by Dan Eden for viewzone

Cannabis reveals its secrets to science

Marijuana is now legal in many states. Of course, it has always been widely available almost everywhere on the planet. I've been offered pot in a dozen remote countries by camel, taxi and rickshaw drivers, CEOs and especially religious people. It's everywhere and it's been around for a long time.

A few years ago they discovered what is being called the "oldest stash" of pot in a remote village near the Gobi Desert (China). It was almost 3000 years old and was buried with a mummy along with other gifts. The inclusion of a cannabis stash in a grave shows it was something even a dead person might enjoy in the afterlife. (see right column for story)

The pleasurable and sometimes mystical properties of cannabis have been recognized for millennia but only recently has advanced technology been able to show us exactly what happens inside our brain when we get high. And there are some surprises.

Before this hi-tech research, the effects of smoking cannabis were inferred strictly by observation and statistics. A group of smokers would be asked to perform some measurable task or give some biological samples. Then their results would be compared with a similar group of non-smokers.

These kinds of studies taught us that cannabis is not as dangerous as alcohol or other recreational drugs. Although users were twice as likely to have an auto accident [10], people who used cannabis were not dropping dead from liver or lung disease like users of alcohol and tobacco. There were no cannabis overdoses and hospitals were not filling up with cancer patients.

In fact, The Journal of General Internal Medicine (2011) reported that there was "no association between frequency of marijuana use and health or healthcare utilization." So frequent cannabis use does not appear to affect physical health in any dramatic, measurable way [9].

For a while now there have been published studies in well respected scientific journals that show amazing benefits of cannabis. Viewzone has documented studies claiming to have cured cancer, reduce Multiple Sclerosis symptoms, help allergic skin disease, prevent Alzheimer's and prostate cancer, grow new cells in the brain and alleviate inflammatory bowel disease [sources]. Is it all too good to be true?

Let's take a look at some of the other research

There's a wonderful search engine called "scholar google" where you can access professional and peer reviewed studies on just about any topic. I spent some time looking at studies about cannabis in preparing to write this story.

Instead of a plethora of health benefits attributed to cannabis, I found some cutting-edge research -- breaking news -- about some brain changes in important areas as measured with various types of brain scans. I will be telling you about these in this report.

With the current popular support for legalized marijuana, cannabis is not only here to stay but expanding legalization will make pot use as common as coffee and cigarettes. Soon many more people will have the observed brain changes that result from cannabis -- and along with it the altered behavior resulting from these affected brain regions.

How serious is this? Decide for yourself after you continue reading about how pot gets you high. Here is the latest cannabis study that is just beginning to cause a stir:

Heavy Marijuana Users Have Abnormal Brain Structure, Poor Memory

Dec. 16, 2013 -- A new Northwestern Medicine study found that teens who were heavy marijuana users -- smoking it daily for about three years -- had abnormal changes in their brain structures related to working memory and performed poorly on memory tasks.

Working memory is the ability to remember and process information in the moment and -- if needed -- transfer it to long-term memory. It is similar to the RAM memory in your computer which allows for many different programs to run at the same time. A poor working memory is a known predictor of poor academic performance and everyday functioning.

In the study, the brain abnormalities and memory problems were observed during the individuals' early twenties, two years after they stopped smoking marijuana. This could indicate the long-term effects of chronic use.

Memory-related brain structures, like the thalamus, appeared to shrink and collapse inward, possibly reflecting a decrease in neurons. This part of the brain is a hub of many different brain systems, allowing many tasks to be carried out at the same time. Other areas enlarge, like the striatus, which is responsible for our reward system and motivation center. While this may not seem very significant it becomes more so when scientists note that these same patterns of brain changes have been seen before -- in schizophrenic patients [2].

The new study warns that having a family history of schizophrenia may put you at risk for using marijuana and may initiate psychosis.

The study concluded that the younger the individuals were when they started chronically using marijuana, the more abnormally their brain regions were shaped. These regions related to memory may be more susceptible to the effects of the drug if abuse starts at an earlier age.

"The study links the chronic use of marijuana to these concerning brain abnormalities that appear to last for at least a few years after people stop using it. With the movement to decriminalize marijuana, we need more research to understand its effect on the brain."
[Matthew Smith, an assistant research professor in psychiatry and behavioral sciences at Northwestern University Feinberg School of Medicine.]

The paper was published Dec. 16 in the journal Schizophrenia Bulletin [1]

Smith reminds us that in the U.S., marijuana is the most commonly used illicit drug and young adults have the highest -- and growing -- prevalence of use. Decriminalization of the drug may lead to greater use. If the brains of the young are altered by cannabis use, we have a responsibility to investigate what behavior changes are associated with these brain abnormalities and how to minimize the impairment.

Because the study results examined only one point in time, a longitudinal study is needed to definitively show if marijuana is responsible for the brain changes and memory impairment. It is possible that the abnormal brain structures reveal a pre-existing vulnerability to marijuana abuse. Right now it is not known which came first, the marijuana abuse or the brain abnormalities.

