Marijuana Compound Spurs Brain Cell Growth

THURSDAY, Oct. 13 (HealthDay News) -- When it comes to the controversy surrounding medical marijuana, an international team of researchers is busy stirring the pot by releasing findings that suggest the drug helps promote brain cell growth while treating mood disorders.

According to the study in rats, a super-potent synthetic version of the cannabinoid compound found in marijuana can reduce depression and anxiety when taken over an extended period of time.

This mood boost seems to be the result of the drug's ability to promote the growth of new brain cells, something no other addictive drug appears able to do, the researchers say.

The findings, which appear in the November issue of the Journal of Clinical Investigation, remain preliminary, however.

"Our results were obtained from rats, and there's a big difference between rats and humans," said study co-author Dr. Xia Zhang, of the neuropsychiatry research unit in the department of psychiatry at the University of Saskatchewan in Saskatoon, Canada. "So, I don't really don't know yet if our findings apply to humans. But our results indicate that the clinical use of marijuana could make people feel better by helping control anxiety and depression."

The new findings come on the heels of a U.S. Supreme Court ruling in June granting federal authorities the power to stop doctors from prescribing marijuana. That decision also bars individuals from cultivating the herb for medical purposes.

The decision overrides laws currently on the books in 11 states which had legalized the use of marijuana for patients receiving a doctor's approval. According to the ruling, the Supreme Court justices made their decision on the basis of interstate commerce regulations rather than on an evaluation of the pros and cons of medical marijuana use.

But does medical marijuana work? To help settle that question, Zhang's team focused on the potential of a synthetic laboratory-produced form of the cannabinoid compound naturally found in the marijuana plant.

Humans and other animals also naturally produce the compound, and are known to have cannabinoid receptors lying on the surface of cells in the nervous system and the immune system.

Prior research has shown that, when exposed to cannabinoids, these receptors can provoke an anti-inflammatory and anti-convulsive response. They can also instigate a range of psychotropic effects such as euphoria.

The current study focused on a particular formulation of synthetic cannabinoid known as HU210 -- a compound which Zhang described as the most powerful cannabinoid in the world.

The authors explored both the short-term and long-term effects of exposure to HU210 in rats.

To measure the drug's short-term response, they gave adult rats a single injection of HU210. To study the same drug's effect over the longer term, the researchers gave a separate group of adult rats twice-daily injections of the cannabinoid over a two-week period.

Autopsies revealed that by the end of the 10-day HU210 treatment regimen, new neurons had been generated and integrated into the circuitry of the hippocampus region of the rat's brains. This process, known as neurogenesis, was still in evidence a full month after treatment had been initiated.

Neurogenesis was not triggered in response to brain cells being killed through cannabinoid exposure, the researchers add. In fact, HU210 injections did not appear to prompt any loss of neurons in the hippocampus.

Cannabinoid use appeared to boost mood, as well: According to the scientists, behavioral tests suggest that long-term treatment reduced the rodent's anxiety- and depression-linked behaviors.

For example, one month post-treatment, treated rats deprived of food for 48 hours were quicker than similarly deprived, non-treated rats to begin eating food when it was finally offered to them in an unfamiliar environment.

The researchers believe treated rats may have been less anxious in the manner they handled this novel situation. They stress the results were not related to cannabinoids' appetite-stimulating effects, since the treated rats' eating behavior was similar to that of untreated rats when they were offered food in a familiar setting.

Treated rats also responded in a less anxious manner to swimming and climbing tests, and displayed shorter periods of immobility compared with untreated rats. The latter finding was interpreted to mean that HU210 had an antidepressant effect on rats receiving the cannabinoid over the longer term.

However, while long-term administration of higher doses worked to reduce anxiety and depression, lower doses did not appear to have the same effect, the researchers added.

Zhang and his associates credit cannabinoid-linked neurogenesis with the apparent mood shifts seen in the animals.

The hippocampus area of the brain where the neuronal growth occurred is key to the regulation of stress and other mood disorders, Zhang's team point out. This region is also important to the control of cognitive processes such as learning and memory.

Among the common addictive drugs, marijuana alone appears able to promote neurogenesis when used over time and in the right dosage, the researchers say. In contrast, prior research has demonstrated that chronic administration of cocaine, opiates, alcohol and nicotine inhibits brain cell growth.

