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General

History

For 5 millennia, Cannabis sativa has been used throughout the world medically, recreationally, and spiritually. As a folk medicine marijuana has been “used to treat an endless variety of human miseries,” although typically under the aegis of strict cultural controls, according to DuPont. The first medical use probably occurred in Central Asia and later spread to China and India. The Chinese emperor Shen-Nung is known to have prescribed it nearly 5 millennia ago. Between 2000 and 1400 bc, it traveled to India and from there to Egypt, Persia, and Syria. Greeks and Romans valued the plant for its ropelike qualities as hemp, although it also had medical applications. The medieval physician Avicenna included it in his formulary, and Europeans of the same epoch ate its nutritional seeds and made its fibers into paper, a practice that continued for centuries. Indeed, the American Declaration of Independence was purported to have been drafted on hemp-based paper.

Traditional Eastern medicine met Western medicine when W. B. O'Shaughnessy, an Irish physician working in Calcutta in the 1830s, wrote a paper extolling “Indian hemp.” The list of indications for which he recommended cannabis—pain, vomiting, convulsions, and spasticity—strikingly resembles the conditions for which modern medical marijuana proponents extol its virtues. As of 1854, the medical use of cannabis received official legitimacy by its listing in the US Dispensatory. The black leather bags of 19th-century US physicians commonly contained (among many other plant-based medicaments) cannabis tinctures and extracts for ailments ranging from insomnia and headaches to anorexia and sexual dysfunction in both sexes. Cannabis-containing remedies were also used for pain, whooping cough, asthma, and insomnia and were compounded into extracts, tinctures, cigarettes, and plasters. More recently, the Institute of Medicine issued a report based on a summary of the peer-reviewed literature addressing the efficacy of therapeutic marijuana use. The 1999 study found at least some benefit for smoked marijuana in stimulating appetite, particularly in AIDS-related wasting syndrome, and in combating chemotherapy-induced nausea and vomiting, severe pain, and some forms of spasticity.PMC 3538401

As medicine

Marijuana is taken from the leaves and flowering tops of the hemp plant, Cannabis sativa, which grows in most regions of the world. PUBMED 22129912

"The medical use of marijuana can be traced back to 2737 B.C., when Emperor Shen Neng was prescribing marijuana tea to treat gout, rheumatism, malaria, and even poor memory'. In Western medicine, between 1840 and 1900, more than 100 articles citing marijuana’s therapeutic qualities were published in American and European medical journals. These early American medical journals were recommending hemp seeds and roots for conditions including inflamed skin, incontinence and venereal disease, and in 1851, the United States Pharmacopoeia included hemp in its catalog of medicines. Marijuana was routinely prescribed by American physicians and enjoyed legal status in the United States until 1937 PUBMED 22129912

"Very few drugs, if any, have such a tangled history as a medicine. In fact, prejudice, superstition, emotionalism, and even ideology have managed to lead cannabis to ups and downs concerning both its therapeutic properties and its toxicological and dependence-inducing effects." E. A. Carlini Abstract

Therapeutic potential

Cannabis preparations exert numerous therapeutic effects. They have antispastic, analgesic, antiemetic, neuroprotective, and anti-inflammatory actions, and are effective against certain psychiatric diseases. PUBMED 23008748

Present discoveries indicates that cannabis-based drugs has shown ability to alleviate of autoimmunological disorders such as: Multiple sclerosis (MS), Rheumatoid arthritis (RA) or inflammatory bowel disease. Another studies indicates that cannabinoids play role in treatment of neurological disorders like Alzheimer disease or Amyotrophic lateral sclerosis (ALS) or even can reduce spreading of tumor cells. Cannabinoids stand out high safety profile... PUBMED 23421098 (need full)

Safety

Forbes

In truth, as Lester Grinspoon observes, marijuana does not fit any of the schedules very well. It is not the sort of medicine the FDA is used to approving. But it clearly can be used safely, as Obama conceded when he noted that it is less dangerous than alcohol. Back in 1988, when he urged the DEA to reschedule marijuana, Administrative Law Judge Francis Young called it “one of the safest therapeutically active substances known to man.” And while marijuana surely can be abused (what can’t?), its potential for abuse seems lower than that of many pharmaceuticals, not to mention alcohol and tobacco, which the CSA specifically excludes from its schedules.

In the US

Marijuana is classified by the Drug Enforcement Agency (DEA) as an illegal Schedule I drug which has no accepted medical use. However, recent studies have shown that medical marijuana is effective in controlling chronic non-cancer pain, alleviating nausea and vomiting associated with chemotherapy, treating wasting syndrome associated with AIDS, and controlling muscle spasms due to multiple sclerosis. These studies state that the alleviating benefits of marijuana outweigh the negative effects of the drug, and recommend that marijuana be administered to patients who have failed to respond to other therapies. Despite supporting evidence, the DEA refuses to reclassify marijuana as a Schedule II drug, which would allow physicians to prescribe marijuana to suffering patients. The use of medical marijuana has continued to gain support among states, and is currently legal in 16 states and the District of Columbia. This is in stark contrast to the federal government's stance of zero-tolerance, which has led to a heated legal debate in the United States. After reviewing relevant scientific data and grounding the issue in ethical principles like beneficence and nonmaleficence, there is a strong argument for allowing physicians to prescribe marijuana. Patients have a right to all beneficial treatments and to deny them this right violates their basic human rights. PUBMED 22129912

