of Phospholipase A2 Activity by Cannabinoids in Whole Cells and Subcellular Preparations
Authors: BURSTEIN SUMNER , HUNTER SHEILA A.
Published: March 2013

Abstract: The previously reported release of arachidonic acid by THC has now been demonstrated in murine Leydig cells and WI‐38 human lung fibroblasts showing the generality of the effect. The release reaction could be antagonized by phospholipase A2 inhibitors such as quinacrine and quinine, suggesting that THC can stimulate the activity of this enzyme. Further evidence for this possibility was obtained by demonstrating the release effect on a subcellular fraction which contained the phospholipase A2 activity. The stimulation of this enzyme could have profound effects on prostaglandin synthesis and/or on the integrity of various membrane structures.
Cannabinoids And The Cholinergic System
Authors: DOMINO EDWARD F.
Published: March 2013

Abstract: Δ9‐Tetrahydrocannabinol (THC) decreases EEG activation and causes slow waves in the cat. The EEG slow‐wave activity is accompanied by a concomitant decrease in acetylcholine release from the neocortex. The findings suggest that THC depresses the brain stem activating system. Large doses of Δ8‐ and Δ‐THC increase brain acetylcholine levels in rodents such as the mouse and rat, but this effect is not seen with minimal doses of the cannabinoids which show behavioral effects. The most dramatic change produced by THC is that brain acetylcholine utilization is reduced primarily in the hippocampus.
Levonantradol‐Induced Inhibition of Acetylcholine Turnover in Rat Hippocampus and Striatum
Authors: COSTA E. , CHENEY D.L. , MURRAY T.F.
Published: March 2013

Abstract: The effects of levonantradol, a structurally novel cannabinoid‐related analgesic, on the turnover rate of acetylcholine (TRACh) have been studied in various regions of the rat brain. Levonantradol (0.3 mg/kg subcutaneously) decreases the TRACh in the hippocampus and striatum by 53 and 30 per cent, respectively. The extent of the reduction in TRAch is dose dependent, with a maximal decrease of 80 per cent in the hippocampus and 57 per cent in the striatum following the 3 mg/kg dose. In contrast, cortical TRAch is not affected by any dose of levonantradol. This pattern of activity on cholinergic dynamics elicited by levonantradol is qualitatively similar to that of cannabinoids but differs from that previously reported for narcotic analgesics. Moreover, naltrexone (2 mg/kg intraperitoneally) does not reverse the effects of levonantradol on striatal or hippocampal TRAch. This pattern of activity on cholinergic dynamics elicited by levonantradol is consistent with a cannabinoid‐like rather than an opioid‐like mode of action.
GABA‐like Actions of Levonantradol
Authors: LEADER JOAN P. , KOE B. KENNETH , WEISSMAN ALBERT
Published: March 2013

Abstract: The interaction of levonantradol and its pharmacologically less active (+)‐enantiomer with GABAergic mechanisms was studied in several in vivo systems: (1) rat cerebellar cGMP, based on the inverse relationship of GABAergic activity and cGMP levels; (2) convulsions elicited by 3‐mercaptopropionic acid, an inhibitor of GABA synthesis; and (3) activated dopamine synthesis in rat striatum following blockade of dopamine receptors. Levonantradol decreased rat cerebellar cGMP content at low doses (1.0 mg/kg intraperitoneally) and antagonized elevation of cGMP levels by the GABA biosynthesis inhibitor isoniazid at even lower doses (0.32 mg/kg intraperitoneally); this activity pattern is suggestive of GABAergic activity. This conclusion is also supported by levonantradol's protection of mice against the convulsant effects of 3‐mercaptopropionic acid. GABAergic agents are known to antagonize the enhanced dopamine synthesis and turnover that accompany dopamine receptor blockade by neuroleptics. Levonantradol (0.047 mg/kg intravenously) stereospecifically attenuated the elevated dopa accumulation induced by haloperidol. Levonantradol is at least 100‐fold more active than THC in blocking isoniazid‐induced elevation of cGMP levels in rat cerebellum or haloperidol‐induced enhanced dopa accumulation in rat striatum.
Selective and Potent Analgetics Derived from Cannabinoids
Authors: JOHNSON M. R. , MELVIN L. S. , ALTHUIS T. H. , BINDRA J. S. , HARBERT C. A. , MILNE G. M. , WEISSMAN A.
Published: March 2013

