The endocannabinoid system, eating behavior and energy homeostasis: the end or a new beginning?

The endocannabinoid system (ECS) consists of two receptors (CB(1) and CB(2)), several endogenous ligands (primarily anandamide and 2-AG), and over a dozen ligand-metabolizing enzymes. The ECS regulates many aspects of embryological development and homeostasis, including neuroprotection and neural plasticity, immunity and inflammation, apoptosis and carcinogenesis, pain and emotional memory, and the focus of this review: hunger, feeding, and metabolism. This mini-review summarizes the main findings that supported the clinical use of CB1 antagonists/inverse agonists, the clinical concerns that have emerged, and the possible future of cannabinoid-based therapy of obesity and related diseases. The ECS controls energy balance and lipid metabolism centrally (in the hypothalamus and mesolimbic pathways) and peripherally (in adipocytes, liver, skeletal muscle and pancreatic islet cells), acting through numerous anorexigenic and orexigenic pathways. Obese people seem to display an increased endocannabinoid tone, driving CB(1) receptor in a feed-forward dysfunction. Several CB(1) antagonists/inverse agonists have been developed for the treatment of obesity. Although these drugs were found to be efficacious at reducing food intake as well as abdominal adiposity and cardiometabolic risk factors, they resulted in adverse psychiatric effects that limited their use and finally led to the end of the clinical use of systemic CB(1) ligands with significant inverse agonist activity for complicated obesity. However, the existence of alternatives such as CB(1) partial agonists, neutral antagonists, antagonists restricted to the periphery, allosteric modulators and other potential targets within the ECS indicate that a cannabinoid-based therapy for the management of obesity and its associated cardiometabolic sequelae should remain open for consideration.

Critical role of the endocannabinoid system in the regulation of food intake and energy metabolism, with phylogenetic, developmental, and pathophysiological implications.

The endocannabinoid system (ECS) consists of two receptors (CB(1) and CB(2)), several endogenous ligands (primarily anandamide and 2-AG), and over a dozen ligand-metabolizing enzymes. The ECS has deep phylogenetic roots and regulates many aspects of embryological development and homeostasis, including neuroprotection and neural plasticity, immunity and inflammation, apoptosis and carcinogenesis, pain and emotional memory, and the focus of this review: hunger, feeding, and metabolism. The ECS controls energy balance and lipid metabolism centrally (in the hypothalamus and mesolimbic pathways) and peripherally (in adipocytes and pancreatic islet cells), acting through numerous anorexigenic and orexigenic pathways (e.g., ghrelin, leptin, orexin, adiponectin, endogenous opioids, and corticotropin-releasing hormone). Obesity leads to excessive endocannabinoid production by adipocytes, which drives CB(1) in a feed-forward dysfunction. Phylogenetic research suggests the genes for endocannabinoid enzymes, especially DAGLalpha and NAPE-PLD, may harbor mildly deleterious alleles that express disease-related phenotypes. Several CB(1) inverse agonists have been developed for the treatment of obesity, including rimonabant, taranabant, and surinabant. These drugs are efficacious at reducing food intake as well as abdominal adiposity and cardiometabolic risk factors. However, given the myriad beneficial roles of the ECS, it should be no surprise that systemic CB(1) blockade induces various adverse effects. Alternatives to systemic blockade include CB(1) partial agonists, pleiotropic drugs, peripherally restricted antagonists, allosteric antagonists, and endocannabinoid ligand modulation. The ECS offers several discrete targets for the management of obesity and its associated cardiometabolic sequelae.

Meta-analysis of cannabinoid ligand binding affinity and receptor distribution: interspecies differences.

