Going on my 4th decade as a medical professional. There are NO major negative side effects with cannabis and very few minor undesirable side effects such as paranoia and/or anxiety. Even then there are numerous strains to work with and choose from. We noticed the anti-emetic properties very early on starting in the 70's in a huge way.
Cannabis does not cause nausea, per se. It can induce vertigo which in turn causes nausea. Ceasing smoking when that happens leads to a "cure" as the THC and CBD levels drop.
Marijuana has little effect on the motility of the gut.
Interesting thread, and the gut motility issue wrt cannabis is all over the map. I realize that this thread is about gastroparesis (delayed emptying of stomach), but IMHO patients presenting with gastroparetic symptoms may also have problems with gut motility, and that the two are sometimes related via feedback mechanisms. I have had the gut motility and gastroparesis tests, and basically they had me eat a sandwich and then watch the digestive process via NMR over a couple of hours, so I am actually quite interested in this topic of GI motility, and have been doing my own studies on the topic for quite some time. For some this post may not be an "easy read".
The literature (refereed journals) appears to be pointing to a clinically significant impact on gut motility for humans, with numerous mouse studies providing more detailed information on the CB1 and CB2 receptors (and receptor independent studies on cannabichromene).
Changes in gut motility due to exogenous cannabinoid mimetics of the bodies own endocannabinoid system can be quite useful for patients presenting with gut motility problems (e.g., hypermotility). It sounds like the impact of cannabis on motility is dependent on the individual, and that those with the rs806378 CT/TT (Cytosine-Thymine/Thymine-Thymine alleles) SNP (Single Nucleotide Polymorphism) do respond well to cannabis, reducing gut motility. So to patients with hypermotility problems, the impact of cannabinoids on motility is "a good thing". Here is the genetic info (note: The genome databases typically refer to CB1 as CNR1):
http://www.genecards.org/index.php?path=/Search/keyword/rs806378+/0/20 (be sure to click the + sign)
http://www.genecards.org/cgi-bin/carddisp.pl?gene=CNR1&search=rs806378+#snp
In the last link, scroll down to "Genomic Variants for CNR1 gene" and click on "see all 444" to see all genomic variants, including rs806378. The section a couple of sections above that entitled "Expression for CNR1 gene" provides a visual depiction of where CNR1 receptors can be found in the body.
Here are some other links to CNR1:
http://www.uniprot.org/uniprot/P21554
http://www.hgmd.cf.ac.uk/ac/gene.php?gene=CNR1 (You must be associated with a research institution to see the expanded version)
http://genatlas.medecine.univ-paris5.fr/fiche.php?symbol=CNR1
http://geneticassociationdb.nih.gov/cgi-bin/tableview.cgi?table=geneview&cond=GENE+like+'CNR1'
(there are numerous other links in the HGMD expanded database for registered users)
Let's start with a look at the impact of pure THC via dronabinol. There are lots of papers on this, but many of them refer back to Wong et al. as a primary source, so let's start with Wong:
http://www.ncbi.nlm.nih.gov/pubmed/22288893
Neurogastroenterol Motil. 2012 Apr;24(4):358-e169. doi: 10.1111/j.1365-2982.2011.01874.x. Epub 2012 Jan 30.
Randomized pharmacodynamic and pharmacogenetic trial of dronabinol effects on colon transit in irritable bowel syndrome-diarrhea.
Wong BS, Camilleri M, Eckert D, Carlson P, Ryks M, Burton D, Zinsmeister AR.
Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic, Rochester, Minnesota, USA.
BACKGROUND:
Genetic variation in endocannabinoid metabolism is associated with colonic transit in irritable bowel syndrome (IBS) with diarrhea (IBS-D). The nonselective cannabinoid (CB) receptor agonist, dronabinol (DRO), reduced fasting colonic motility in nonconstipated IBS. FAAH and CNR1 variants influenced DRO's effects on colonic motility. Our aims were: (i) to compare dose-related effects of DRO to placebo (PLA) on gut transit in IBS-D, and (ii) to examine influence of genetic variations in CB mechanisms on DROs transit effects.