Abstract: Based on the hypothesis that analgetic activity is a dissociable feature of the cannabinoid molecule, we examined modifications of the side chain, the phenolic moiety, and, most significantly, structures that lack the benzopyran functionality present in THC and (—)‐9‐nor‐9β‐hydroxyhexahydrocannabinol (HHC). A new grouping, the 1‐methyl‐4‐phenylbutyloxy C‐3 side chain, elaborates a unique lipopholic region. Replacement of the phenol substituent produced several derivatives which retain analgetic activity in the codeine potency range. Introduction of a weakly basic nitrogen at C‐5 and deletion of the axial methyl group in the B ring, two structural changes forbidden by traditional cannabinoid SAR, resulted in a unique family of benzoquinolines with potent analgetic activity. The prototype of this series, levonantradol, exhibits potent and stereospecific analgetic and antiemetic activity.
Biological Activity of Cannabichromene, its Homologs and Isomers
Authors: TURNER CARLTON E. , ELSOHLY MAHMOUD A.
Published: March 2013

Abstract: Cannabichromene (CBC) is one of four major cannabinoids in Cannabis sativa L. and is the second most abundant cannabinoid in drug‐type cannabis. Cannabichromene and some of its homologs, analogs, and isomers were evaluated for antiinflammatory, antibacterial, and antifungal activity. Antiinflammatory activity was evaluated by the carrageenan‐induced rat paw edema and the erythrocyte membrane stabilization method. In both tests, CBC was superior to phenylbutazone. Antibacterial activity of CBC and its isomers and homologs was evaluated using gram‐positive, gram‐negative, and acid‐fast bacteria. Antifungal activity was evaluated using yeastlike and filamentous fungi and a dermatophyte. Antibacterial activity was strong, and the antifungal activity was mild to moderate.
Pharmacokinetics and Mechanisms of Action of Analgesics in Clinical Pain
Authors: STAMBAUGH JOHN E.
Published: March 2013

Abstract: Due to recent interest in the development of drug assay techniques, the pharmacokinetics of many analgesics have been defined. In addition, mechanisms of action of the commonly used analgesics have been partly delineated, and currently accepted analgesic regimens and usages are being questioned. By considering both the pharmacokinetics and the mechanism of action of each of these analgesics, it would appear that only a few of the currently available agents are needed for the treatment of acute and chronic pain. Newer agents with reduced toxicity have been introduced but have resulted in little expansion of novel ways to interfere with pain. The recent discovery of the β‐endorphin system, the reevaluation of older agents, and the development of new agents that work at pain pathways other than the classical sites hold out the promise of alternative means of control of certain types of pain. An agent that has analgesic efficacy equivalent to morphine but with reduced toxicity is especially exciting in the development of new analgesics. An agent that, in addition, does not lead to intolerable psychomimetic reactions but instead addresses multiple aspects of treating the fear, pain, and tension triad of pain will be beneficial in acute pain but will epecially enhance the spectrum of the control of chronic pain such as cancer, neuralgia and arthralgia.
Effects of Moderate and High Doses of Marihuana on Thermal Pain: A Sensory Decision Theory Analysis
Authors: CLARK W. CRAWFORD , JANAL MALVIN N. , ZEIDENBERG PHILLIP , NAHAS GABRIEL G.
Published: March 2013

Abstract: Sixteen habitual marihuana users, selected for their good mental and physical health, were hospitalized for three months in the New York State Psychiatric Institute. During the first month, the subjects were drug free; during the second month, they smoked marihuana cigarettes provided by NIDA (2% THC, 20 mg per cigarette) at the rate of 3 to 12 a day. A modified Hardy‐Wolff dolorimeter was used to present 20 thermal stimuli of 30‐second duration in a random manner at nine different intensities. Subjects responded from a 14‐category scale, and data were analyzed according to sensory decision theory analysis. During the third month, the subjects were again drug free. At the noxious thermal intensities, there was a decrease in the pain report criterion during the first two weeks of smoking. The pain enhancement effect was followed by return to the presmoking pain level during weeks 3 and 4 and in the postsmoking period, indicating that tolerance had developed. There was also an increase in pain discriminability during the four weeks of smoking which extended for one week after smoking. Tolerance developed to the pain report criterion but not to the thermal discriminability. This study suggests that marihuana may have hyperalgesic activity and probably enhances the perception of pain, in moderate smokers. In contrast, heavy smoking had little effect on discriminability and caused an increase in the pain report criterion.
A Comparison of THC, Nantradol, Nabilone, and Morphine in the Chronic Spinal Dog
Authors: GILBERT PAUL E.
Published: March 2013