A meta-analysis, unlike a literature review, synthesizes previous studies into new results. Pooled data from 211 studies measured ligand binding affinities at human (Hs) or rat (Rn) cannabinoid receptors CB1 and CB2. Cochrane methods were modified for this non-clinical analysis. Meta-regression detected data heterogeneity arising from methodological factors: use of sectioned tissues, lack of PMSF and choice of radioligand. Native brain tissues exhibited greater affinity (lower nM) than transfected cells, but the trend fell short of significance, as did the trend between centrifugation and filtration methods. Correcting for heterogeneity, mean Ki values for delta 9-tetrahydrocannabinol differed significantly between HsCB1 and RnCB1 (25.1 and 42.6 nM, respectively) but not between HsCB1 and HsCB2 (25.1 and 35.2). Mean Kd values for HsCB1, RnCB1 and HsCB2 of CP55,940 (2.5, 0.98, 0.92) and WIN55,212-2 (16.7, 2.4, 3.7) differed between HsCB1 and RnCB1 and between HsCB1 and HsCB2. SR141716A differed between HsCB1 and RnCB1 (2.9 and 1.0 nM). Anandamide at HsCB1, RnCB1 and HsCB2 (239.2, 87.7, 439.5) fell short of statistical differences due to heterogeneity. We consider these Kd and Ki values to be the most valid estimates in the literature. Sensitivity analyses did not support the numerical validity of cannabidiol, cannabinol, 2-arachidonoyl glycerol and all ligands at RnCB2. Aggregate rank order analysis of CB(1) distribution in the brain (pooled from 119 autoradiographic, immunohistochemical and in situ hybridization studies) showed denser HsCB1 expression in cognitive regions (cerebral cortex) compared to RnCB1, which was relatively richer in movement-associated areas (cerebellum, caudate-putamen). Implications of interspecies differences are discussed.

A shifted repertoire of endocannabinoid genes in the zebrafish (Danio rerio).

The zebrafish has served as a model organism for developmental biology. Sequencing its genome has expanded zebrafish research into physiology and drug-development testing. Several cannabinoid pharmaceuticals are in development, but expression of endocannabinoid receptors and enzymes remains unknown in this species. We conducted a bioinformatics analysis of the zebrafish genome using 17 human endocannabinoid genes as a reference set. Putative zebrafish orthologs were identified in filtered BLAST searches as reciprocal best hits. Orthology was confirmed by three in silico methods: phylogenetic testing, synteny analysis, and functional mapping. Zebrafish expressed orthologs of cannabinoid receptor 1, transient receptor potential channel vanilloid receptor 4, GPR55 receptor, fatty acid amide hydrolase 1, monoacylglycerol lipase, NAPE-selective phospholipase D, abhydrolase domain-containing protein 4, and diacylglycerol lipase alpha and beta; and paired paralogs of cannabinoid receptor 2, fatty acid amide hydrolase 2, peroxisome proliferator-activated receptor alpha, prostaglandin-endoperoxide synthase 2, and transient receptor potential cation channel subtype A1. Functional mapping suggested the orthologs of transient receptor potential vanilloid receptor 1 and peroxisome proliferator-activated receptor gamma lack specific amino acids critical for cannabinoid ligand binding. No orthologs of N-acylethanolamine acid amidase or protein tyrosine phosphatase, non-receptor type 22 were identified. In conclusion, the zebrafish genome expresses a shifted repertoire of endocannabinoid genes. In vitro analyses are warranted before using zebrafish for cannabinoid development testing.

Cannabinoid receptors in invertebrates.

Two cannabinoid receptors, CB1 and CB2, are expressed in mammals, birds, reptiles, and fish. The presence of cannabinoid receptors in invertebrates has been controversial, due to conflicting evidence. We conducted a systematic review of the literature, using expanded search parameters. Evidence presented in the literature varied in validity, ranging from crude in vivo behavioural assays to robust in silico ortholog discovery. No research existed for several clades of invertebrates; we therefore tested for cannabinoid receptors in seven representative species, using tritiated ligand binding assays with [3H]CP55,940 displaced by the CB1-selective antagonist SR141716A. Specific binding of [3H]CP55,940 was found in neural membranes of Ciona intestinalis (Deuterstoma, a positive control), Lumbricusterrestris (Lophotrochozoa), and three ecdysozoans: Peripatoides novae-zealandiae (Onychophora), Jasus edwardi (Crustacea) and Panagrellus redivivus (Nematoda); the potency of displacement by SR141716A was comparable to measurements on rat cerebellum. No specific binding was observed in Actinothoe albocincta (Cnidaria) or Tethya aurantium (Porifera). The phylogenetic distribution of cannabinoid receptors may address taxonomic questions; previous studies suggested that the loss of CB1 was a synapomorphy shared by ecdysozoans. Our discovery of cannabinoid receptors in some nematodes, onychophorans, and crustaceans does not contradict the Ecdysozoa hypothesis, but gives it no support. We hypothesize that cannabinoid receptors evolved in the last common ancestor of bilaterians, with secondary loss occurring in insects and other clades. Conflicting data regarding Cnidarians precludes hypotheses regarding the last common ancestor of eumetazoans. No cannabinoid receptors are expressed in sponges, which probably diverged before the origin of the eumetazoan ancestor.