"If our results can be confirmed in humans, we should anticipate the chronic use of marijuana as a medical treatment for anxiety and depression," Zhang said.

However, he cautioned that "this treatment is not the same as smoking marijuana. Whether smoking marijuana can produce the same effect, we just don't know."

Dr. Perry G. Fine, a professor of anesthesiology at the University of Utah School of Medicine Pain Research Center, said more than enough data has already been gathered to confirm medical marijuana's potential benefits.

"It's great that there's new science, but to me this is no longer an epiphany," he said. "It's just proving what's been long-suspected. We're behind the curve with the cannabinoids largely because of the stigma of marijuana going years and years back."

"I think most people with clinical expertise in the area of palliative medicine know that if patients had access to all the tools we currently have, we could certainly do a whole lot better to help people live with multiple chronic diseases," he added. "The social policies are way behind our technology, and that's where we need some catching up."

Special Report British Journal of Pharmacology (2001) 132, 969−971; doi: 10.1038/sj.bjp.0703919 Cannabinoid inhibition of the capsaicin-induced calcium response in rat dorsal root ganglion neurones Paul J Millns1, Victoria Chapman1 and David A Kendall1 1School of Biomedical Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham NG72UH Correspondence: David A Kendall, School of Biomedical Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham NG72UH Received 23 November 2000; Revised 04 January 2001; Accepted 05 January 2001. Top of pageAbstract Cannabinoids have marked inhibitory effects on somatosensory processing, which may arise from actions at both peripheral and central cannabinoid receptors. Here, the effect of a synthetic cannabinoid agonist HU210 on capsaicin-evoked responses in adult rat dorsal root ganglion (DRG) neurones was studied. The vanilloid capsaicin produced a concentration-related increase in intracellular calcium in DRG neurones, which was significantly inhibited by HU210 (1 M). The cannabinoid CB1 receptor antagonist SR141716A (1 M) had no effect alone and did not influence the response to capsaicin but significantly reversed the inhibitory effect of HU210. These data indicate that DRG CB1 receptors are functional and can inhibit nociceptive responses. Keywords: Cannabinoids, vanilloids, dorsal root ganglion neurones Abbreviations: [Ca2+]i, intracellular Ca2+ concentration; CB, cannabinoid; DRG, dorsal root ganglion; HU210, (6aR)-trans-3-(1,1-Dimethylheptyl)-6a,7,10,10a-tetrahydro-1-hydroxy-6,6-dimethyl-6H-dibenzo[b,d]pyran-9-methanol); SR141716A, (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride); VR, vanilloid receptor Top of pageIntroduction Recent studies indicate that cannabinoids have diverse effects on sensory nerve function. For example endogenous cannabinoids such as anandamide have vasodilator effects via an agonist action on sensory nerve vanilloid (VR1) receptors (Zygmunt et al., 1999; Ralevic et al., 2000). However, both synthetic cannabinoids (Drew et al., 2000) and anandamide (Harris et al., 2000) inhibit C-fibre driven neuronal responses in vivo via cannabinoid1 (CB1) receptor activation. Nociceptive primary afferent fibres express both pro-nociceptive VR1 and anti-nociceptive CB1 receptors and are therefore an ideal model for investigating interactions between these two receptor systems. Here we report the effect of the synthetic cannabinoid receptor agonist HU210 on capsaicin-evoked Ca2+ responses in adult rat dorsal root ganglion neurones (DRG) in primary culture. Top of pageMethods DRG were isolated from adult Wistar rats (200−300 g) and neurones cultured as described by Lindsay (1988) with minor modifications. Cells were grown on 13 mm