Abstract: Morphine and Δ9‐tetrahydrocannabinol (THC) have been shown to have certain pharmacologic characteristics in common. Among these are antinociception, hypothermia, and the suppression of precipitated abstinence in morphine‐dependent rats. In the present study the effects of morphine were compared with the effects of THC and two synthetic cannabinoids, nantradol and nabilone, in both nondependent and morphine‐dependent chronic spinal dogs. Single doses of THC, nantradol, and nabilone depressed the flexor and skin twitch reflexes and had a calming effect after intravenous infusion. These effects are similar to those of morphine. Morphine, nantradol, and nabilone, but not THC, depressed rectal temperature. Unlike morphine, however, the cannabinoids produced mydriasis and an increased startle response, and these effects were not antagonized by naltrexone. THC, nantradol, and nabilone suppressed withdrawal abstinence in 40‐hour and maximally abstinent morphine‐dependent chronic spinal dogs. The results suggest that THC, nantradol, and nabilone share some properties with morphine since they increased the latency of the skin twitch reflex and suppressed withdrawal abstinence. It is doubtful, however, that these actions of the cannabinoids are mediated through opioid receptors since they were not antagonized by naltrexone.
Evaluation of Intramuscular Levonantradol and Placebo in Acute Postoperative Pain
Authors: JAIN ADESH K. , RYAN JEROME R. , McMAHON F. GILBERT , SMITH GLADYS
Published: March 2013

Abstract: Double‐blind administration of a single intramuscular dose of 1.5, 2.0, 2.5, or 3.0 mg levonantradol or placebo to 56 patients with moderate to severe postoperative or trauma pain showed significant analgesic effects of each dose of levonantradol as compared to placebo (P < 0.05). However, no significant dose response was observed. Compared to 2/16 patients on placebo, 23/40 patients (57 per cent) on levonantradol reported one or more side effect. Drowsiness was most frequent. Dry mouth, dizziness, “weird dreams,” mild hallucinations, nervousness, apprehension and confusion occurred less frequently. Changes in resting heart rate and blood pressure were minor and general acceptability was good.
A Pharmacological Analysis of Levonantradol Antinociception in Mice
Authors: JACOB JOSEPH J. , RAMABADRAN KRISHNASWAMI , CAMPOS‐MEDEIROS MARY
Published: March 2013

Abstract: Using the hot plate test, the potency and mechanism of the analgesic activity of levonantradol was studied in mice. Levonantradol is 10 to 30 times more potent than morphine; the antinociception can be only partially blocked by naloxone. Similar limited antagonism by cholinergics indicates possible opiodergic mechanism. The role of serotoninergic pathways is unclear; antinociception is partially blocked by 5,7‐dihydroxytryptamine, unaffected by p‐chlorophenylalanine, and potentiated by cyproheptadine. Levonantradol blocks naloxone‐induced signs of abstinence in morphine‐dependent mice, being 3000 times more potent than morphine and 300 times more potent than Δ9‐tetrahydrocannabinol (THC).
The Antinociceptive Effects of Intrathecally Administered Levonantradol and Desacetyllevonantradol in the Rat
Authors: YAKSH TONY L.
Published: March 2013

Abstract: Levonantradol and its desacetylated metabolite (desacetyllevonantradol) produced a dose‐dependent increase in the hot plate and tail flick response latencies following intrathecal administration in a dose range from 4 to 40 μg. No difference in potency between the two drugs was observed, as defined by the ED50 values obtained in either test. The duration of the effect of either drug was also dose dependent, ranging from 30 to 120 minutes. No effect on placing, stepping or righting reflexes or the ability of the rats to negotiate a 60° inclined plane was observed at these doses. At the highest doses, however, an exaggerated myoclonic response to abrupt muscle stretch was observed. None of those effects was antagonized by naloxone (2 mg/kg) administered intraperitoneally before or after levonantradol.
Effects of Morphine, Levonantradol, and N‐Methyllevonantradol on Shock Intensity Discrimination
Authors: DYKSTRA LINDA A.
Published: March 2013