Benign prostatic hyperplasia treated with saw palmetto: a literature search and an experimental case study.

European physicians treat benign prostatic hyperplasia (BPH) with saw palmetto extract (SPE), while American physicians generally disregard SPE because "research is lacking." The authors investigated this discrepancy with a literature search and a clinical trial. The literature search began with MEDLINE, then expanded to "alternative" databases, including AGRICOLA, EMBASE, IBIS, and Cochrane, plus a manual search of unindexed herbal journals. The clinical trial was an experimental case study in which a 67-year-old man with symptomatic BPH was randomly administered SPE (160 mg standardized extract twice daily) or placebo. Outcome measures included the American Urological Association Symptom Index (AUASI), serum prostate-specific antigen, and prostate volume. Our expanded literature search revealed 58 clinical trials, whereas MEDLINE yielded only 19 clinical trials, or 33% of the total. Our clinical trial measured a baseline AUASI score of 20, which improved to 7 after unblinded administration of SPE. Subsequent double-blinded placebo produced a score of 14, and final single-blinded allotment of SPE produced a score of 11. Prostate-specific antigen was 10.3 ng/mL at baseline and 10.7 ng/mL at trial's conclusion. Baseline prostatic volume was 92 mL, and end volume was 75 mL. In conclusion, MEDLINE proved inadequate as a stand-alone search engine for locating information about an herbal medicine. Our experimental case study, similar to N = 1 research methodology, proved suitable for clinical evaluation of an herbal medicine in a rural private practice. SPE improved the patient's BPH. Unstandardized look-alike herbs may act as nontherapeutic placebos and may undermine consumer confidence in herbal medicine.

Side effects of pharmaceuticals not elicited by comparable herbal medicines: the case of tetrahydrocannabinol and marijuana.

OBJECTIVE: Herbalists claim that the polypharmacy of botanical remedies provides 2 advantages over single-ingredient drugs: (1) primary active ingredients in herbs are synergized by secondary compounds, and (2) secondary compounds mitigate the side effects caused by primary active ingredients. To examine this second claim, medical marijuana was compared with its primary active ingredient, tetrahydrocannabinol. DATA SOURCES: A search on MEDLINE (1966-1999), AGRICOLA (1990-1999), and Biological and Agricultural Index (1964-1999) using keywords "cannabinoids," "marijuana," "tetrahydrocannabinol," "Cannabis," and "hemp." Phytochemical and ethnobotanical data were searched with the Agricultural Research Service database. Unindexed botanical journals were scanned by hand. STUDY SELECTION: Studies documenting the efficacy of secondary compounds mitigating side effects of tetrahydrocannabinol consisting of double-blind trials, unblinded studies, animal models, and in vitro experiments. DATA EXTRACTION AND DATA SYNTHESIS: Data validity was assessed by consensus, weighted by source (peer-reviewed article vs popular press), identification methodology (analytical chemistry vs clinical history), and frequency of independent observations. CONCLUSIONS: Good evidence suggests that some side effects of tetrahydrocannabinol are mitigated by other volatile compounds present in the essential oil of marijuana. Inhaling tetrahydrocannabinol, which avoids first-pass hepatic metabolism, has advantages over ingesting it. Other cannabinoids, terpenoids, and flavonoids can reduce tetrahydrocannabinol-induced anxiety, cholinergic deficits, and immunosuppression. Other compounds increase cerebral blood flow, enhance cortical activity, kill respiratory pathogens, and provide anti-inflammatory activity. The hazards of marijuana smoke can be reduced with appropriate technology. Proprietary Cannabis extracts containing a mixture of cannabinoids, terpenoids, and flavonoids are currently being developed and tested.

Opinions of MDs, RNs, allied health practitioners toward osteopathic medicine and alternative therapies: results from a Vermont survey.