METHODS:
Thirty-six IBS-D volunteers were randomized (double-blind, concealed allocation) to twice per day PLA (n = 13), DRO 2.5 mg (n = 10), or DRO 5 mg (n = 13) for 2 days. We assessed gastric, small bowel, and colonic transit by validated radioscintigraphy and genotyped the single nucleotide polymorphisms CNR1 rs806378 and FAAH rs324420. Data analysis utilized a dominant genetic model.
KEY RESULTS:
Overall treatment effects of DRO on gastric, small bowel, or colonic transit were not detected. CNR1 rs806378 CT/TT was associated with a modest delay in colonic transit at 24 h compared with CC (P = 0.13 for differential treatment effects on postminus pretreatment changes in colonic transit by genotype). No significant interaction of treatment with FAAH rs324420 was detected.
CONCLUSIONS & INFERENCES:
Overall, DRO 2.5 or 5 mg twice per day for 2 days had no effect on gut transit in IBS-D. There appears to be a treatment-by-genotype effect, whereby DRO preferentially delays colonic transit in those with the CNR1 rs806378 CT/TT genotypes. Further study of CB pharmacogenetics may help identify a subset of IBS-D patients most likely to benefit from CB agonist therapy.
The above abstract deals with Dronabinol (generic Marinol) , so of course only deals with the THC component of cannabis. Here is another study from the same lead author (Wong et al.). The good news about this older article is that the full paper is online.
http://www.ncbi.nlm.nih.gov/pubmed/21803011
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3202649/ (full paper)
Gastroenterology. 2011 Nov;141(5):1638-47.e1-7. doi: 10.1053/j.gastro.2011.07.036. Epub 2011 Jul 29.
Pharmacogenetic trial of a cannabinoid agonist shows reduced fasting colonic motility in patients with nonconstipated irritable bowel syndrome.
Wong BS, Camilleri M, Busciglio I, Carlson P, Szarka LA, Burton D, Zinsmeister AR.
Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
BACKGROUND & AIMS:
Cannabinoid receptors are located on cholinergic neurons. Genetic variants that affect endocannabinoid metabolism are associated with colonic transit in patients with irritable bowel syndrome (IBS) with diarrhea. We compared the effects of dronabinol, a nonselective agonist of the cannabinoid receptor, with those of placebo on colonic motility and sensation in patients with IBS, and examined the effects of IBS subtype and specific genetic variants in cannabinoid mechanisms.
METHODS:
Seventy-five individuals with IBS (35 with IBS with constipation, 35 with IBS with diarrhea, and with 5 IBS alternating) were randomly assigned to groups that were given 1 dose of placebo or 2.5 mg or 5.0 mg dronabinol. We assessed left colonic compliance, motility index (MI), tone, and sensation during fasting and after a meal. We analyzed the single nucleotide polymorphisms CNR1 rs806378, fatty acid amide hydrolase (FAAH) rs324420, and MGLL rs4881.
RESULTS:
In all patients, dronabinol decreased fasting proximal left colonic MI compared with placebo (overall P = .05; for 5 mg dronabinol, P = .046), decreased fasting distal left colonic MI (overall P = .08; for 5 mg, P = .13), and increased colonic compliance (P = .058 ). The effects of dronabinol were greatest in patients with IBS with diarrhea or IBS alternating (proximal colonic MI, overall P = .022; compliance, overall P = .03). Dronabinol did not alter sensation or tone. CNR1 rs806378 (CC vs CT/TT) appeared to affect fasting proximal MI in all patients with IBS (P = .075). Dronabinol affected fasting distal MI in patients, regardless of FAAH rs324420 variant (CA/AA vs CC) (P = .046); the greatest effects were observed among IBS with constipation patients with the FAAH CC variant (P = .045). Dronabinol affected fasting proximal MI in patients with IBS with diarrhea or alternating with the variant FAAH CA/AA (P = .013).