Evidence that the younger the subjects were when they started using marijuana the greater their brain abnormalities were observed seemed to indicate that marijuana was the cause.

The study looked at the shapes of the striatum, globus pallidus and thalamus, structures in the subcortex that are critical for motivation and working memory.

Marijuana and Schizophrenia?

Cannabis abuse has been linked to developing schizophrenia in prior research, but only in statistical observations. These studies were never definitive. Some showed a relationship [2] while others could find none [3].

Now that the same structural brain changes have been seen in exactly the same parts of the brain in both schizophrenics and chronic cannabis users, the link is much stronger.

"The abuse of popular street drugs, such as marijuana, may have dangerous implications for young people who are developing or have developed mental disorders. This paper [above] is among the first to reveal that the use of marijuana may contribute to the changes in brain structure that have been associated with having schizophrenia."

"If someone has a family history of schizophrenia, they are increasing their risk of developing schizophrenia if they abuse marijuana."*

[*John Csernansky, M.D., chair of psychiatry and behavioral sciences at Northwestern University Feinberg School of Medicine and Northwestern Memorial Hospital].

Matthew Smith, an assistant research professor in psychiatry and behavioral sciences at Northwestern University Feinberg School of Medicine added to the warning:

"If you have schizophrenia and you frequently smoke marijuana, you may be at an increased risk for poor working memory, which predicts your everyday functioning."
Parts of stoned brain out of synch

A 2011 study described being stoned as "cognitive chaos" and again made the observation that the cognitive impairments of marijuana were reminiscent of those seen in schizophrenia. It compared brain activity to the performance of a philharmonic orchestra in which string, brass, woodwind and percussion sections are coupled together in rhythms dictated by the conductor.

Similarly, specific structures in the brain tune in to one another at defined frequencies: their rhythmic activity gives rise to brain waves, and the tuning of these brain waves normally allows processing of information used to guide our behaviour.

[above image source]

Using state-of-the-art technology, researchers measured electrical activity from hundreds of neurons in rats that were given a drug that mimics the psychoactive ingredient of marijuana. While the effects of the drug on individual brain regions were subtle, the drug completely disrupted co-ordinated brain waves across the hippocampus and prefrontal cortex, as though two sections of the orchestra were playing out of synch. Both of these brain structures are essential for memory and decision-making and heavily implicated in the pathology of schizophrenia.

The results from the study showed that, as a consequence of this decoupling of hippocampus and prefrontal cortex, the rats became unable to make accurate decisions when navigating around a maze [4].

Dr Jones, lead author and MRC Senior Non-clinical Fellow at the University, commented:

"Marijuana abuse is common among sufferers of schizophrenia and recent studies have shown that the psychoactive ingredient of marijuana can induce some symptoms of schizophrenia in healthy volunteers. These findings are therefore important for our understanding of psychiatric diseases, which may arise as a consequence of 'disorchestrated brains' and could be treated by re-tuning brain activity." [5]

How Marijuana Affects the Way the Brain Processes Emotional Information

Drugs like marijuana act on naturally occurring receptors in the brain called cannabinoid receptors. You will often see them abbreviated as CB1. However, the mechanisms by which these drugs produce their sensory and mood altering effects within the brain is just being understood.

Current brain theory describes the mind as an interconnection of specific processes or programs, each with their specific location in the brain. We learn about these mainly when that part of the brain is damaged or inhibited. Some of them are quite surprising.

There are parts of the brain dedicated to recognizing someone's face or of keeping track of the space around you as you drive a car. When these parts of the brain are damaged and not functioning, the ability is lost.

One of these programs is located in a part of the brain called the amygdala and tags our memories with emotional reactions depending on the significance of the event. Research led by Steven Laviolette at The University of Western Ontario (2011) has now identified a critical brain pathway responsible for the effects of marijuana on how the brain processes emotional information [6].

The findings, published in The Journal of Neuroscience, also help to explain the possible link between marijuana use and schizophrenia.

Laviolette and his team at the Schulich School of Medicine & Dentistry discovered that activating cannabinoid receptors directly in the amygdala can strongly influence the significance of emotional information and memory processes.

The stimulation of the CB1 receptors also dramatically increased the activity patterns of neurons in a connected region of the brain called the prefrontal cortex. Together with the amygdala the prefrontal cortex controls our emotional response to incoming sensory information and attaches emotional significance to certain memories.

That Paranoid Feeling: Explained

In other words, our mind has a kind of emotional rating system for experiences and memories. When we think about something that happened in the past we react according to the rating. We can feel (to various degrees) fear, love, hatred or nothing at all. Our reaction is supposedly based upon past experiences and the expectation of either a reward or punishment... or neither. The fact that marijuana interferes with this process is surprising and the consequences of this interference are alarming.

The paranoid feeling that some cannabis users experience can be blamed on the wrongly tagged emotional significance of experienced events -- caused by the effect of cannabis on the amygdala and prefrontal cortex. Ordinary and insignificant happenings can seem extraordinary, insightful or horrific when these areas are malfunctioning. Likewise, dangerous situations can be misunderstood with fear inhibited.