Compassionate Use Program

Since 1978, the federal government has provided 20 patients with medical marijuana under a compassionate investigation new drug program. The Institute of Drug Abuse pays the University of Mississippi to grow a consistent, reliable source of research-grade cannabis. This is a pure (unadulterated and standardized) form of marijuana without contaminants or pesticides. A North Carolina manufacturer receives $62,000 a year from the federal government to roll the marijuana cigarettes and ship them in sealed tins of 300 cigarettes, to the patients’ doctors and pharmacists. Each participant was given a letter from the FDA authorizing them to use this illegal substance that can bring a federal prison term of five years. In 1991, the federal government terminated this program, which was the only legal way to obtain access to marijuana. This program was terminated because, in the government’s opinion, too many people became aware of the program and were asking for access to medical marijuana supplies. Twelve individuals were receiving marijuana cigarettes in 1991 and they were “grandfathered” when the program was terminated. Since that time, four individuals have died from AIDS and the remaining eight continue to receive their supply of marijuana cigarettes . While the federal government at one time appeared to be moving toward acceptance and perhaps legalization of medical marijuana, it has instead decided to allow this program to disappear through attrition. PUBMED 22129912

Administration

As these therapeutic potentials are confirmed, it will be useful if marijuana and its constituents can be prescribed, dispensed, and regulated in a manner similar to other medications that have psychotropic effects and some abuse potential. Given that we do not know precisely which cannabinoids or in which combinations achieve the best results, larger and more representative clinical trials of the plant product are warranted. Because cannabinoids are variably and sometimes incompletely absorbed from the gut, and bioavailability is reduced by extensive first pass metabolism, such trials should include delivery systems that include smoking, vaporization, and oral mucosal spray in order to achieve predictable blood levels and appropriate titration. Advances in understanding the medical indications and limitations of cannabis in its various forms should facilitate the regulatory and legislative processes. PMC 3358713

Smoked cannabis

In relation to smoked marijuana, all of these alternatives are just that – alternatives, and are not necessarily as effective. It has been argued that smoked marijuana is substantially more effective than these alternatives. The THC in the inhaled smoke is absorbed within seconds and is delivered to the brain rapidly and efficiently, as would be expected of a highly lipid-soluble drug. Maximum blood concentrations are reached about the time smoking is finished and then rapidly dissipate. Psychopharmacologic effects peak at 30 to 60 minutes. The clear advantage of smoked marijuana is the rapid onset and dissipation of effects, because the patient is able to self-titrate the dose. In addition, the plant contains many other compounds (including about 60 cannabinoids) that may produce some additional benefits, Oncologists were among the first medical professionals to advocate for the medical use of smoked marijuana. Reacting to a DEA suggestion that only a “fringe group” of oncologists accepted marijuana as an antiemetic agent, a random survey of the members of the American Society of Oncology was conducted in 1990. More than 1000 oncologists responded to the survey; 44% reported that they had recommended marijuana to at least one patient. Smoked marijuana was believed to be more effective than oral Marinol by the respondents. Of those who believed they had sufficient information to compare the two drugs directly, 44% believed smoked marijuana was more effective and 13% that Marinol was more effective. PUBMED 22129912

Tolerance

Tolerance develops to many of the undesired effects of cannabinoids—particularly tiredness, dizziness, and cardiovascular and psychoactive effects—over a period of days or weeks (e113– e116). Withdrawal symptoms only ever occur in heavy users of cannabis after abrupt cessation of consumption. They are similar in character and intensity to those experienced after sudden cessation of cigarette smoking and include uneasiness, irritability, sleeplessness, increased perspiration, and loss of appetite (19). Withdrawal symptoms seldom represent a problem, however, in the controlled medical administration of cannabinoids (20).PUBMED 23008748

Effects

Numerous diseases, such as anorexia, emesis, pain, inflammation, multiple sclerosis, neurodegenerative disorders (Parkinson's disease, Huntington's disease, Tourette's syndrome, Alzheimer's disease), epilepsy, glaucoma, osteoporosis, schizophrenia, cardiovascular disorders, cancer, obesity, and metabolic syndrome-related disorders, to name just a few, are being treated or have the potential to be treated by cannabinoid agonists/antagonists/cannabinoid-related compounds. In view of the very low toxicity and the generally benign side effects of this group of compounds, neglecting or denying their clinical potential is unacceptable. PUBMED 18286801

Studies on cannabis also provide evidence of positive or “neutral” effects from cannabis consumption. For example, though inhalation of marijuana may induce acute coronary symptoms, ingestion of cannabinoids may have a positive effect on atherosclerotic heart disease via effects on the endocannabinoid system. Also, cannabis use has not been specifically linked to increased hospitalization due to cardiovascular disease or increased mortality from cardiovascular etiology. PUBMED 24350211

Studies show that the alleviating benefits of marijuana outweigh the negative effects of the drug. Medical marijuana can be used as a stand-alone treatment for these conditions or as a complement to conventional ones in order to help patients better withstand the conventional treatments’ effects and thereby obtain the full benefit, whether a cure or improvement of their condition PUBMED 22129912

Following the release of the Institute of Medicine’s report on medical marijuana in 1999, evidence supporting medical marijuana has increased. In the last three years, cannabinoids have been found to help kill breast cancer cells , fight liver cancer , reduce inflammation , have antipsychotic effects and even potentially help stave off the development of Alzheimer’s disease and reduce progression of Huntington’s disease . PUBMED 22129912

Adverse

Reported adverse effects are typically not serious. "Most trials indicate that medical cannabis produces mild to moderate adverse effects" (from full text) PUBMED 23386598

From "Hypothesizing that marijuana smokers are at a significantly lower risk of carcinogenicity relative to tobacco-non-marijuana smokers: evidenced based on statistical reevaluation of current literature":