glass cover slips for 24 h prior to incubation with Fura 2-AM (5 M, 30 min, 37°C). The mean diameter of the cells sampled was 24.30.8 m. Intracellular Ca2+ concentrations ([Ca2+]i) in individual neurones in fields of 30−40 cells were estimated as the ratios of peak fluorescence intensities (measured at 500 nm) at excitation wavelengths of 340 and 380 nm respectively (Bundey & Kendall, 1999), using an Improvision imaging system. DRG neurones were superfused (2 ml min-1) with different concentrations of the vanilloid receptor agonist capsaicin for 60 s, alone or in combination with the cannabinoid receptor agonist HU210 (1 M) in the presence or absence of the cannabinoid CB1 receptor antagonist SR141716A (1 M), with 45 min wash-out periods between applications of capsaicin. Data are expressed as meanss.e.mean. Statistical analysis was performed using one way ANOVA or Mann Whitney test. Drugs HU210, (6aR) -trans-3- (1,1-Dimethylheptyl) -6a,7,10,10a -tetrahydro-1-hydroxy- 6, 6-dimethyl-6H-dibenzo [b,d] pyran-9-methanol) and capsaicin were purchased from Tocris Cookson Ltd. SR141716A (N-(piperidin-1-yl)-5-(4-chlorophenyl ) -1- ( 2,4-dichlorophenyl) -4 -methyl-1H-pyrazole-3-carboxamide hydrochloride) was provided by Research Biochemicals International as part of the chemical synthesis programme of the National Institute of Mental Health, Contract number N01MH300003. HU 210, SR141716A and capsaicin were dissolved in ethanol to a concentration of 10-2 M and stored at -30°C. Drug dilutions were made in superfusion buffer of composition (mM) NaCl 145; KCl 5; CaCl2 2; MgSO4 1; HEPES 10; glucose 10. Top of pageResults In untreated DRGs, the mean 340/380 nm ratio (reflecting basal [Ca2+]i) was 1.30.03 (n=29). Capsaicin produced a concentration-dependent increase in [Ca2+]i (Figure 1) with an estimated EC50 value (calculated using GraphPad Prism) of 63 nM, (n=29). Forty-five per cent of cells examined responded to capsaicin. There was little evidence of desensitization and a second exposure of the cells to 100 nM capsaicin 45 min after an initial challenge with the same concentration, produced a signal that was 856% (n=26) of the first response. In generating the concentration-response curve each of the cells was exposed to the full range of capsaicin concentrations. HU210 (1 M) alone had no effect on [Ca2+]i (Figure 2). Figure 1. Increases in 340 : 380 nm ratios in single Fura 2 -loaded DRG neurones treated with capsaicin. Results are expressed as percentages of the peak responses to 100 nM capsaicin. Estimated EC50=63 nM (n=29). Full figure and legend (37K) Figure 2. A representative trace showing changes in 340 : 380 nm ratios in a single DRG neurone, in response to capsaicin, in the absence or presence of HU210 and SR141716A. At point A, the cell was exposed to capsaicin (100 nM) for 60 s. Forty-five minutes later, at point B, HU210 (1 M) was applied (first arrow) followed by capsaicin (second arrow) for 60 s. After another 45 min (C) SR141716A (1 M) was applied (first arrow) followed by HU210 (1 M, second arrow) followed by capsaicin (third arrow). Full figure and legend (47K) In the presence of HU210 (1 M) peak responses to capsaicin (100 nM) were significantly reduced to 455% of the control capsaicin response (Figure 3; P<0.001, n=58). SR141716A alone had no significant effect on capsaicin (100 nM)-evoked responses (922% of control capsaicin response, n=20). Co-application of SR141716A (1 M) partly reversed the inhibitory effect of HU210 (1 M) on the capsaicin (100 nM)-evoked response (704% of control response, n=58, Figure 3). The duration of the [Ca2+]i response was also reduced by HU210 (1 M) to 663% (n=75) of the control capsaicin response and was restored, in fact somewhat prolonged, in the presence of SR141716A (1 M) to 1166% of the control response (n=75). Figure 3. Inhibition of capsaicin responses in the