Abstract: The effects of morphine, levonantradol, and N‐methyllevonantradol administered to squirrel monkeys by intramuscular injection were examined on an electric shock discrimination test. Two discrete responses were used to measure discrimination of the presence or absence of a shock at two different intensities (0.45 and 0.15 mA). The percentage of responses that were correct, the response latency, and the response probability in the presence or absence of shock were determined. Morphine (0.3–1.0 mg/kg) decreased the percentage of correct responses in the presence of both shock intensities, although effects at the higher intensity were slight. Levonantradol (0.017–0.03 mg/kg) and N‐methyllevonantradol (0.01–0.017 mg/kg) only decreased the percentage of correct responses at the lower shock intensity. Neither morphine, levonantradol, nor N‐methyllevonantradol consistently decreased the percentage of correct responses in the absence of shock. Morphine, levonantradol, and N‐methyllevonantradol also produced dose‐related increases in response latency both in the presence and absence of shock; increases in response latency were greater in the absence of shock than in the presence of shock.
Behavioral Effects of Levonantradol and Nantradol in the Rhesus Monkey
Authors: YOUNG ALICE M. , KATZ JONATHAN L. , WOODS JAMES H.
Published: March 2013

Abstract: In rhesus monkeys, acute administration of levonantradol and nantradol produced signs of CNS depression, including ataxia with body sag, pupil dilation, ptosis, dozing, and reduced responsivity to external stimuli. Neither compound suppressed the morphine withdrawal syndrome; however, both alleviated the chronic abdominal contraction associated with withdrawal. The directly observable effects of these compounds were not antagonized by naloxone. When levonantradol was administered every 6 hours, marked tolerance developed to both the effects of levonantradol and nabilone and THC. No signs of withdrawal were observed when levonantradol injections were abruptly discontinued. When substituted in lieu of codeine under an intravenous drug self‐administration procedure, neither levonantradol nor nantradol maintained responding at rates higher than those maintained by their vehicle. Finally, the discriminative effects of levonantradol were not equivalent to those of the narcotics ethylketazocine or etorphine.
Effectiveness of Nantradol in Blocking Narcotic Withdrawal Signs Through Nonnarcotic Mechanisms
Authors: LAL HARBANS , BENNETT DEBRA A. , SHEARMAN GARY T. , McCARTEN MICHAEL D. , MURPHY RUSSELL , ANGEJA ANTONIO
Published: March 2013

Abstract: Male rats were made narcotic dependent through continuous intravenous infusion of morphine. During withdrawal, nantradol, clonidine, and morphine were found to block withdrawal signs in a dose‐dependent manner. Almost complete alleviation of withdrawal occurred with nantradol or clonidine at 0.16 mg/kg and with morphine at 40 mg/kg. The effectiveness of morphine, but not of nantradol or clonidine, was reversed by naloxone. Likewise, in naive rats given castor oil, naloxone did not block the antidiarrheal effect of nantradol or clonidine. In order to compare possible subjective effects of nantradol with other antiwithdrawal drugs, naive rats were trained to discriminate either morphine, cyclazocine, or clonidine from vehicle by selecting different levers for reinforcement. Nantradol failed to produce any generalization to morphine, cyclazocine, or clonidine, suggesting that this drug does not produce central subjective effects like those of the training drugs. In additional testing in behavioral experiments, nantradol failed to produce any sign of anxiogenic activity.
Levonantradol: A Role for Central Prostanoid Mechanisms?
Authors: MILNE GEORGE M. , JOHNSON M. ROSS
Published: March 2013

Abstract: Although Δ9‐tetrahydrocannabinol (THC) possesses many pharmacologic activities, attempts to define sites of biochemical action for the natural cannabinoids have been hampered by their low solubility, their low potency, and their relative lack of biologic selectivity. We have recently described a potent, cannabinoid‐related analgetic, levonantradol, which acts stereospecifically in animals to produce analgesia qualitatively similar to morphine but at 1/9 to 1/34 the dose. While levonantradol does not act at or through the opiate receptor, the finding of one‐way cross tolerance in animals suggests that morphine and levonantradol influence common nociceptive pathways. This report describes a striking structural homology between PGE1 and levonantradol as elucidated by x‐ray and conformational studies. This observation is consistent with the generally recognized involvement of prostaglandins in pain and emesis and may have relevance to the site of levonantradol's analgetic actions. More importantly, it provides an ongoing, heuristic basis for exploring, in depth, the role of prostaglandins in the action of levonantradol and cannabinoids.
The Efficacy and Safety of Nabilone (A Synthetic Cannabinoid) in the Treatment of Anxiety
Authors: FABRE LOUIS F. , McLENDON DAVID
Published: March 2013