The authors surveyed 191 allopathic physicians (MDs), registered nurses (RNs), and allied health professionals (AHPs) regarding their opinions toward osteopathic medicine and alternative therapies. A self-administered questionnaire was distributed to these healthcare professionals practicing in a rural region of west-central Vermont. Participants responded to six questions concerning osteopathic medicine and 18 types of alternative therapies. These questions addressed safety issues, efficacy, personal experience, patient referrals, interest in learning more about alternative medicine, and whether alternative medicine should be provided at the regional hospital. The number of positive responses was totaled as a positive opinion score (POS) for each respondent. Survey results indicated that MDs' general acceptance of osteopathic medicine was less than that of relaxation techniques, massage therapy, self-help groups, and acupuncture. Allopathic physicians' opinions toward osteopaths mirrored that shown toward chiropractors. Nevertheless, MDs responded more positively to osteopathy than did RNs and AHPs. Overall, RNs had a higher opinion of alternative therapies (mean POS 50.4) than did AHPs (mean POS 41.7) or MDs (mean POS 36.0; F = 4.98; P-value = 0.009). Among MDs, primary care providers averaged a POS of 41.1, while specialists had a mean POS of 24.0 (F = 6.85; P-value = 0.012). Overall, female respondents had a mean POS of 45.7 and men had a mean POS of 37.0 (F = 3.91; P-value = 0.051). The POS did not correlate with age (Pearson's r test; r = -0.105).

Medical marijuana and its use by the immunocompromised.

BACKGROUND: Those immunocompromised by AIDS or cancer chemotherapy use marijuana to allay symptoms of their disease or treatment. Some researchers believe that marijuana may further suppress the immune system. A list of immunological hazards that may be present in marijuana was collated and assessed, and clinical recommendations regarding the use of marijuana by immunocompromised individuals were made. METHODS: Databases and other sources from 1964 to 1996 were searched using keywords (e.g., cannabinoids, cannabis, hemp, marijuana). This was supplemented by a manual search of bibliographies, nonindexed books, and journals, and by consultation with experts. All reports were analyzed for antecedent sources. Data validity was assessed by source, identification methodology, and frequency of independent observations. RESULTS: Substances implicated as potential immunological hazards in marijuana include endogenous constituents (cannabinoids, pyrolyzed gases, and particulates) and a longer list of exogenous contaminants, both natural (fungi and their metabolites) and synthetic (pesticides and adulterants). CONCLUSION: Burning of marijuana creates toxins of combustion. Particulate toxins (tars) are reduced by the use of vaporizer apparati. Gas-phase toxins are filtered by water pipes, but water pipes also filter some tetrahydrocannabinol, making this strategy counterproductive. Viable fungal spores in marijuana pose the greatest hazard to immunocompromised patients, though they can be sterilized by several methods. Pesticide residues and other adulterants may be present in black-market marijuana, but are absent in sources of marijuana that are approved by the Food and Drug Administration.

Mushroom poisoning.

The majority of cases of mushroom poisoning occur in children and involve benign gastrointestinal irritants. Critical poisonings most frequently occur in adults who ingest Amanita phalloides or other mushrooms containing amanitin. Critical versus noncritical poisonings can be diagnosed with a high degree of confidence by the patient's history and initial symptoms. The most promising new medical treatment for Amanita mushroom poisoning is silibinin. In suspected cases of mushroom poisoning, it is important to obtain specimens of the ingested mushrooms, if possible, since treatment is specific to the species.

Caffeine and chronic back pain.

OBJECTIVE: Tobacco use and other behavioral factors are associated with chronic back pain. Anecdotes suggest excess caffeine use may also be associated with chronic back pain. We compared caffeine consumption by chronic back pain patients with caffeine consumption by controls. DESIGN: Retrospective case-control study. SETTING: A multispecialty outpatient facility. PATIENTS: Sixty new, consecutive patients with chronic back pain compared to 60 new, consecutive patients without chronic back pain. INTERVENTION: Patients were prospectively asked to complete an intake questionnaire. MAIN OUTCOME MEASURE: Daily caffeine consumption was estimated by analyzing the intake questionnaire. Differences between groups were analyzed by both normal and nonparametric statistics. RESULTS: Consumption of caffeine by patients with chronic back pain averaged 392.4 mg/day. Controls consumed 149.8 mg/ day, a significant difference (p = .0001). Men consumed 86% more caffeine per day than women (p = .02). Age and caffeine consumption showed little correlation (r = .126). CONCLUSIONS: Patients with chronic back pain consume over twice as much caffeine as patients without chronic back pain. Confounding variables and possible mechanisms associating caffeine with chronic back pain are discussed.

Entrainment and the cranial rhythmic impulse.