It's easy to see where delusions originate from this type of interference. In experienced marijuana users this can be tolerated and even compensated for, but in young marijuana users or those who are predisposed to Schizophrenia (family history etc.) this can become a trigger for psychosis.

"These findings are of great clinical relevance given recent evidence suggesting that exposure to marijuana during adolescence can increase the likelihood of developing schizophrenia later in life. We know there are abnormalities in both the amygdala and prefrontal cortex in patients who have schizophrenia, and we now know these same brain areas are critical to the effects of marijuana and other cannabinoid drugs on emotional processing." -- Laviolette

The findings by Laviolette's laboratory identify a novel new brain pathway by which drugs acting on the cannabinoid system can distort the emotional relevance of incoming sensory information which in turn may lead to psychotic side-effects, such as paranoia, associated with heavy marijuana use.

Developing pharmacological compounds, and there already are some, that block or modify this pathway could help control psychotic episodes. It could also be used to help patients with Post Traumatic Stress Disorder who have difficulty controlling the resurgence of highly emotional events into their memory.

Marijuana increases risk taking

Psychologists speak of brain "circuitry" and "rewards" when discussing the striatum -- a part of the brain that seems especially impacted by cannabis. This is the part of the brain where most of the negative impacts of cannabis originate.

In the inner sanctuaries of the brain, when we do something that is the goal of our instincts and drives (sex, food, power etc.) we experience pleasure in the form of a neurotransmitter called dopamine. Simply said, dopamine = pleasure.

In the striatum, the brain makes certain important decisions depending on their chance of getting a dopamine hit. If it senses dopamine has been released then it knows the current behavior was one that should be repeated and encouraged. It also knows (usually) how to evaluate the status of "risk v. reward" such that it usually does not take risks unless success is likely.

This evaluation involves past experience, trial and error, and so it is stronger in more mature minds. In the developing mind of adolescents there is little experience to guide the brain's decision making and so much of this function is controlled by the striatum.

Cannabis use in adolescence has been shown to make the striatum enlarged and overstimulated. This has the effect of making the decision process "stuck" in the "go ahead" mode. This shows itself in risk taking behavior and misplaced motivation.

A joint study between American and European adolescents, with non-smokers and frequent cannabis smokers, used functional MRI scanners to measure the activity in the striatum [8]. They found:

Frequent cannabis use during adolescence may induce diminished ability to disengage the motivational circuit when no reward can be obtained. This could strengthen the search for reinforcements like drugs of abuse, even when facing the negative (non-rewarding) consequences.

It seems as if there is a stronger than normal "craving" for dopamine rewards in the striatum of chronic cannabis users. A recent study found that the striatum of cannabis users is deficient in dopamine. This was a complete surprise because researchers expected to see elevated dopamine levels similar to what is measured in schizophrenics [14].

The current theory is that diminished dopamine forces the striatum to approve of any action that might yield a dopamine reward, regardless of the improbability.

A 2011 experiment looked at the number of dopamine receptors in the striatum of both users and non-users of cannabis. They discovered there was no difference [11]. So why was there less dopamine? A later study found that the cannabinoid receptors (CB1) decreased with chronic use. The more cannabis the chronic users took, the fewer CB1 receptors that could react to the THC. This could be responsible for the idea of (as the old Camel cigarette commercial used to say) "smoking more now but enjoying it less."

It was also revealed that CB1 receptors in offspring of chronic cannabis users numbered less than those born to non-cannabis using mothers. So if your mother smoked cannabis heavily, you will likely have fewer CB1 receptors. As a result, you may be more of a risk taker since your striatum will be craving the dopamine it would normally have gotten through CB1 stimulation.

The relationship between dopamine and THC has yet to be fully explored. A study in 2009 asked the question, "Can recreational doses of THC produce significant dopamine release in the human striatum?" Using a typical user dose of 10 mg the study showed that recreational cannabis users do not release significant amounts of dopamine from an oral THC dose equivalent to a standard cannabis cigarette [15]. This result challenges current models of striatal dopamine release as the mechanism mediating cannabis as risk factor for schizophrenia and, so far, is the only real significant difference between the growing number of similarities between the two. But tis difference is highly significant.

Chronic Marijuana Smoking Decreases CB1 Receptors

Scientists used molecular imaging to visualize changes in the brains of heavy marijuana smokers versus non-smokers and found that abuse of the drug led to a decreased number of cannabinoid CB1 receptors, which are involved in not just pleasure, appetite and pain tolerance but a host of other psychological and physiological functions of the body.

"Addictions are a major medical and socioeconomic problem. Unfortunately, we do not fully understand the neurobiological mechanisms involved in addiction. With this study, we were able to show for the first time that people who abuse cannabis have abnormalities of the cannabinoid receptors in the brain.

This information may prove critical for the development of novel treatments for cannabis abuse. Furthermore, this research shows that the decreased receptors in people who abuse cannabis return to normal when they stop smoking the drug."