A hypothetical link between marijuana smoking and cancer has been established based on a number of misleading assumptions. However, recent studies tend to suggest, if anything, an inverse association between marijuana use and cancers. (2008) Abstract (have full)

THC

(Per Tashkin) The largest study of its kind has unexpectedly concluded that smoking marijuana, even regularly and heavily, does not lead to lung cancer. The new findings "were against our expectations," said Donald Tashkin of the University of California at Los Angeles, a pulmonologist who has studied marijuana for 30 years. "We hypothesized that there would be a positive association between marijuana use and lung cancer, and that the association would be more positive with heavier use," he said. "What we found instead was no association at all, and even a suggestion of some protective effect." THC...may kill aging cells and keep them from becoming cancerous. Tashkin's study, funded by the National Institutes of Health's National Institute on Drug Abuse, involved 1,200 people in Los Angeles who had lung, neck or head cancer and an additional 1,040 people without cancer matched by age, sex and neighborhood. They were all asked about their lifetime use of marijuana, tobacco and alcohol. The heaviest marijuana smokers had lighted up more than 22,000 times, while moderately heavy usage was defined as smoking 11,000 to 22,000 marijuana cigarettes. Tashkin found that even the very heavy marijuana smokers showed no increased incidence of the three cancers studied. WaPo reference only

The study by researchers at the University of California, San Francisco, and the University of Alabama at Birmingham was released by the Journal of the American Medical Association. The findings echo results in some smaller studies that showed while marijuana contains some of the same toxic chemicals as tobacco, it does not carry the same risks for lung disease. It's not clear why that is so, but it's possible that THC makes the difference. THC causes the "high" that users feel. It also helps fight inflammation and may counteract the effects of more irritating chemicals in the drug, said Dr. Donald Tashkin, a marijuana researcher and an emeritus professor of medicine at the University of California, Los Angeles. Tashkin was not involved in the new study. other studies haven't found any definitive link between marijuana use and cancer. Fox - has not been reviewed. reference only

Tashkin is teaching about these effects in med school now: reference only Alternet:

The National Institute on Drug Abuse supported Tashkin's marijuana-related research over the decades and gave him a grant to conduct a large, population-based, case-controlled study that would prove definitively that heavy, long-term marijuana use increases the risk of lung and upper-airways cancers. What Tashkin and his colleagues found, however, disproved their hypothesis.

As to the highly promising implication of his own study -- that something in marijuana stops damaged cells from becoming malignant -- Tashkin noted that an anti-proliferative effect of THC has been observed in cell-culture systems and animal models of brain, breast, prostate, and lung cancer. THC has been shown to promote known apoptosis (damaged cells die instead of reproducing) and to counter angiogenesis (the process by which blood vessels are formed -- a requirement of tumor growth). Other antioxidants in cannabis may also be involved in countering malignancy, Tashkin said.

• Pulmonary Effects - Some research identifies an anti-inflammatory effect from consumption of the C. sativa plant. For example, one study of 5,115 adult males that took place over 20 years noted that occasional and low cumulative cannabis use was not associated with adverse effects on pulmonary function (114). Murine studies suggest that CBD has an immunosuppressive and anti-inflammatory effect on acute lung injury because of an increase in extracellular adenosine PUBMED 24350211

CBD (Psychological)

• Recent studies have suggested a possible protective effect of CBD. PMC 3797438

Rottanburg and colleagues were the first to propose a protective effect of CBD on THC-induced psychosis. They suggested that the high incidence of cannabis-related psychosis among their patients occurred because cannabis variants in South Africa are more potent in terms of THC content and because they lack CBD. As early as 1982, there were indications that the psychosis- and anxiety-inducing effects of THC can be suppressed by CBD (41, 42). Several other studies have found support for the antipsychotic effects of CBD. fMRI studies have shown that the effects of THC are correlated with a decrease in brain activity in the striatum. The striatum plays an important role in planning activities, modulating motor activity (movement), and performing cognitive tasks. CBD has been found to increase the activity in this brain area. Moreover, in other brain areas, the effects of CBD on neurological activity have been shown to be opposite those of THC.

There are indications that CBD may have some neuroprotective properties. In some neurodegenerative diseases that are often associated with declines in cognitive functioning, such as Alzheimer’s and Parkinson’s diseases, CBD may have some role in treatment or prevention.

Cancer

• Recent epidemiological studies suggest that cannabis is not carcinogenic. (2007) EC

• Specific link of cannabis to lung cancer remains unproven. (2013) PUBMED 24350211

• The antiproliferative action of cannabinoids on cancer cells was first noticed in the 1970s. Since then cannabinoids were found to act on various cancer cell lines, through various mechanisms.252,253 Cannabinoids were also found to be suppressors of angiogenesis and tumor invasion.254 Our knowledge on the anticancer activity of cannabinoids is rapidly expanding. PMC 3202504

• Cancer research has identified that cannabinoids can inhibit cancer growth, angiogenesis, and metastasis. (2013) full PUBMED 243502

• A specific link of cannabis to lung cancer remains unproven review. Current literature suggests that cannabis-only smokers are at lower risk of lung cancer than tobacco-only smokers.study

Mounting evidence shows ‘cannabinoids’ in marijuana slow cancer growth, inhibit formation of new blood vessels that feed a tumor (see angiogenesis), and help manage pain, fatigue, nausea, and other side effects.Researchers: Marijuana fights cancer, help manage side effects Daily Beast September 6, 2012 for reference only