CONCLUSIONS:
In patients with IBS with diarrhea or alternating, dronabinol reduces fasting colonic motility; FAAH and CNR1 variants could influence the effects of this drug on colonic motility.
Of course there are other cannabinoids in cannabis, so here is a paper on cannabichromene and its impact on a mouse model of gut motility. This is significant since cannabichromene is apparently not operating through the CB1 and CB2 receptors:
http://www.ncbi.nlm.nih.gov/pubmed/22300105
Br J Pharmacol. 2012 Jun;166(4):1444-60. doi: 10.1111/j.1476-5381.2012.01879.x.
Inhibitory effect of cannabichromene, a major non-psychotropic cannabinoid extracted from Cannabis sativa, on inflammation-induced hypermotility in mice.
Izzo AA, Capasso R, Aviello G, Borrelli F, Romano B, Piscitelli F, Gallo L, Capasso F, Orlando P, Di Marzo V.
Department of Experimental Pharmacology, University of Naples Federico II, Naples, Italy.
[email protected]
BACKGROUND AND PURPOSE:
Cannabichromene (CBC) is a major non-psychotropic phytocannabinoid that inhibits endocannabinoid inactivation and activates the transient receptor potential ankyrin-1 (TRPA1). Both endocannabinoids and TRPA1 may modulate gastrointestinal motility. Here, we investigated the effect of CBC on mouse intestinal motility in physiological and pathological states.
EXPERIMENTAL APPROACH:
Inflammation was induced in the mouse small intestine by croton oil. Endocannabinoid (anandamide and 2-arachidonoyl glycerol), palmitoylethanolamide and oleoylethanolamide levels were measured by liquid chromatography-mass spectrometry; TRPA1 and cannabinoid receptors were analysed by quantitative RT-PCR; upper gastrointestinal transit, colonic propulsion and whole gut transit were evaluated in vivo; contractility was evaluated in vitro by stimulating the isolated ileum, in an organ bath, with ACh or electrical field stimulation (EFS).
KEY RESULTS:
Croton oil administration was associated with decreased levels of anandamide (but not 2-arachidonoyl glycerol) and palmitoylethanolamide, up-regulation of TRPA1 and CB₁ receptors and down-regulation of CB₂ receptors. Ex vivo CBC did not change endocannabinoid levels, but it altered the mRNA expression of TRPA1 and cannabinoid receptors. In vivo, CBC did not affect motility in control mice, but
normalized croton oil-induced hypermotility. In vitro, CBC reduced preferentially EFS- versus ACh-induced contractions. Both in vitro and in vivo, the inhibitory effect of CBC was not modified by cannabinoid or TRPA1 receptor antagonists.
CONCLUSION AND IMPLICATIONS:
CBC selectively reduces inflammation-induced hypermotility in vivo in a manner that is not dependent on cannabinoid receptors or TRPA1.
People on this site probably already know that components (i.e., THC) of herbal cannabis act as mimetics to the bodies own endocannabinoid anandamide (which is why cannabis works so well). Notice further that acetylcholine (ACh) is mentioned, which is of course associated with smooth muscle contractions (we will get to that).
Here is another paper from a refereed journal pointing to the CB2 receptor and gut motility:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2219529/?report=abstract
Br J Pharmacol. 2008 January; 153(2): 263270.