[Jussi Hirvonen, MD, PhD, lead author of the collaborative study between the National Institute of Mental Health and National Institute on Drug Abuse, Bethesda, Md.]

Cannabinoid CF1 receptors disappear with chronic cannabis use: return with abstinence

According to the National Institute on Drug Abuse, marijuana is the number-one illicit drug of choice in America. The psychoactive chemical in marijuana, or cannabis, is delta-9-tetrahydrocannabinol (THC), which binds to numerous cannabinoid receptors (CB1) in the brain and throughout the body when smoked or ingested, producing a distinctive high.

Cannabinoid receptors in the brain influence a range of mental states and actions, including pleasure, concentration, perception of time and memory, sensory perception, and coordination of movement. There are also cannabinoid receptors throughout the body involved in a wide range of functions of the digestive, cardiovascular, respiratory and other systems of the body. Currently two subtypes of cannabinoid receptors are known, CB1 and CB2, the former being involved mostly in functions of the central nervous system and the latter more in functions of the immune system and in stem cells of the circulatory system.

For this study, researchers recruited 30 chronic daily cannabis smokers who were then monitored at a closed inpatient facility for approximately four weeks. The subjects were imaged using positron emission tomography (PET), which provides information about physiological processes in the body. Subjects were injected with a radioligand, 18F-FMPEP-d2, which is a combination of a radioactive fluorine isotope and a neurotransmitter analog that binds with CB1 brain receptors.

Results of the study show that receptor number was decreased about 20 percent in brains of cannabis smokers when compared to healthy control subjects with limited exposure to cannabis during their lifetime.

These changes were found to have a correlation with the number of years subjects had smoked. Of the original 30 cannabis smokers, 14 of the subjects underwent a second PET scan after about a month of abstinence. There was a marked increase in receptor activity in those areas that had been decreased at the outset of the study, an indication that while chronic cannabis smoking causes downregulation of CB1 receptors, the damage is reversible with abstinence.

Information gleaned from this and future studies may help other research exploring the role of PET imaging of CB1 receptors -- not just for drug use, but also for a range of human diseases, including metabolic disease and cancer [7].

How Marijuana Causes Memory Deficits

Memory loss associated with marijuana use is caused by the drug's interference with the brain's natural protein synthesis machinery, according to a study published in Nature Neuroscience.

Though it has been well known that marijuana impairs memory, the precise mechanism for this memory impairment was unknown until just recently. Scientists at the Universitat Pompeu Fabra in Spain, along with colleagues in France and Germany, focused on the hippocampus which is known to be vital to both long and short-term memory. The discovered that a specific protein, necessary for memory to be formed, was being modulated (changed) by THC through the CB1 receptors. They also discovered that certain medications (rapamycin), usually used in preventing organ transplant rejection, could stop this negative effect on memory degradation caused by the THC.[13]

What's even more exciting is that there may be a simple cure for this cannabis side-effect in your medicine cabinet.

Preventing Marijuana-Induced Memory Problems With Over-The-Counter Painkillers (ibuprofen)

As reported in ScienceDaily, a study published by Cell Press November 21st in the journal Cell has revealed the molecular pathways responsible for marijuana-induced learning and memory problems. The findings suggest that preventing these side effects could be as easy as taking an over-the-counter painkiller.

"Our studies have solved the longtime mystery of how marijuana causes neuronal and memory impairments... The results suggest that the use of medical marijuana could be broadened if patients concurrently take a nonsteroidal anti-inflammatory drug such as ibuprofen."*

[*Chu Chen of Louisiana State University Health Sciences Center.]

The main active ingredient in marijuana is Δ9-tetrahydrocannabinol (Δ9-THC), and drugs based on this compound have been approved by the Food and Drug Administration (FDA) to treat nausea and vomiting in chemotherapy patients. But these drugs have not been approved for a wider range of conditions, in part because of Δ9-THC-induced side effects. Moreover, there are no effective FDA-approved treatments for these side effects because, until now, little was known about the molecular pathways underlying these impairments.

In the new study, Chen and his team discovered that Δ9-THC treatment caused an increase in levels of an enzyme called cyclooxygenase-2 (COX-2) in the mouse hippocampus, a brain region involved in learning and memory.

Drugs or genetic techniques that reduced COX-2 levels in mice prevented memory problems and neuronal abnormalities caused by repeated Δ9-THC exposure.

Because COX-2 is inhibited by over-the-counter painkillers such as ibuprofen, the findings suggest an easy strategy to prevent the side effects of marijuana.

The researchers also discovered that Δ9-THC treatment reduced neuronal damage in a mouse model of Alzheimer's disease, and this beneficial effect persisted when the animals were simultaneously treated with a COX-2 inhibitor.