Giving marijuana to mice with cancer shrank their lung tumors by half and slowed spread of the disease, findings that may one day expand legal use of the substance as a treatment, researchers said. The research is the first to show that marijuana's active ingredient, tetrahydrocannabinol, or THC, blocks a known cancer-related protein. Scientists speculate THC may activate biological pathways that halt cancer cell division or block development of blood vessels that feed tumors. In addition to reducing tumor size by half, THC was also associated with a 60 percent reduction in cancer lesions in the lungs of mice. A British study of nine brain-tumor patients last year found THC reduced growth of cancer cells, and other tests suggest it has potential in skin and breast cancers. Marijuana stops growth of lung cancer tumours in mice Bloomberg April 17,2007 for reference only

In a paper published in October's Anticancer Research, Wai Liu, a senior research fellow at St. George's University of London, reports that he found six cannabinoids...that can slow or outright kill cancer cells. Though THC is the main cannabinoid associated with marijuana and has been recognized to have a "really strong anti-cancer effect," Liu says, "it's not a good candidate for therapeutic use because of its psychoactive properties." He examined whether several lesser-known cannabinoids would impact the growth of leukemia cells both individually and in combination. The result? "They're good at killing cancer cells," he says. And "because they're not psychoactive, you can actually have the benefits associated with anti-cancer technology but not have the feelings of high, which are associated with THC." Some cannabinoids are better at killing cancer cells and others are better at slowing their growth, so combining certain cannabinoids has a heightened effect. "It's like a double hit," he says. Plus, they do not appear to target all rapidly dividing cells the way chemotherapy or radiation does - which leads to side effects, such as hair loss. Rather, they appear to attack just the cancer. Can Cannabis cure cancer? Newsweek, November 1, 2013 for reference only

• Δ9-Tetrahydrocannabinol (THC) and other cannabinoids inhibit tumour growth and angiogenesis in animal models, so their potential application as antitumoral drugs has been suggested. However, the antitumoral effect of cannabinoids has never been tested in humans. Here we report the first clinical study aimed at assessing cannabinoid antitumoral action, specifically a pilot phase I trial in which nine patients with recurrent glioblastoma multiforme were administered THC intratumoraly. The patients had previously failed standard therapy (surgery and radiotherapy) and had clear evidence of tumour progression. The primary end point of the study was to determine the safety of intracranial THC administration. We also evaluated THC action on the length of survival and various tumour-cell parameters. A dose escalation regimen for THC administration was assessed. Cannabinoid delivery was safe and could be achieved without overt psychoactive effects. Median survival of the cohort from the beginning of cannabinoid administration was 24 weeks (95% confidence interval: 15–33). Δ9-Tetrahydrocannabinol inhibited tumour-cell proliferation in vitro and decreased tumour-cell Ki67 immunostaining when administered to two patients. The fair safety profile of THC, together with its possible antiproliferative action on tumour cells reported here and in other studies, may set the basis for future trials aimed at evaluating the potential antitumoral activity of cannabinoids. Nature

• THC does not facilitate tumour growth nor decreases patient survival, at least in our cohort of brain tumour patients expressing cannabinoid receptors. In view of the fair safety profile of THC, together with its possible antiproliferative action on tumour cells reported here and in other studies (Guzmán, 2003), it would be desirable that additional trials – on this and other types of tumours – were run to determine whether cannabinoids – as single drugs or in combination with established antitumoral drugs – could be used, other than for their palliative effects, to inhibit tumour growth. Nature

• Cannabis-like compounds offer therapeutic potential for the treatment of breast, prostate and bone cancer in patients. Further basic research on anti-cancer properties of cannabinoids as well as clinical trials of cannabinoid therapeutic efficacy in breast, prostate and bone cancer is therefore warranted. PUBMED 21410463

• In the last two decades, research has dramatically increased the knowledge of cannabinoids biology and pharmacology. In mammals, compounds with properties similar to active components of Cannabis sativa, the so called ‘endocannabinoids', have been shown to modulate key cell-signalling pathways involved in cancer cell growth, invasion and metastasis. To date, cannabinoids have been licensed for clinical use as palliative treatment of chemotherapy, but increased evidences showed direct antiproliferative actions of cannabinoid agonists on several tumour cells in vitro and in animal models. PMC 1617062

• Although there is a strong set of data in vitro, in cellular model systems, and in mouse model systems, there is a dearth of clinical data on the effects of cannabinoids in the treatment of cancer in humans. This fact is quite surprising considering the large library of compounds that have been developed and used to study the effects of cannabinoids on cancer in model systems. Despite the lack of preclinical and clinical data, there is a strong agreement that pharmacological targeting of the endocannabinoid system is emerging as one of the most promising new methods for reducing the progression of cancer. OMC 3366283

• THC inhibits growth and metastasis of lung cancer. Recent studies have shown that THC possess anti-tumor properties against various types of cancers....Cumulatively, these studies indicate that THC has anti-tumorigenic and anti-metastatic effects against lung cancer. 98th American Association for Cancer Research Annual Meeting; Apr 14-18, 2007; Los Angeles, CA:

• Critical appraisal of the potential use of cannabinoids in cancer management <-- 2013

• Evidence is emerging to suggest that CBD is a potent inhibitor of both cancer growth and spread. Abstract (Have access to full text)