Entrainment is the integration or harmonization of oscillators. All organisms pulsate with myriad electrical and mechanical rhythms. Many of these rhythms emanate from synchronized pulsating cells (eg, pacemaker cells, cortical neurons). The cranial rhythmic impulse is an oscillation recognized by many bodywork practitioners, but the functional origin of this impulse remains uncertain. We propose that the cranial rhythmic impulse is the palpable perception of entrainment, a harmonic frequency that incorporates the rhythms of multiple biological oscillators. It is derived primarily from signals between the sympathetic and parasympathetic nervous systems. Entrainment also arises between organisms. The harmonizing of coupled oscillators into a single, dominant frequency is called frequency-selective entrainment. We propose that this phenomenon is the modus operandi of practitioners who use the cranial rhythmic impulse in craniosacral treatment. Dominant entrainment is enhanced by "centering," a technique practiced by many healers, for example, practitioners of Chinese, Tibetan, and Ayurvedic medicine. We explore the connections between centering, the cranial rhythmic impulse, and craniosacral treatment.

Chronic neck pain, standing balance, and suboccipital muscle atrophy--a pilot study.

OBJECTIVE: To study the relationship between chronic neck pain, standing balance and suboccipital muscle atrophy. We hypothesize that patients with chronic neck pain have more somatic dysfunction in the cervical spine than control subjects without neck pain. We also hypothesize that patients with chronic neck pain and somatic dysfunction exhibit more atrophy of suboccipital muscles. Lastly, because suboccipital muscles have a high density of proprioceptors, we hypothesize that chronic pain patients exhibit a loss in standing balance. DESIGN: Randomized, controlled, partially blind study examining chronic neck pain patients and control subjects for differences in degree of upper cervical somatic dysfunction, standing balance and suboccipital muscle atrophy. SETTING: Subjects were recruited from a clinical practice at Michigan State University; controls were recruited from the faculty, staff and students. PARTICIPANTS: Seven chronic neck pain patients and seven asymptomatic control subjects. MAIN OUTCOME MEASURES: Palpation was used to diagnose somatic dysfunction in the upper cervical spine. Balance parameters were calculated using a force platform; muscle atrophy was judged with magnetic resonance images. RESULTS: Chronic neck pain patients had almost twice as many somatic dysfunctions as controls (p = .028). Force platform results showed a decrease in standing balance in patients compared with control subjects (p = .004). MRI showed that chronic neck pain subjects had marked atrophy of the rectus capitis posterior major and minor muscles, including fatty infiltration. CONCLUSIONS: This study suggests that there is a relationship between chronic pain, somatic dysfunction, muscle atrophy and standing balance. We hypothesize a cycle initiated by chronic somatic dysfunction, which may result in muscle atrophy, which can be further expected to reduce proprioceptive output from atrophied muscles. The lack of proprioceptive inhibition of nociceptors at the dorsal horn of the spinal cord would result in chronic pain and a loss of standing balance.

Alternative medicine in Vermont--a census of practitioners: prevalence, patterns of use, and national projections.

The number of alternative/holistic practitioners in Vermont was estimated by two methods: scanning advertisements (yellow pages, newspaper and magazine ads, brochures), and by word-of-mouth canvassing. We located 897 Vermonters who derive most of their annual income practicing at least 1 of 97 different types of alternative medicine and therapy. Most practitioners were female and most practiced more than one type of healing. Bodyworkers were the most prevalent practitioners, followed by chiropractors, acupuncturists, herbalists, and holistic psychotherapists. On a per-capita basis, there is 1 alternative practitioner per 652 Vermonters (or 153 practitioners per 100,000 population). This census nearly equals that of Vermont's M.D. population. Extrapolating this Vermont census to a nationwide estimate of alternative practitioners suggests there are over 403,000 full-time alternative/holistic healers practicing in the United States.

Cranial findings and iatrogenesis from craniosacral manipulation in patients with traumatic brain syndrome.

Craniosacral findings were recorded for all patients with traumatic brain injury entering an outpatient rehabilitation program between 1978 and 1992. The average cranial rhythmic impulse was low in all 55 patients (average, 7.2 c/min). At least one cranial strain pattern was exhibited by 95%, and 87% had one or more bony motion restrictions. Sacral findings were similar to those in patients with low back pain. Although craniosacral manipulation has been found empirically useful in patients with traumatic brain injury, three cases of iatrogenesis occurred. The incidence rate is low (5%), but the practitioner must be prepared to deal with the possibility of adverse reactions.