"There are no effective medications currently available for preventing and treating Alzheimer's disease or halting disease progression. Our results suggest that the unwanted side effects of cannabis could be eliminated or reduced, while retaining its beneficial effects, by administering a COX-2 inhibitor along with Δ9-THC for the treatment of intractable medical conditions such as Alzheimer's disease."*


Coffee and Cannabis: Closer than you think

The findings of a 2004 study indicate that caffeine, the main stimulant in coffee, has effects on dopamine neuro-transmission in the human brain, especially in the striatum and the thalamus [14]. More recent studies have found a relationship between caffeine and cannabis (THC) in these same areas of the brain. While caffeine does not measurably increase the sensitivity of the CB1 receptors to THC, it does prolong their altered state to above pre-stimulation levels and makes the effects of cannabis last longer [15].

The logical consequence of this fact means that you could extend the high from smoking cannabis by having a good cup of coffee or a caffeinated energy drink; but be warned: studies with rats showed that consumption of both caffeine and THC did not improve memory problems but actually made them worse [16]. This is a concern because studies (Bernstein et al. 2002; Miller 2008) have shown that college students frequently mix caffeine with cannabis. Most disconcerting is the thought that many college aged marijuana users also drink highly caffeinated energy drinks and soft drinks. All of this puts an extra burdon on the mind and is a recipe for poor academic performance.



[1] M. J. Smith, D. J. Cobia, L. Wang, K. I. Alpert, W. J. Cronenwett, M. B. Goldman, D. Mamah, D. M. Barch, H. C. Breiter, J. G. Csernansky. Cannabis-Related Working Memory Deficits and Associated Subcortical Morphological Differences in Healthy Individuals and Schizophrenia Subjects, Schizophrenia Bulletin, 2013; DOI: 10.1093/schbul/sbt176

[2] Ananth H, Popescu I, Critchley HD, Good CD, Frackowiak RS, Dolan RJ., Cortical and subcortical gray matter abnormalities in schizophrenia determined through structural magnetic resonance imaging with optimized volumetric voxel-based morphometry, Am J Psychiatry 2002 Sep;159(9):1497-505.

[3] Hickman et al. If cannabis caused schizophrenia-how many cannabis users may need to be prevented in order to prevent one case of schizophrenia? England and Wales calculations. Addiction, 2009; 104 (11): 1856 DOI: 10.1111/j.1360-0443.2009.02736.x

[4] M. T. Kucewicz, M. D. Tricklebank, R. Bogacz, M. W. Jones. Dysfunctional Prefrontal Cortical Network Activity and Interactions following Cannabinoid Receptor Activation, Journal of Neuroscience, 2011; 31 (43): 15560 DOI: 10.1523/JNEUROSCI.2970-11.2011

[5] M. T. Kucewicz, M. D. Tricklebank, R. Bogacz, M. W. Jones. Dysfunctional Prefrontal Cortical Network Activity and Interactions following Cannabinoid Receptor Activation, Journal of Neuroscience, 2011; 31 (43): 15560 DOI: 10.1523/JNEUROSCI.2970-11.2011

[6] H. Tan, N. M. Lauzon, S. F. Bishop, N. Chi, M. Bechard, S. R. Laviolette. Cannabinoid Transmission in the Basolateral Amygdala Modulates Fear Memory Formation via Functional Inputs to the Prelimbic Cortex, Journal of Neuroscience, 2011; 31 (14): 5300 DOI: 10.1523/JNEUROSCI.4718-10.2011

[7] Society of Nuclear Medicine (2011, June 13). Chronic marijuana smoking affects brain chemistry, molecular imaging shows ScienceDaily. Retrieved December 18, 2013, from­ /releases/2011/06/110606131705.htm

[8] Jager G, Block RI, Luijten M, Ramsey NF. Tentative evidence for striatal hyperactivity in adolescent cannabis-using boys: a cross-sectional multicenter fMRI study, J Psychoactive Drugs. 2013 Apr-Jun;45(2):156-67.

[9] Daniel Fuster, Debbie M. Cheng, Donald Allensworth-Davies, Tibor P. Palfai, Jeffrey H. Samet, Richard Saitz. No Detectable Association Between Frequency of Marijuana Use and Health or Healthcare Utilization Among Primary Care Patients Who Screen Positive for Drug Use, Journal of General Internal Medicine, 2013; DOI: 10.1007/s11606-013-2605-z

[10] Cell Press (2013, November 21). Preventing marijuana-induced memory problems with over-the-counter painkillers. ScienceDaily. Retrieved December 18, 2013, from­ /releases/2013/11/131121125855.htm

[11] Stokes PR, Egerton A, Watson B, Reid A, Lappin J, Howes OD, Nutt DJ, Lingford-Hughes AR History of cannabis use is not associated with alterations in striatal dopamine D2/D3 receptor availability J Psychopharmacol. 2012 Jan;26(1):144-9. doi: 10.1177/0269881111414090. Epub 2011 Sep 2.

[12] Ananth H, Popescu I, Critchley HD, Good CD, Frackowiak RS, Dolan RJ. Cortical and subcortical gray matter abnormalities in schizophrenia determined through structural magnetic resonance imaging with optimized volumetric voxel-based morphometry, Am J Psychiatry. 2002 Sep;159(9):1497-505.