Gliomas

• Autophagy can promote cell survival or cell death, but the molecular basis underlying its dual role in cancer remains obscure. Here we demonstrate that Δ9-tetrahydrocannabinol (THC), the main active component of marijuana, induces human glioma cell death through stimulation of autophagy. Our data indicate that THC induced ceramide accumulation and eukaryotic translation initiation factor 2α (eIF2α) phosphorylation and thereby activated an ER stress response that promoted autophagy via tribbles homolog 3–dependent (TRB3-dependent) inhibition of the Akt/mammalian target of rapamycin complex 1 (mTORC1) axis. We also showed that autophagy is upstream of apoptosis in cannabinoid-induced human and mouse cancer cell death and that activation of this pathway was necessary for the antitumor action of cannabinoids in vivo. These findings describe a mechanism by which THC can promote the autophagic death of human and mouse cancer cells and provide evidence that cannabinoid administration may be an effective therapeutic strategy for targeting human cancers. JCI 37948

Breast

CBD turns off the overexpression of ID-1, which makes the cells lose their ability to travel to distant tissues; keeps the cells more local and blocks their ability to metastasize. Cancer kills through its ability to metastasize. (The researchers stressed CBD works only on cancer cells that have these high levels of ID-1 and these do not include all cancerous tumors but, rather, aggressive, metastatic cells. But they've found such high levels in leukemia, colorectal, pancreatic, lung, ovarian, brain and other cancers.) SFG for reference only

• Here, we report that cannabidiol (CBD), a cannabinoid with a low-toxicity profile, could down-regulate Id-1 expression in aggressive human breast cancer cells. The CBD concentrations effective at inhibiting Id-1 expression correlated with those used to inhibit the proliferative and invasive phenotype of breast cancer cells. CBD was able to inhibit Id-1 expression at the mRNA and protein level in a concentration-dependent fashion. These effects seemed to occur as the result of an inhibition of the Id-1 gene at the promoter level. Importantly, CBD did not inhibit invasiveness in cells that ectopically expressed Id-1. In conclusion, CBD represents the first nontoxic exogenous agent that can significantly decrease Id-1 expression in metastatic breast cancer cells leading to the down-regulation of tumor aggressiveness. (see Triple negative breast cancer) PUBMED 18025276/full text

• Recent research on CBD source
• Dr Shawn McAllister

Anti-inflammatory

Cannabinoids, the active components of Cannabis sativa, and endogenous cannabinoids mediate their effects through activation of specific cannabinoid receptors known as cannabinoid receptor 1 and 2 (CB1 and CB2). The cannabinoid system has been shown both in vivo and in vitro to be involved in regulating the immune system through its immunomodulatory properties. Cannabinoids suppress inflammatory response and subsequently attenuate disease symptoms. This property of cannabinoids is mediated through multiple pathways such as induction of apoptosis in activated immune cells, suppression of cytokines and chemokines at inflammatory sites and upregulation of FoxP3+ regulatory T cells. Cannabinoids have been tested in several experimental models of autoimmune disorders such as multiple sclerosis, rheumatoid arthritis, colitis and hepatitis and have been shown to protect the host from the pathogenesis through induction of multiple anti-inflammatory pathways. Cannabinoids may also be beneficial in certain types of cancers that are triggered by chronic inflammation. In such instances, cannabinoids can either directly inhibit tumor growth or suppress inflammation and tumor angiogenesis. PMC 20191092

Neuroprotection

Cannabinoids, such as THC from Cannabis, as well as anandamide and 2-arachidonoyl glycerol, produced by the mammalian body, have been shown to protect the brain from various insults and to improve several neurodegenerative diseases. The current review summarizes the evidence for cannabinoid neuroprotection in vivo, and refers to recent in vitro studies, which help elucidate possible molecular mechanisms underlying this protective effect. Some of these mechanisms involve the activation of CB1 and CB2 cannabinoid receptors, while others are not dependent on them. In some cases, protection is due to a direct effect of the cannabinoids on neuronal cells, while in others, it results from their effects on non-neuronal elements within the brain. In many experimental set-ups, cannabinoid neurotoxicity, particularly by THC, resides side by side with neuroprotection. Abstract - need full text

The researchers concluded that the use of low doses of THC can prevent long-term cognitive damage that results from brain injury in mice, but the drug needs to be tested in human trials. "Since we deal, in this case, in a basic process (THC is protective against a variety of insults, not just a specific condition), I personally believe it will go beyond rodents," Sarne wrote in an email. Fox reference only

MS

Data from animal models of MS and clinical studies have supported the anecdotal data that cannabis can improve symptoms by the modulation of excessive neuronal signalling. cannabinoids have activity, not only in symptom relief but also potentially in neuroprotective strategies which may slow disease progression and thus delay the onset of symptoms such as spasticity. PUBMED 22583441

Psychosis

Risk

• The question of whether cannabis is a precipitative or causative factor in the development of psychosis remains unanswered. Reviews considered show a potential risk of psychotic symptoms associated with cannabis use, however these results are by no means definitive as far as the causality of the association is concerned. We conclude that there is insufficient knowledge to determine the level of risk associated with cannabis use in relation to psychotic symptoms and that more information is needed on both the risks of cannabis use and the benefits of preventive interventions to support evidence-based approaches in this area. (2010) PUBMED 20565524 (have full)
• During the last 3 decades of the 20th century, cannabis use had significantly increased in Australia without a corresponding increase in schizophrenia prevalence, an observation that gravitated against a simple cause-and-effect relationship between the two. However, they also found that cannabis use precipitated the onset of the disease in the vulnerable and exacerbated the course of the illness in those who already had it. Abstract (2003)