Abstract: The anxiolytic properties of nabilone, a synthetic cannabinoid resembling the natural cannabinoids, were studied in 25 outpatients suffering from anxiety. The drug was compared with a placebo in a double‐blind manner over a 28‐day treatment period. Patients were seen weekly by the physician and were rated by the Hamilton Rating Scale for Anxiety and the Patient's Global Evaluation as well as by patient‐rated evaluations. The results of the study showed a dramatic improvement in anxiety in the nabilone group when compared with placebo (P < 0.001). Side effects reported were dry mouth, dry eyes, and drowsiness. Patients did not report any of the subjective “altered state” experience of marihuana.
Single‐Dose Study of Nabilone in Anxious Volunteers
Authors: GLASS RICHARD M. , UHLENHUTH E. H. , HARTEL FRANK W. , SCHUSTER CHARLES R. , FISCHMAN MARIAN W.
Published: March 2013

Abstract: The effects of single oral doses of nabilone, a synthetic cannabinoid, were studied in eight anxious volunteer subjects. Each subject had two exposures to placebo and three dose levels of nabilone at one‐week intervals in a single‐blind balanced Latin‐square design after the nabilone dose range was determined by each subject's response to a test dose. Heart rate and blood pressure were monitored. The Profile of Mood States (POMS), a self‐rating adjective checklist, was used as the quantitative measure of subjective effects. Four subjects performed a continuous avoidance procedure. High doses (4 or 5 mg) of nabilone produced orthostatic hypotension in these subjects. Mild dose‐related increases in heart rate also occurred. Despite the occurrence of highly significant levels of sedation, there were no significant effects of nabilone on the continuous avoidance procedure. Two of these four subjects experienced an antianxiety effect from low (1 or 2 mg) nabilone doses. Four other subjects received comparatively lower doses of nabilone and performed on three behavioral tasks at intervals before and after drug: a recognition memory procedure, a task requiring spaced responding at a controlled rate, and a reaction time task. In these subjects there were no reliable effects on blood pressure or heart rate, no significant subjective effects on the POMS, and no antianxiety effects. Drug effects were also minimal on the three behavioral tasks.
Facilitation of Benzodiazepine Binding by Levonantradol
Authors: KOE B. KENNETH , WEISSMAN ALBERT
Published: March 2013

Abstract: Levonantradol enhanced binding of 3H‐diazepam to rat cortical membranes. Scatchard analysis of this effect showed apparent KD and Bmax changes at 100 μM levonantradol and a KD decrease at 50 μM. Dextronantradol caused a similar enhancement, suggesting a lack of stereospecificity in vitro. Subsequently, levonantradol at pharmacologic doses (0.15 mg/kg subcutaneously) was found to enhance the binding of intravenous 3H‐flunitrazepam to mouse brain. In contrast to the results in vitro, dextronantradol showed no enhancement of 3H‐flunitrazepam binding at doses up to 15 mg/kg subcutaneously. This stereospecific interaction with benzodiazepine receptors in vivo suggests that levonantradol may facilitate the pharmacologic actions of benzodiazepines. Levonantradol, at doses of 0.32 and 3.2 mg/kg subcutaneously, which did not block the convulsant effect of pentylenetetrazol, enhanced both the potency and efficacy of diazepam in elevating the absolute threshold of pentylenetetrazol for eliciting clonic seizures. Consistent with its lack of facilitation of benzodiazepine binding, dextronantradol at 3.2 mg/kg, a dose without effect on pentylenetetrazol‐induced convulsions, showed little or no enhancement of diazepam's anticonvulsant activity against the latter.
Levonantradol Potentiates the Anticonvulsant Effects of Diazepam and Valproic Acid in the Kindling Model of Epilepsy
Authors: EHLERS C. L. , HENRIKSEN S. J. , BLOOM F. E.
Published: March 2013

Abstract: The anticonvulsant effects of the cannabinoid derivative levonantradol and its ability to potentiate the anticonvulsant effects of diazepam and valproic acid were studied in rats with previously established amygdala‐kindled seizures. Levonantradol administered in doses of 100 to 400 μg/kg did not block any components of the motor seizure. However, levonantradol did increase the latency of appearance of fully kindled seizures at the 400 μg/kg dose. Administration of diazepam at doses of 1 or 2 mg/kg or valproic acid at doses of 100 or 200 mg/kg produced seizure control as measured by a reduction in motor components of the seizure or a reduction in afterdischarge length or both. The anticonvulsant effects of diazepam and valproic acid were potentiated by administration of 100 μg/kg levonantradol without apparent increases in sedation. Although the mechanism underlying this potentiation of the antiepileptic effects of valproic acid and diazepam remains unknown, levonantradol may have potential as adjunctive therapy in the treatment of complex partial seizures.
Treatment of Human Spasticity with Δ9‐Tetrahydrocannabinol
Authors: PETRO DENIS J. , ELLENBERGER CARL
Published: March 2013