Published online 2007 October 1. doi: 10.1038/sj.bjp.0707486
PMCID: PMC2219529
Cannabinoid CB2 receptors in the gastrointestinal tract: a regulatory system in states of inflammation
K L Wright,1 M Duncan,2,3 and K A Sharkey2,3,*
Abstract
The emerging potential for the cannabinoid (CB) system in modulating gastrointestinal inflammation has gained momentum over the last few years. Traditional and anecdotal use of marijuana for gastrointestinal disorders, such as diarrhoea and abdominal cramps is recognized, but the therapeutic benefit of cannabinoids in the 21st century is overshadowed by the psychoactive problems associated with CB1 receptor activation. However, the presence and function of the CB2 receptor in the GI tract, whilst not yet well characterized, holds great promise due to its immunomodulatory roles in inflammatory systems and its lack of psychotropic effects. This review of our current knowledge of CB2 receptors in the gastrointestinal tract highlights its role in regulating abnormal motility, modulating intestinal inflammation and limiting visceral sensitivity and pain. CB2 receptors represent a braking system and a pathophysiological mechanism for the resolution of inflammation and many of its symptoms. CB2 receptor activation therefore represents a very promising therapeutic target in gastrointestinal inflammatory states where there is immune activation and motility dysfunction.
Keywords: inflammatory bowel disease, colitis, cannabis, endocannabinoids, enteric nervous system, gastrointestinal motility, bowel cancer, visceral sensation
The above abstract also has the full paper online:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2219529/
Here is an interesting paragraph from the full paper:
Antibodies to CB2 receptor have been used to examine the distribution of protein in the human GI tract. In humans, CB2 receptors are either absent or weakly expressed in intestinal epithelium (Figure 1), but are evident in the apical membranes at ulcerative margins in IBD (Wright et al., 2005; Figure 1).
What I find interesting about the above is the absence or weak expression of CB2 receptors in the intestinal epithelium of healthy intestinal tissue, but the appearance in the diseased colon (click on figure 2 of full paper). That explains why *some* of these papers are so focused on colon pathology and gut motility, with clinically significant results showing for diseased colons of individuals with the SNP rs806378 CT/TT.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2219529/figure/fig2/ (figure 2)
I really like this paper since it discusses mechanisms of action in addition to experimental findings. Here is a section from the summary:
As indicated throughout this review, there are substantial areas where we have little or no knowledge of the CB2 receptor in the GI tract. These include further knowledge of the sites of receptor expression in normal animals and in disease states, the regulation of the CB2 receptor in the gut and the full consequences of CB2 receptor activation. However, based on what we know so far, it is clear that CB2 receptors represent a braking system and a pathophysiological mechanism for the resolution of inflammation and its many symptoms. CB2 receptor activation therefore represents a very promising therapeutic target in GI inflammatory states where there is immune activation and motility dysfunction.
As mentioned earlier, acetylcholine operating in the smooth muscles of the colon are responsible for peristaltic action. What I like about the following paper (yeah, another mouse model) is that it discusses the biochemical interaction between acetylcholine release and CB1 activation:
http://www.ncbi.nlm.nih.gov/pubmed/18234188
Eur J Pharmacol. 2008 Mar 17;582(1-3):132-8. doi: 10.1016/j.ejphar.2007.12.016. Epub 2007 Dec 27.
Cannabinoid CB(1) receptor activation modulates spontaneous contractile activity in mouse ileal longitudinal muscle.
Baldassano S, Serio R, Mule' F.
Dipartimento di Biologia cellulare e dello Sviluppo, Università di Palermo, Viale delle Scienze, 90128 Palermo, Italy.