Ameliorative

• Cannabidiol was found to have therapeutic potential with antipsychotic, anxiolytic, and antidepressant properties, in addition to being effective in other conditions. Delta(9)-tetrahydrocannabinol and its analogues were shown to have anxiolytic effects in the treatment of cannabis dependence and to function as an adjuvant in the treatment of schizophrenia, although additional studies are necessary to support this finding. PUBMED 20512271
• Some research notes a lower mortality rate among adults with schizophrenia and related psychotic disorders in those who smoked cannabis versus those who did not smoke cannabis. PUBMED 24350211
• A trend towards more insight and of fewer abusive or accusatory hallucinations was seen amongst cannabis users. This argues against a distinct schizophrenia-like psychosis caused by cannabis. Less avolition and fewer apathy symptoms were detected in patients with schizophrenia and cannabis abuse than in those with no abuse. PMC 3202504

Addiction

• Cannabis with a high CBD content confers less risk for developing an addiction than cannabis with a low-CBD content. PUBMED 24137134
• Some have placed the dependence rate at 7–10% of regular users PUBMED 243350211
• DSMIII codified a view of substance dependence for which symptoms of physical dependence were neither necessary nor sufficient for establishing a diagnosis . Among regular cannabis users, a dependence syndrome very similar to that described for other drugs of abuse was reliably described. "Unsuccessful attempts to cut down, use despite knowledge of persistent psychological or physical problems, excessive time spent buying, using or recovering from cannabis effects, and loss of control over use" PMC 3371269
• The researchers concluded that cannabis with a high CBD content confers less risk for developing an addiction than cannabis with a low-CBD content. Review

Former Surgeon General Jocelyn Elders characterized marijuana succinctly on CNN recently, while declaring her support for legalization: “Marijuana is not addictive, not physically addictive anyway.” TIME

Pain

Non-cancer pain

Most recently in 2011, cannabinoids’ treatment of chronic non-cancer pain was examined using a randomized controlled trial. The cannabinoids studied were smoked cannabis, oromucosal extracts of cannabis based medicine, nabilone, Marinol and a novel THC analog. The non-cancer pain conditions were neuropathic pain, fibromyalgia, rheumatoid arthritis, and mixed chronic pain. Of the eighteen trials, fifteen showed a significant analgesic effect of cannabinoid compared to the placebo, and more importantly, there were no serious adverse effects. The overall results of the study stated that cannabinoids are safe and modestly effective in the treatment of the above mentioned non-cancer pain. PUBMED 22129912

Entourage effect

The therapeutic entity is the aggregate of cannabinoids and terpenes, not just a single terpene or cannabinoid.

• THC has been the primary focus of cannabis research since 1964, when Raphael Mechoulam isolated and synthesized it. More recently, the synergistic contributions of CBD to cannabis pharmacology and analgesia have been scientifically demonstrated. Other phytocannabinoids, including tetrahydrocannabivarin, cannabigerol and cannabichromene, exert additional effects of therapeutic interest. Innovative conventional plant breeding has yielded cannabis chemotypes expressing high titres of each component for future study. This review will explore another echelon of phytotherapeutic agents, the cannabis terpenoids: limonene, myrcene, α-pinene, linalool, β-caryophyllene, caryophyllene oxide, nerolidol and phytol. Terpenoids share a precursor with phytocannabinoids, and are all flavour and fragrance components common to human diets that have been designated Generally Recognized as Safe by the US Food and Drug Administration and other regulatory agencies. Terpenoids are quite potent, and affect animal and even human behaviour when inhaled from ambient air at serum levels in the single digits ng·mL−1. They display unique therapeutic effects that may contribute meaningfully to the entourage effects of cannabis-based medicinal extracts. Particular focus will be placed on phytocannabinoid-terpenoid interactions that could produce synergy with respect to treatment of pain, inflammation, depression, anxiety, addiction, epilepsy, cancer, fungal and bacterial infections (including methicillin-resistant Staphylococcus aureus). PMC 3165946

ECS

Research on marijuana’s effects led directly to the discovery of a molecular signaling system in the human brain and body, the endocannabinoid system, which plays a crucial role in regulating a broad range of physiological processes: hunger, sleep, inflammation, stress, blood pressure, body temperature, glucose metabolism, bone density, intestinal fortitude, reproductive fertility, circadian rhythms, mood and much more. Within the scientific community, the discovery of the endocannabinoid system is increasingly recognized as a seminal advance in our understanding of human biology. The Rubicon was crossed in 1988, when a government-funded study at the St. Louis University School of Medicine determined that the mammalian brain has an abundance of receptor sites—specialized protein molecules embedded in cell membranes—that respond pharmacologically to compounds in cannabis. More than 100 unique cannabinoids have been identified in cannabis. The Nation October 30,2013 reference only

• The physiological function of the ECS in energy balance and the therapeutic potential of targeting this system. PUBMED 22076835

• The endocannabinoid system is a very complex one and regulates numerous processes, in parallel with other wellknown systems, such as the adrenergic, cholinergic, and dopaminergic systems. PMC 3202504 (article)

Cannabinoids

Cannabinoids have been tested in several experimental models of autoimmune disorders such as multiple sclerosis, rheumatoid arthritis, colitis and hepatitis and have been shown to protect the host from the pathogenesis through induction of multiple anti-inflammatory pathways. Cannabinoids may also be beneficial in certain types of cancers that are triggered by chronic inflammation. In such instances, cannabinoids can either directly inhibit tumor growth or suppress inflammation and tumor angiogenesis. PUBMED 20191092