Abstract: Spasticity is a common neurologic condition in patients with multiple sclerosis, stroke, cerebral palsy or an injured spinal cord. Animal studies suggest that THC has an inhibitory effect on polysynaptic reflexes. Some spastic patients claim improvement after inhaling cannabis. We tested muscle tone, reflexes, strength and performed EMGs before and after double‐blinded oral administration of either 10 or 5 mg THC or placebo. The blinded examiner correctly identified the trials in which the patients received THC in seven of nine cases. For the group, 10 mg THC significantly reduced spasticity by clinical measurement (P < 0.01). Quadriceps EMG interference pattern was reduced in those four patients with primarily extensor spasticity. THC was administered to eight other patients with spasticity and other CNS lesions. Responses varied, but benefit was seen in three of three patients with “tonic spasms.” No benefit was noted in patients with cerebellar disease.
Hypnotic and Antiepileptic Effects of Cannabidiol
Authors: CARLINI ELISALDO A. , CUNHA JOMAR M.
Published: March 2013

Abstract: Clinical trials with cannabidiol (CBD) in healthy volunteers, insomniacs, and epileptic patients conducted in the authors' laboratory from 1972 up to the present are reviewed. Acute doses of cannabidiol ranging from 10 to 600 mg and chronic administration of 10 mg for 20 days or 3 mg/kg/day for 30 days did not induce psychologic or physical symptoms suggestive of psychotropic or toxic effects; however, several volunteers complained of somnolence. Complementary laboratory tests (EKG, blood pressure, and blood and urine analysis) revealed no sign of toxicity. Doses of 40, 80, and 160 mg cannabidiol were compared to placebo and 5 mg nitrazepam in 15 insomniac volunteers. Subjects receiving 160 mg cannabidiol reported having slept significantly more than those receiving placebo; the volunteers also reported significantly less dream recall with the three doses of cannabidiol than with placebo. Fifteen patients suffering from secondary generalized epilepsy refractory to known antiepileptic drugs received either 200 to 300 mg cannabidiol daily or placebo for as long as 4.5 months. Seven out of the eight epileptics receiving cannabidiol had improvement of their disease state, whereas only one placebo patient improved.
Antiepileptic Potential of Cannabidiol Analogs
Authors: CONSROE P. , MARTIN A. , SINGH V.
Published: March 2013

Abstract: In audiogenic seizure (AGS) susceptible rats, the acute (intraperitoneal and intravenous) dose‐response effects of (–)‐cannabidiol (CBD) for preventing AGS and for causing rototod neurotoxicity (ROT) were determined. Also, the anti‐AGS and ROT effects of 10 CBD analogs, given in intravenous doses equivalent to the AGS‐ED50 (15 mg/kg) and ROT‐ID50 (31 mg/kg) of CBD, were ascertained. Compared to CBD, (–)‐CBD diacetate and (–)‐4‐(2′‐olivetyl)‐α‐pinene were equally effective whereas (–)‐CBD monomethyl ether, (–)‐CBD dimethyl ether, (–)‐3′‐acetyl‐CBD monoacetate, (+)‐4‐(2′‐olivetyl)‐α‐pinene, (–)‐and (+)‐4‐(6′‐olivetyl)‐α‐pinene, (±)‐AF‐11, and olivetol were less effective anticonvulsants. Except for (–)‐ and (+)‐4‐(2′‐olivetyl)‐α‐pinene and olivetol, all analogs showed less ROT than CBD. Also, CBD and all analogs were not active in tetrahydrocannabinol seizure‐susceptible rabbits, the latter a putative model of cannabinoid psychoactivity in humans. These data suggest anticonvulsant requirements of 2 free phenolic hydroxyl groups, exact positioning of the terpinoid moiety in the resorcinol system and correct stereochemistry. Moreover, findings of separation of anticonvulsant from neurotoxic and psychoactive activities, notably with CBD diacetate, suggest that additional structural modifications of CBD may yield novel antiepileptic drugs.