Abstract
The purpose of the present study was to examine whether cannabinoid receptor agonists influence spontaneous contractile activity of longitudinal muscle in mouse ileum in vitro. Isolated segments of mouse ileum displayed spontaneous contractions with an amplitude and frequency of about 300 mg and 30 cpm, respectively. The endocannabinoid anandamide (1-100 microM), the selective cannabinoid CB(1) receptor agonist, ACEA (0.1 microM-10 microM), but not the selective cannabinoid CB(2) receptor agonist, JWH 133 (0.1 microM-10 microM), reduced in a concentration-dependent manner the spontaneous mechanical activity. The inhibitory effect consisted in a decrease of the mean amplitude of longitudinal spontaneous contractions, without changes in the resting tone. The inhibitory effect induced by cannabinoids was significantly antagonized by the selective cannabinoid CB(1) receptor antagonist, SR141716A (0.1 microM), but not by the selective cannabinoid CB(2) receptor antagonist, AM630 (0.1 microM). None of the cannabinoid antagonists, at the concentration used, did affect the spontaneous mechanical activity. The ACEA-induced reduction of spontaneous contractions was almost abolished by tetrodotoxin, atropine or apamin and it was unaffected by hexamethonium or N(omega)-nitro-l-arginine methyl ester (l-NAME), inhibitor of nitric oxide synthase. The myogenic contractions evoked by carbachol were not affected by ACEA. In conclusion, the present results suggest that activation of neural cannabinoid CB(1) receptors may play a role in the control of spontaneous mechanical activity through inhibition of acetylcholine release from cholinergic nerve. Activation of small conductance Ca(2+)-dependent K(+) channels is involved in this action.
Another interesting point is that inhibition of acetylcholine release from cholinergic nerve needs to be contrasted with the well known research on the reversible competitive inhibition of acetylcholinesterase (which breaks down acetylcholine) and cannabinoids. This is the proposed mechanism that is believe to provide neuroprotection for Alzheimer's.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2562334/
Mol Pharm. Author manuscript; available in PMC 2008 October 6.
Published in final edited form as:
Mol Pharm. 2006; 3(6): 773777.
doi: 10.1021/mp060066m
PMCID: PMC2562334
NIHMSID: NIHMS61230
A Molecular Link Between the Active Component of Marijuana and Alzheimer's Disease Pathology
Lisa M. Eubanks, Claude J. Rogers, Albert E. Beuscher, IV, George F. Koob,§ Arthur J. Olson, Tobin J. Dickerson, and Kim D. Jandacorresponding author
Abstract
Alzheimer's disease is the leading cause of dementia among the elderly, and with the ever-increasing size of this population, cases of Alzheimer's disease are expected to triple over the next 50 years. Consequently, the development of treatments that slow or halt the disease progression have become imperative to both improve the quality of life for patients as well as reduce the health care costs attributable to Alzheimer's disease.
Here, we demonstrate that the active component of marijuana, Δ9-tetrahydrocannabinol (THC), competitively inhibits the enzyme acetylcholinesterase (AChE) as well as prevents AChE-induced amyloid β-peptide (Aβ
aggregation, the key pathological marker of Alzheimer's disease. Computational modeling of the THC-AChE interaction revealed that THC binds in the peripheral anionic site of AChE, the critical region involved in amyloidgenesis. Compared to currently approved drugs prescribed for the treatment of Alzheimer's disease, THC is a considerably superior inhibitor of Aβ aggregation, and this study provides a previously unrecognized molecular mechanism through which cannabinoid molecules may directly impact the progression of this debilitating disease.
Of course Alzheimer's is off topic, but the above paper is frequently cited for its research on competitive inhibition of acetylcholinesterase.
Before closing out this post, let's take a look at a paper on the "proposed third cannabinoid receptor" GPR55:
http://www.ncbi.nlm.nih.gov/pubmed?term=22759743
Pharmacology. 2012;90(1-2):55-65. doi: 10.1159/000339076. Epub 2012 Jun 28.
Evidence for the putative cannabinoid receptor (GPR55)-mediated inhibitory effects on intestinal contractility in mice.
Ross GR, Lichtman A, Dewey WL, Akbarali HI.
Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298-0613, USA.
[email protected]
BACKGROUND:
Cannabinoids inhibit intestinal motility via presynaptic cannabinoid receptor type I (CB1) in enteric neurons while cannabinoid receptor type II (CB2) receptors are located mainly in immune cells. The recently de-orphanized G-protein-coupled receptor, GPR55, has been proposed to be the 'third' cannabinoid receptor. Although gene expression of GPR55 is evident in the gut, functional evidence for GPR55 in the gut is unknown. In this study, we tested the hypothesis that GPR55 activation inhibits neurogenic contractions in the gut.