CBD

Cannabidiol (CBD), a nonpsychoactive component of the cannabis plant, is generating quite a buzz among medical scientists and health professionals. Nothing else is able to help treatment-resistant epileptic children with Dravet syndrome and related disorders. On August 11, 2013, Dr. Sanjay Gupta’s nationally televised report on CNN discussed the astonishing transformation of Charlotte Figi, a 7-year-old epileptic who had 300 “tonic-clonic” seizures a week until she ingested a CBD-infused tincture. She has been nearly seizure-free since her parents began giving her a daily dose of CBD. Nor is Charlotte an isolated case: dozens of families with children suffering from intractable epilepsy are reporting dramatic results with cannabidiol. A gifted compound with a wide spectrum of action, CBD shows promise as a treatment for many pathological conditions, including cardiovascular disease, diabetes, depression and psychosis. Preclinical studies indicate that CBD can shrink malignant tumors, alter gene expression, improve insulin sensitivity, normalize irregular heartbeat and protect the brain against alcohol poisoning. CBD can also counter the psychoactive effects of THC, which makes some people anxious and dysphoric rather than mellow and euphoric. The reduced psychoactivity of CBD-rich cannabis may make it an appealing option for ailing individuals who otherwise would never consider patronizing a medical marijuana dispensary. The Nation for reference only

• Studies using animal models of anxiety and involving healthy volunteers clearly suggest an anxiolytic-like effect of CBD. Moreover, CBD was shown to reduce anxiety in patients with social anxiety disorder. full text
• Cannabinoid-related agents in the treatment of anxiety disorders: current knowledge and future perspectives explore
• The data presented in this review show that cannabinoids may, in the future, become an important option in the treatment of psychiatric symptoms and disorders. Due to the absence of psychoactive or cognitive effects, to its safety and tolerability, to the existence of clinical trials with positive results, and to its broad pharmacological spectrum, CBD is possibly the cannabinoid more likely to have initial findings translated into clinical practice. In particular, the results indicating that CBD has antipsychotic and anxiolytic properties seem to be well established. PUBMED 20512271
• Few or no adverse effects of CBD have been proffered, and where CBD has been found to have an effect, it is usually in a “positive” (i.e., salubrious)

direction. PUBMED 24137134

• Few undesirable effects are reported, and tolerance for CBD does not seem to occur. full text (review)

THC

• This review analyses the therapeutic usefulness of Delta(9)-tetrahydrocannabinol and its potential to induce adverse reactions on humans. During the last 30 years an enormous amount of research was carried out resulting in the disclosure of the cannabinoid system in Central Nervous System, with its CB(1) and CB(2) receptors, and the agonist anandamide. Under the clinical point of view, Delta(9)-THC produces some therapeutic benefits which are beyond reasonable doubt. Thus, the effects on nausea/emesis due to cancer chemotherapy, as appetite promoter, on some painful conditions and on symptoms of multiple sclerosis are clearly demonstrated. Delta(9)-THC is not devoid of ill effects. On the cognitive domain it impairs the human capacity to discriminate time intervals and space distances, vigilance, memory and the performance for mental work. On the psychic area Delta(9)-THC may induce unpleasant reactions such as disconnected thoughts, panic reactions, disturbing changes in perception, delusions and hallucinatory experiences. However, the long term effects on the psyche and cognition are not known as there are no reports of prolonged use of Delta(9)-THC. Actually, it has been proposed by WHO that Delta(9)-THC should be rescheduled to schedule IV of the United Nations Convention on Psychotropic Drugs, as it does not constitute a substantial risk to public health and its abuse is rare if at all. PUBMED 15302527

Marinol

Marinol . First, some patients complained that the effects of the pill were too strong at first, and then wore off quickly . Second, it is very expensive, costing patients anywhere from $200–$800 monthly . Third, Marinol can be difficult for nauseous patients to consume; some patients fail to keep the pill down long enough for it to be effective PUBMED 22129912

Restrictions on research

Schedule I

In order to reschedule marijuana, the FDA requires controlled, double-blind clinical trials. However, there is a major obstacle preventing these trials. Like all other herbal medicines, marijuana faces a major roadblock that inhibits conducting sophisticated clinical trials: a lack of patentable product . Without the financial incentive of being able to patent the substance as a commercial product, few have pursued the path of carrying out research using the sophisticated, difficult, and expensive procedures proscribed by best practice. PUBMED 22129912 "The illegality of marijuana hinders epidemiologic research. Without stratified data, effects of chronic use are diluted by the negligible effects of occasional use" Abstract 2008 (have full)

Harvard psychiatrist Lester Grinspoon, co-author of Marihuana: The Forbidden Medicine and a leading expert on cannabis, agrees that marijuana’s Schedule I status has impeded research. “Since 1970,” he says, “it has been the major reason why the kinds of large double-blind studies which have been the basis for FDA approval of medicines since the mid-1960s have been impossible to pursue in this country.” Forbes February 2014

Studies designed to investigate harm

For many years, the federal government has subsidized studies designed to prove the negative effects of marijuana, while blocking inquiry into its potential benefits. Ironically, the government’s steadfast search for harm has yielded remarkable scientific insights that explain why cannabis is such a versatile remedy and why it is the most sought-after illicit substance on the planet. The Nation October 30, 2013

Only 6% of research on marijuana published in analysed benefits. The other 93% are designed primarily to investigate harm. According to Sanjay Gupta, "That imbalance paints a highly distorted picture." BI CNN August 13, 2013