[13] Emma Puighermanal, Giovanni Marsicano, Arnau Busquets-Garcia, Beat Lutz, Rafael Maldonado & Andrés Ozaita. Cannabinoid modulation of hippocampal long-term memory is mediated by mTOR signaling, Nature Neuroscience, 2009; DOI: 10.1038/nn.2369

[14] Kaasinen V, Aalto S, Nagren K, Rinne JO. Dopaminergic effects of caffeine in the human striatum and thalamus, Neuroreport. 2004 Feb 9;15(2):281-5.

[15] Rossi S, De Chiara V, Musella A, Mataluni G, Sacchetti L, Siracusano A, Bernardi G, Usiello A, Centonze D. Caffeine drinking potentiates cannabinoid transmission in the striatum: interaction with stress effects, Neuropharmacology. 2009 Mar;56(3):590-7. doi: 10.1016/j.neuropharm.2008.10.013. Epub 2008 Nov 8.

[16] Leigh V Panlilio, Sergi Ferré, Sevil Yasar, Eric B Thorndike, Charles W Schindler, and Steven R Goldberg, Combined effects of THC and caffeine on working memory in rats, Br J Pharmacol. 2012 April; 165(8): 2529–2538. doi:  10.1111/j.1476-5381.2011.01554.x PMCID: PMC3423236

[17] Michael A.P. Bloomfield, Celia J.A. Morgan, Alice Egerton, Shitij Kapur, H. Valerie Curran, Oliver D. Howes. Dopaminergic Function in Cannabis Users and Its Relationship to Cannabis-Induced Psychotic Symptoms, Biological Psychiatry, 2013; DOI: 10.1016/j.biopsych.


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World's Oldest Stash of Marijuana

Researchers say they have located the world's oldest stash of marijuana, in a tomb in a remote part of China. The cache of cannabis is about 2,700 years old and was clearly "cultivated for psychoactive purposes," rather than as fibre for clothing or as food, says a research paper in the Journal of Experimental Botany.

The 789 grams of dried cannabis was buried alongside a light-haired, blue-eyed Caucasian man [below], likely a shaman of the Gushi culture, near Turpan in northwestern China.

The extremely dry conditions and alkaline soil acted as preservatives, allowing a team of scientists to carefully analyze the stash, which still looked green though it had lost its distinctive odor.

"To our knowledge, these investigations provide the oldest documentation of cannabis as a pharmacologically active agent," says the newly published paper, whose lead author was American neurologist Dr. Ethan B. Russo.

Remnants of cannabis have been found in ancient Egypt and other sites, and the substance has been referred to by authors such as the Greek historian Herodotus. But the tomb stash is the oldest so far that could be thoroughly tested for its properties.

The 18 researchers, most of them based in China, subjected the cannabis to a battery of tests, including carbon dating and genetic analysis. Scientists also tried to germinate 100 of the seeds found in the cache, without success.

The marijuana was found to have a relatively high content of THC, the main active ingredient in cannabis, but the sample was too old to determine a precise percentage.

Researchers also could not determine whether the cannabis was smoked or ingested, as there were no pipes or other clues in the tomb of the shaman, who was about 45 years old.

The large cache was contained in a leather basket and in a wooden bowl, and was likely meant to be used by the shaman in the afterlife.

"This materially is unequivocally cannabis, and no material has previously had this degree of analysis possible," Russo said in an interview from Missoula, Mont.

"It was common practice in burials to provide materials needed for the afterlife. No hemp or seeds were provided for fabric or food. Rather, cannabis as medicine or for visionary purposes was supplied."

The tomb also contained bridles, archery equipment and a harp, confirming the man's high social standing.

Russo is a full-time consultant with GW Pharmaceuticals, which makes Sativex, a cannabis-based medicine approved in Canada for pain linked to multiple sclerosis and cancer.

The company operates a cannabis-testing laboratory at a secret location in southern England to monitor crop quality for producing Sativex, and allowed Russo use of the facility for tests on 11 grams of the tomb cannabis.

Researchers needed about 10 months to cut red tape barring the transfer of the cannabis to England from China, Russo said.

The inter-disciplinary study was published this week by the British-based botany journal, which uses independent reviewers to ensure the accuracy and objectivity of all submitted papers.

The substance has been found in two of the 500 Gushi tombs excavated so far in northwestern China, indicating that cannabis was either restricted for use by a few individuals or was administered as a medicine to others through shamans, Russo said.

"It certainly does indicate that cannabis has been used by man for a variety of purposes for thousands of years."

Russo, who had a neurology practice for 20 years, has previously published studies examining the history of cannabis.

"I hope we can avoid some of the political liabilities of the issue," he said, referring to his latest paper.

The region of China where the tomb is located, Xinjiang, is considered an original source of many cannabis strains worldwide.

Molecule Discovered That Protects Brain from Cannabis Intoxication

Jan. 2, 2014 -- Two INSERM research teams led by Pier Vincenzo Piazza and Giovanni Marsicano (INSERM Unit 862 "Neurocentre Magendie" in Bordeaux) recently discovered that pregnenolone, a molecule produced by the brain, acts as a natural defence mechanism against the harmful effects of cannabis in animals. Pregnenolone prevents THC, the main active principle in cannabis, from fully activating its brain receptor, the CB1 receptor, that when overstimulated by THC causes the intoxicating effects of cannabis. By identifying this mechanism, the INSERM teams are already developing new approaches for the treatment of cannabis addiction.