presence of HU210 and reversal by SR141716A in individual DRG neurones. Results are expressed as percentages of the responses to 100 nM capsaicin alone. In the presence of HU210 (1 M) the capsaicin response was reduced to 455% of control (P<0.001, n=58). Co-administration of SR141716A (1 M) partially reversed this to 704% of control (***P<0.001, Mann Whitney, compared with HU210 plus capsaicin. Full figure and legend (40K) Top of pageDiscussion In this study, capsaicin-evoked increases in [Ca2+]i in adult DRG neurones have been employed to investigate interactions between VR1 and CB1 receptors in sensory nerves. Our results corroborate previous electrophysiological studies of capsaicin-evoked responses (Helliwell et al., 1988), which are mediated by VR1 receptor activation (Caterina et al., 1997). We report here that the synthetic cannabinoid agonist HU210 inhibited capsaicin-evoked Ca2+ responses in DRG neurones. This effect of HU210 was largely reversed by the cannabinoid CB1 receptor antagonist SR141716A. Thus, HU210 appears to modify VR1 responses indirectly through CB1 receptor activation and it is unlikely that inhibition of capsaicin-evoked responses by HU210 arises as a result of a direct interaction with the VR1 complex. Although capsaicin responses in DRG neurones can desensitize in a Ca2+ and voltage sensitive fashion (Piper et al., 1999), there was little evidence of desensitization of responses in the present experimental protocol. In addition, effects of HU210 were readily reversible on washout, further suggesting that desensitization does not markedly contribute to these effects. The present experiments support the existence of functional CB1 receptors in DRG neurones and contrast a recent report that spinal CB1 receptors are exclusively located at post-synaptic sites (Farquhar-Smith et al., 2000). Our functional data are in agreement with other, previously reported, expression studies of CB receptors in adult DRG neurones (Hohmann & Herkenham, 1999). Collectively the current body of evidence suggests that vanilloid and cannabinoid receptors are co-localized on the same sensory fibres. Interestingly the endogenous cannabinoid anandamide is an agonist at both pro-nociceptive VR1 (Smart et al., 2000) and anti-nociceptive CB1 receptors. Anandamide has a similar affinity for human VR1 and CB1 receptors in model cell systems (low micromolar range; Smart et al., 2000; Rinaldi-Carmona et al., 1996) and increases Ca2+ signals to levels comparable to those produced by capsaicin (Smart et al., 2000). In contrast we report here that the synthetic cannabinoid agonist HU210 does not influence Ca2+ signals. This finding is in keeping with previous reports that synthetic CB agonists such as WIN-55,212 and CP55,940 and antagonists such as AM281 and AM630 have no direct effect on VR1 receptors (Smart et al., 2000). The present study provides strong evidence for a functional inhibitory role of pre-synaptic CB1 receptors on adult DRG neurones. Our results strengthen the evidence that cannabinoids are antinociceptive in vivo (Drew et al., 2000), these effects arising, at least in part, from the activation of pre-synaptic CB receptors on sensory fibres. A recent study reported anandamide inhibition of capsaicin-induced bronchospasm via CB1 receptor activation in the pulmonary sensory nerves (Calignano et al., 2000). This effect may arise from inhibition of excitatory transmitter release, as reported for CGRP release from vascular sensory nerves (Zygmunt et al., 1999), or inhibition of capsaicin-evoked VR1 receptor responses similar to those reported here. Overall, there appear to be marked differences in the effects of endogenous versus synthetic cannabinoids on this sensory system expressing both VR1 and CB receptors, although the relevance of these differences in an intact physiological system remains unknown.