With cannabis declared to have “no currently accepted medical use,” the FDA designated it a Schedule I drug, a categorization reserved for street drugs with high abuse potential, such as heroin, quaaludes, lysergic acid diethylamide, and 3,4-methylenedioxymethamphetamine.3 This designation has resulted in a near-cessation of scientific research on cannabis in the United States, particularly because the only federally authorized source of cannabis is a strain grown at the University of Mississippi and accessible to researchers only by applying to the National Institute on Drug Abuse, which is reluctant to support medical research and has historically focused its efforts (almost) exclusively on demonstrating the drug's harmful effects. According to Ware et al, most cannabis research in the United States occurs “under a paradigm of prohibition and the study of risk is not yet balanced by much-needed research on benefits.” In challenging the one-sided devaluation of cannabis as a dangerous substance, Cohen emphasizes that medical decision making is not based on risk alone. “The linchpin for medical decision-making is not risk—for no treatment is without risk—but the balancing of risks and benefits.” Any rational consideration of legalizing medical marijuana should thus include both sides of the equation. Martin writes that the “basic principles of medicine should take precedence over political expediency in the development of a rational strategy for any therapeutic agent, even one as controversial as marijuana.” Marijuana being relegated to Schedule I status appears especially irrational when precedence exists for assigning potential drugs of abuse Schedule II status when they also possess manifest medical benefits. PUBMED 3538401

Federal barriers

Scientific research on the medical effects of marijuana has been limited due to the stipulation that all studies must be funded by the National Institutes of Health. PUBMED 22129912

In 1970, citing marijuana's potential for abuse and addiction, the US Congress declared Cannabis to have no medical value, rendering illegal a plant that had been used medicinally throughout the world for thousands of years. PMC 3202504

Ironically, given the recent hue and cry over medical marijuana having been legalized without scientific input, the US Congress had failed to follow its usual review process dictated by the Controlled Substances Act that requires scientific evaluation and testimony before legislative action. It declared cannabis illegal in the absence of such evidence. PUBMED 20880248

In 2011, the California Medical Association became "the first state-based association in the United States to call for the legalization of marijuana, so that it can be properly regulated and assessed for its medical value...There simply isn't the scientific evidence to understand the benefits and risks of medical cannabis," Dr. Paul Phinney, chair of the California association said in a press release). "We need to regulate cannabis so that we know what we're recommending to our patients. Currently, medical and recreational cannabis have no mandatory labeling standards of concentration or purity. First, we've got to legalize it so that we can properly study and regulate it." The new policy was based on an association-commissioned study which concluded that the criminalization of marijuana was a "failed public health policy" (PDF). "Cannabis illegality has perpetuated the effective prohibition of clinical research on the properties of cannabis and has prevented the development of state and national standards governing the cultivation, manufacture, and labeling of cannabis products, similar to those governing food, tobacco and alcohol products, most of which are promulgated by federal agencies," the white paper states. "Cannabis is currently not sufficiently regulated. In order to allow for a robust regulatory scheme to be developed, cannabis must be moved out of its current Schedule I status within the DEA's official schedule of substances. Rescheduling cannabis will allow for further clinical research to determine the utility and risks of cannabis, which will then shape the national regulatory structure for this substance."

Another federal restriction is the requirement that clinical studies be funded from scarce grant money controlled by the National Institutes of Health (NIH). These restrictions have discouraged researchers from studying the medical benefits of marijuana. For example, the 2012 estimate for clinical research on cancer accounts for approximately six billion dollars of the NIH budget, which totals 31.2 billion dollars . The 2011 NIH budget allocated the following funds available for marijuana research for qualified organizations: $2 million in 4–5 awards. According to NIH Grant guidelines on marijuana, applicants may request budgets with direct costs up to $500,000 per year for a maximum period of 5 years. Therefore, the total budget would be $10 million over the 5 year period . Of the yearly NIH budget of approximately $31.2 billion, the $2 million going toward marijuana research can be calculated as comprising 0.006% of the yearly budget, thus illustrating how marijuana research is vastly underfunded. PUBMED 22129912

The Lancet:

Those skeptical of botanical cannabis do not argue that it is necessarily bad. Rather they contend that the benefits of cannabis—particularly when smoked—remain scientifically unproven, not only on its own merits but also compared with other available treatments. They contend that the usual standards for evaluating pharmacotherapies have been largely side-stepped. They want legitimate research. Abstract

American College of Physicians:

"Part II of the article will begin by reviewing the benefits of Cannabis sativa as documented by well designed scientific studies that have been published in the peer-reviewed literature. I will then propose that ability of scientists to conduct impartial studies designed to answer the question of marijuana's role in medical therapy has been greatly hampered by political considerations. I will posit that in spite of the considerable efforts of policymakers, it is becoming apparent that marijuana's benefits should be weighed against its well-described risks. I will conclude that political advocacy is a poor substitute for dispassionate analysis and that neither popular votes nor congressional "findings" should be permitted to trump scientific evidence in deciding whether or not marijuana is an appropriate pharmaceutical agent to use in modern medical practice. Whether or not marijuana is accepted as a legitimate medical therapy should remain in the hands of the usual drug-approval process and that the statutory role of the Food and Drug Administration should be dispositive." Abstract - need full text

Forbes:

There are other research obstacles, unique to marijuana. In 1999, responding to the legalization of medical marijuana in California, the Clinton administration imposed an additional layer of review on research involving cannabis, requiring approval by the Public Health Service as well as the FDA, the DEA, and the relevant institutional review board. And even after they get all the other necessary approvals, researchers have to obtain marijuana from the National Institute on Drug Abuse (NIDA), which has a monopoly on the legal supply—something that is not true of other Schedule I drugs. NIDA, an agency whose mission focuses on marijuana’s hazards, has not been keen to assist research aimed at measuring its benefits. Although neither of these requirements is a necessary consequence of marijuana’s Schedule I status, they would be harder to defend if marijuana were reclassified, which would mean acknowledging that it has medical value and can be used safely.