Over 20 million people around the world are addicted to cannabis, including a little more than a half million people in France. In the last few years, cannabis addiction has become one of the main reasons for seeking treatment in addiction clinics. Cannabis consumption is particularly high (30%) in individuals between 16 to 24 years old, a population that is especially susceptible to the harmful effects of the drug.

While cannabis consumers are seeking a state of relaxation, well-being and altered perception, there are many dangers associated to a regular consumption of cannabis. Two major behavioural problems are associated with regular cannabis use in humans: cognitive deficits and a general loss of motivation. Thus, in addition to being extremely dependent on the drug, regular users of cannabis show signs of memory loss and a lack of motivation that make quite hard their social insertion.

The main active ingredient in cannabis, THC, acts on the brain through CB1 cannabinoid receptors located in the neurons. THC binds to these receptors diverting them from their physiological roles, such as regulating food intake, metabolism, cognitive processes and pleasure. When THC overstimulates CB1 receptors, it triggers a reduction in memory abilities, motivation and gradually leads to dependence.

Developing an efficient treatment for cannabis addiction is becoming a priority of research in the field of drug addiction.

In this context, the INSERM teams led by Pier Vincenzo Piazza and Giovanni Marsicano have investigated the potential role of pregnenolone a brain produced steroid hormone. Up to now, pregnenolone was considered the inactive precursor used to synthesize all the other steroid hormones (progesterone, estrogens, testosterone, etc.). The INSERM researchers have now discovered that pregnenolone has quite an important functional role: it provide a natural defence mechanism that can protect the brain from the harmful effects of cannabis.

Essentially, when high doses of THC (well above those inhaled by regular users) activate the CB1 cannabinoid receptor they also trigger the synthesis of pregnenolone. Pregnenole then binds to a specific site on the same CB1 receptors and reducing the effects of THC.

The administration of pregnenolone at doses that increase the brain's level of this hormone even more, antagonize the behavioral effects of cannabis.

At the neurobiological level, pregnenolone greatly reduces the release of dopamine triggered by THC. This is an important effect, since the addictive effects of drugs involve an excessive release of dopamine.

This negative feedback mediated by pregnenolone (THC is what triggers the production of pregnenolone, which then inhibits the effects of THC) reveal a previously unknown endogenous mechanism that protects the brain from an over-activation of CB1 receptor.

The role of pregnenolone was discovered when rats were given equivalent doses of cocaine, morphine, nicotine, alcohol and cannabis and the levels of several brain steroids (pregnenolone, testosterone, allopregnenolone, DHEA etc.) were measured. It was then found that only one drug, THC, increased brain steroids and more specifically selectively one steroid -- pregnenolone -- that went up 3000% for a period of two hours.

This increase in pregnenolone is a built-in mechanism that moderates the effects of THC. Thus, the effects of THC increase when pregnenolone synthesis is blocked. Conversely, when pregnenolone is administered to rats or mice at doses (2-6 mg/kg) that induce even greater concentrations of the hormone in the brain, the negative behavioural effects of THC are blocked. For example, the animals that were given pregnenolone recover their normal memory abilities, are less sedated and less incline to self-administer cannabinoids.

Experiments conducted in cell cultures that express the human CB1 receptor confirm that pregnenolone can also counteract the molecular action of THC in humans.

Pier Vincenzo Piazza explains that pregnenolone itself cannot be used as a treatment because it is badly absorbed when administerd orally and once in the blood stream it is rapidly transformed in other steroids.

However, the researchers say that there is strong hope of seeing a new addiction therapy emerge from this discovery. "We have now developed derivatives of pregnenolone that are well absorbed and stable. They then present the characteristics of compounds that can be used as new class of therapeutic drugs. We should be able to begin clinical trials soon and verify whether we have indeed discovered the first pharmacological treatment for cannabis dependence."

Does Cannabis Trigger Schizophrenia?

Aside from the memory problems, which apparently can be alleviated by taking ibuprofen with the cannabis, the constant reminder of the effects of marijuana on the brain and their similarity to schizophrenia is a troubling phenomenon. Despite the differences in dopamine in the striatum, the ability of cannabis to trigger schizophrenia in vulnerable individuals appears very real. This is especially true in the very young who have developing brains.

There have been a number of proposals to deal with this fact. In 2008 the UK government reclassified cannabis from a class C to a class B drug, partly out of concerns that cannabis, especially the more potent varieties, may increase the risk of schizophrenia in young people.

But the evidence for the relationship between cannabis and schizophrenia or psychosis remains controversial. A new study has determined that it may be necessary to stop thousands of cannabis users in order to prevent a single case of schizophrenia.