METHODS:
We assessed the inhibitory effect of the atypical cannabinoid O-1602, a GPR55 agonist, in mouse colon. Isometric tension recordings in colonic tissue strips were used from either wild-type, GPR55(-/-) or CB1(-/-)/CB2(-/-) knockout mice.
RESULTS:
O-1602 inhibited the electrical field- induced contractions in the colon strips from wild-type and CB1(-/-)/CB2(-/-) in a concentration-dependent manner, suggesting a non-CB1/CB2 receptor-mediated prejunctional effect. The concentration-dependent response of O-1602 was significantly inhibited in GPR55(-/-) mice. O-1602 did not relax colonic strips precontracted with high K(+) (80 mmol/l), indicating no involvement of Ca(2+) channel blockade in O-1602-induced relaxation. However, 10 µmol/l O-1602 partially inhibited the exogenous acetylcholine (10 µmol/l)-induced contractions. Moreover, we also assessed the inhibitory effects of JWH015, a CB2/GPR55 agonist on neurogenic contractions of mouse ileum. Surprisingly, the effects of JWH015 were independent of the known cannabinoid receptors.
CONCLUSION:
Taken together, these findings suggest that activation of GPR55 leads to inhibition of neurogenic contractions in the gut and are predominantly prejunctional.
Here is some info on GPR55:
http://www.genecards.org/cgi-bin/carddisp.pl?gene=GPR55&search=GPR55
The discussion of GPR55 is conducted in an article by Brown (below) which is also available as a full article:
http://www.ncbi.nlm.nih.gov/pubmed/17906678
www.ncbi.nlm.nih.gov/pmc/articles/pmid/17906678/ (full article)
Br J Pharmacol. 2007 Nov;152(5):567-75. Epub 2007 Oct 1.
Novel cannabinoid receptors.
Brown AJ.
Department of Screening and Compound Profiling, Molecular Discovery Research, GlaxoSmithKline, Essex, UK.
[email protected]
Abstract
Cannabinoids have numerous physiological effects. In the years since the molecular identification of the G protein-coupled receptors CB1 and CB2, the ion channel TRPV1, and their corresponding endogenous ligand systems,
many cannabinoid-evoked actions have been shown conclusively to be mediated by one of these specific receptor targets. However, there remain several examples where these classical cannabinoid receptors do not explain observed pharmacology. Studies using mice genetically deleted for the known receptors have confirmed the existence of additional targets, which have come to be known collectively as non-CB1/CB2 receptors. Despite intense research efforts, the molecular identity of these non-CB1/CB2 receptors remains for the most part unclear. Two orphan G protein-coupled receptors have recently been implicated as novel cannabinoid receptors; these are GPR119, which has been proposed as a receptor for oleoylethanolamide, and
GPR55 which has been proposed as a receptor activated by multiple different cannabinoid ligands. In this review I will present an introduction to non-CB1/CB2 pharmacology, summarize information on GPR55 and GPR119 currently available, and consider their phylogenetic origin and what aspects of non-CB1/CB2 pharmacology, if any, they help explain.
Ross et al. (2012) makes it clear that we are still learning about cannabinoids and their interaction with known receptors (CB1/CB2) and proposed receptors in the gut and elsewhere. It is also clear from the research that
gut motility may be significantly impacted, which is especially relevant to those with the rs806378 CT/TT polymorphism that present with colon pathologies like IBD where the CB2 receptors that are (in some sense) rare or weakly expressed in the healthy intestinal epithelium are found in diseased areas of the colon.
I have a number of other papers I could cite, but I think this is enough to put this issue to rest. If I have time I will address some of the other issues raised in this thread. I apologize in advance for the length and complexity of this post, but some issues are just naturally complex. Since you mentioned you work in the health field, I would like to hear your thoughts on the above.