Harmful Effects of Marijuana

The harmful effects of marijuana on the Brain and Central Nervous System

Impaired thinking, mood, memory, and coordination
Marijuana (THC) is an extremely powerful and pleasurable intoxicant. It affects, alters, and damages brain cells controlling thinking, emotion, pleasure, coordination, mood and memory. The pituitary gland is also damaged which regulates hunger, thirst, blood pressure, sexual behavior, and release of sex hormones.

Clogged synapses, brain damage and addiction
Marijuana accumulates in the microscopic spaces between nerve cells in the brain called "synapses." This clogging interferes by slowing and impairing transfer critical information.

Long term use causes the brain to stop production of brain chemicals necessary to "feel good" - a negative feedback condition. And, the user becomes chemically addicted to marijuana.

The harmful effects of marijuana on the Heart
Speeds up heartbeat as much as 50%, increases blood pressure, and poses great risk to those with hypertension and heart disease.

The harmful effects of marijuana on the Endocrine System
Marijuana damages the network of glands, organs, and hormones involved in growth and development, energy levels, and reproduction.

Organs and glands affected:
pituitary gland
thyroid gland
stomach
duodenum
pancreas
adrenal glands
testis

The harmful effects of marijuana on the Reproductive System males and females

Marijuana use can decrease and degenerate sperm, sperm count, movement, and cause lowered sex drive. Females can have egg damage, suppression of ovulation, disrupt menstrual cycles, and alteration of hormone levels.
Regular use during pregnancy can lower birth weight and cause abnormalities similar to Fetal Alcohol Syndrome (small head, irritability, poor growth and development.
Can destroy the number of chromosomes, resulting in cell abnormalities and impaired function.
Other affects on the central nervous system
distortions of perceptions, thinking and reality
Difficulty in forming concepts and thoughts
Poor concentration
Mental confusion
Loss of motivation
Wide mood swings
Aggression and hostility
Depression, anxiety and paranoia

The harmful effects of marijuana on the Eyes
Sleep looking, blood-shot eyes with dilated pupils.

The harmful effects of marijuana on the Throat
Irritates membranes of the esophagus; increases chance of developing cancer of larynx and esophagus.

The harmful effects of marijuana on the Lungs
Significant damage and destruction of the air sacs of the lungs, reducing the lungs ability to bring oxygen and remove carbon dioxide - Emphysema.
Causes bronchial tubes to be inflamed, thickened and to produce more mucus; resulting in narrowing of the air passages - Chronic Bronchitis.
Marijuana smoke has twice as much "tar" as cigarette smoke and significantly increases chance of lung cancer, inflammation and infection.

*THEY* feared Black jazz musicians??? Who are *They*? Then when MJ became illegal, *THEY* no longer feared Black jazz musicians? Those who support anti-drug laws are racists? Are you suggesting that anti-drug laws are racist laws?

It's not a suggestion. It's a historic fact. "They" were the white racists that used fearmongering to get the laws passed.

http://en.wikipedia.org/wiki/Marijuana#Prohibition_and_criminalization_in_the_US

Prohibition and criminalization in the US

Until 1937, consumption and sale of cannabis was legal in most American states. In some areas it could be openly purchased in bulk from grocers or in cigarette form at newsstands, though an increasing number of states had begun to outlaw it. In that year, federal law made possession or transfer of cannabis (without the purchase of a by-then-incriminating tax stamp) illegal throughout the United States. This was contrary to the advice of the American Medical Association at the time. Legal opinions of the time held that the federal government could not outlaw it entirely. The tax was $100 per pound of hemp, even for clothes or rope. The expense, extremely high for that time, was such that people stopped openly buying and making it.

The decision of the U.S. Congress was based in part on testimony derived from articles in the newspapers owned by William Randolph Hearst, who was heavily interested in DuPont Inc. Some analysts theorize DuPont wanted to boost declining post-war textile sales, and wished to eliminate hemp fiber as competition. Many argue that this seems unlikely given DuPont's lack of concern with the legal status of cotton, wool, and linen; although it should be noted that hemp's textile potential had not yet been largely exploited, while textile factories already had made large investments in equipment to handle cotton, wool, and linen. Others argue that Dupont wanted to eliminate cannabis because its high natural cellulose content made it a viable alternative to the company's developing innovation: modern plastic. Still, others could argue that hemp could never truly compete with the high strength and elasticity of synthetics, such as nylon. Furthermore, hemp would have been an easy target due to its intoxicating effect, while no rational justification could have been made for outlawing cotton, wool, or linen.

U.S. Federal Bureau of Narcotics poster used in the late 1930s and 1940s.

During this period, Henry (Harry) Anslinger alleged that the drug could provoke criminal behavior in previously solid citizens. Anslinger also popularized the word marihuana for the plant, using a Mexican derived word (believed to be derived from an archaic Brazilian Portuguese term for inebriation, "Maria Joana") in order to associate the plant with increasing numbers of Mexican immigrants, creating a negative stereotype which persists to this day.

The 1937 federal marijuana tax act was struck down by the Supreme Court in 1969. In a case brought by Timothy Leary, the Court held that the law's requirement that a would-be possessor of marijuana register with the local bureau of the IRS, thereby placing his name and address on a file available to local law enforcment, violated the Fifth Amendment privilege against self-incrimination, given the fact that at the time all 50 states had state laws on the books outlawing marijuana outright. In 1970, the Controlled Substances Act made possession of marijuana illegal again on a federal level, without the Fifth Amendment issues that scuttled the 1937 act, and without apparent concern for the issues which required the Eighteenth Amendment to effect the prohibition of alcohol. Several petitions for cannabis rescheduling in the United States have been filed, since the Act permits legalization of marijuana through the executive branch.

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