Scientists from Bristol, Cambridge and the London School of Hygiene and Tropical Medicine took the latest information on numbers of cannabis users, the risk of developing schizophrenia, and the risk that cannabis use causes schizophrenia to estimate how many cannabis users may need to be stopped to prevent one case of schizophrenia. The study found it would be necessary to stop 2800 heavy cannabis users in young men and over 5000 heavy cannabis users in young women to prevent a single case of schizophrenia.

Among light cannabis users, those numbers rise to over 10,000 young men and nearly 30,000 young women to prevent one case of schizophrenia.

That's just part of the story. Interventions to prevent cannabis use typically do not succeed for every person who is treated. Depending on how effective an intervention is at preventing cannabis use, it would be necessary to treat even higher numbers of users to achieve the thousands of successful results necessary to prevent a very few cases of schizophrenia.

Matt Hickman, one of the authors of the report recently published in the journal Addiction, said that "preventing cannabis use is important for many reasons -- including reducing tobacco and drug dependence and improving school performance. But our evidence suggests that focusing on schizophrenia may have been misguided. Our research cannot resolve the question whether cannabis causes schizophrenia, but does show that many people need to give up cannabis in order to have an impact on the number of people with schizophrenia. The likely impact of re-classifying cannabis in the UK on schizophrenia or psychosis incidence is very uncertain."

Legalization of pot doubles the price

Because the state gets its cut of a tax on cannabis, the price for legal marijuana is too high for most recreational users. Colorado reported that the average price for an eighth (1/8) of cultivated weed was about $66. That puts an ounce at about $500, more than double the street price in both Colorado and Washington, the two states that have legalized recreational pot to date.

Chronic users worry that this new taxed pot will drive up the price, making it more expensive to use for the average person. Those growing and selling weed to friends will likely continue at their current rate (about $200 for an ounce) but many suspect the price will soon begin to crawl upward.

Some think the heavy sales after January 1, 2014, when pot became officially legal in some states, is just a fad. One customer leaving a Colorado store said it all.

"I just bought an eighth today to mark the day. It's historic. I can go into a store now and actually buy some weed. Wow. But I certainly will not make this a habit. It's too expensive and I smoke too much. I'd go broke at these prices (laugh)."

Like fine wines, various strains of pot have exotic names and demand exotic prices. Weed with names like "Hawaiian Perl" and "Trainwreck" can fetch more per ounce because of their reputation and taste. Other so-called "generic" cannabis will fetch much less. It may burn bad or taste harsh but as one chronic user said, "It'll get you there just the same."


Parental Exposure to Marijuana Linked to Drug Addiction, Compulsive Behavior in Unexposed Progeny, Rodent Sudy Finds

Jan. 22, 2014 (ScienceDaily) Exposing adolescent rats to THC (tetrahydrocannabinol) -- the primary psychoactive ingredient in marijuana -- can lead to molecular and behavioral alterations in the next generation of offspring, even though progeny were not directly exposed to the drug, researchers at the Icahn School of Medicine at Mount Sinai have found.

Male offspring showed stronger motivation to self-administer heroin during their adulthood and molecular changes in the glutamatergic system, which is the most important excitatory pathway for neurotransmission in the brain. Damage in the glutamate pathway, which regulates synaptic plasticity, has been linked to disturbances in goal-directed behavior and habit formation.

"Our study emphasizes that cannabis [marijuana] affects not just those exposed, but has adverse affects on future generations. Finding increased vulnerability to drug addiction and compulsive behavior in generations not directly exposed is an important consideration for legislators considering legalizing marijuana." --Yasmin Hurd, PhD, the study's senior author, and professor of psychiatry and neuroscience at the Icahn School of Medicine at Mount Sinai

In the study, Dr. Hurd and colleagues gave adolescent male rats 1.5 mg/kg of THC, similar to about one joint in human use. None of the rats had been exposed to THC before, but their parents were exposed to THC as teens and then mated later in life. THC-exposed offspring worked harder to self-administer heroin by pressing a lever multiple times to get heroin infusion.

Although marijuana use and safety tends to be discussed in terms of its impact to the individual during the lifetime, few studies have addressed adverse effects in future generations. "What this opens up are many questions regarding the epigenetic mechanisms that mediate cross-generational brain effects," said Dr. Hurd.

Future studies are now being explored to determine whether THC effects continue to be transmitted to even the subsequent grandchildren and great-grandchildren generations. Another important question relates to potential treatment interventions in order to reverse the cross-generational THC effects. Such insights could also have implications for novel treatment opportunities for related psychiatric illnesses.

The study is published online Jan. 22 in Neuropsychopharmacology.

Journal Reference:

Henrietta Szutorisz, Jennifer A DiNieri, Eric Sweet, Gabor Egervari, Michael Michaelides, Jenna M Carter, Yanhua Ren, Michael L Miller, Robert D Blitzer, Yasmin L Hurd. Parental THC Exposure Leads to Compulsive Heroin-Seeking and Altered Striatal Synaptic Plasticity in the Subsequent Generation, Neuropsychopharmacology, 2014; DOI: 10.1038/npp.2013.352

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