NIDA Research on the Therapeutic Benefits of Cannabis and Cannabinoids

Currently there is considerable interest in the possible therapeutic uses of marijuana (see our fact sheet, “Is Marijuana Medicine?”). As of January 31, 2014, there were 28 active grants related to this topic, funded by NIDA, in 6 different disease categories (see table, below). Therapeutic research is defined here as projects that include (as at least one of their specific aims) investigation of the potential medical benefit of the marijuana plant (Cannabis sativa) or its constituentcannabinoid chemicals in human or animal models of disease.

Most of these research projects are examining the medical benefits of individual cannabinoid chemicals derived from or related to those in the marijuana plant, not the plant itself, although a few use unprocessed plant material. Individual cannabinoid chemicals may be isolated and purified from the marijuana plant or synthesized in the laboratory, or they may be naturally occurring (endogenous) cannabinoids found in the body and modified using other, non-cannabinoid chemicals.

Specifically, cannabinoids are classified here as:

  • Plant  – plant leaves, flowers, stems, and seeds collected from the Cannabis sativa plant and ingested in some form (cigarettes, vapor); also known as phytocannabinoids.
  • Endogenous – cannabinoids made by the body: N-arachidonoylethanolamine or anandamide (AE) or 2-arachidonoylglycerol ( 2-AG).  AE and 2-AG activity is manipulated by inhibiting their corresponding hydrolases FAAH or MAGL, preventing their degradation.
  • Purified – naturally occurring cannabinoids purified from plant sources:  Cannabidiol (CBD), D9-tetrahydrocannabinol (THC), and Sativex (mixture of THC and CBD).
  • Synthetic –cannabinoids synthesized in a laboratory: CB1 agonists (CPP-55, ACPA), CB2 agonists (JWH-133, NMP7, AM1241), CB1/CB2 nonselective agonist (CP55,940), Ajulemic Acid (AJA), Nabilone, Dronabinol, and several other proprietary chemicals in development as potential cannabinoid agonists and antagonists for therapeutic use.

How the Portfolio Analysis Was Conducted:

  • An internal NIH database (QVR) was searched on January 31, 2014 using the following:  TEXT word string “cannabinoid OR cannabis OR marijuana”; active grants
  • 317 grants were manually screened to identify studies in which at least one specific aim included a therapeutic focus.
  • 28 projects were identified (25 projects + 3 supplements) and are listed in the table below.

In the table, projects are divided into six disease categories:autoimmune diseases, inflammation, pain, psychiatric disorders, seizures, and substance use disorders (SUDs). Clicking on individual project titles leads to their descriptions in NIH RePorter. Also listed are the cannabinoid substances being examined and, except in cases when the whole plant was used, whether the studied chemicals are purified from the plant, synthetic, or endogenous; and whether the project uses human or animal subjects.

Autoimmune disease
Project Title Cannabinoid Study Model
TRANSDERMAL DELIVERY OF 2-ARACHIDONOYL GLYCEROL (2-AG) FOR THE TREATMENT OF ARTHR Endogenous (2-AG) Animal
Inflammation
Project Title Cannabinoid Study Model
CANNABINOID EPIGENOMIC AND MIRNA MECHANISMS IMPACT HIV/SIV DISEASE PROGRESSION Purified (THC) Animal
CANNABINOID MODULATION OF MICROGLIAL RESPONSE TO THE HIV PROTEIN TAT Purified and Synthetic (THC and CP55940) Cell culture and animal models
Pain
Project Title Cannabinoid Study Model
BEHAVIORAL ECONOMIC ANALYSIS OF MEDICAL MARIJUANA USE IN HIV+ PATIENTS Plant (cannabis cigarettes) Human
CANNABINOID MODULATION OF HYPERALGESIA Endogenous (AE and 2-AG via URB597 FAAH inhibitor and JZL184 MAGL inhibitor) Animal
CANNABINOID RECEPTOR AGONISTS FOR TREATMENT OF CHRONIC PAIN Synthetic (CB2 agonist, proprietary) Animal
OPTIMIZING ANALGESIA BY EXPLOITING CB2 AGONIST FUNCTIONAL SELECTIVITY Synthetic (CB2 agonists, proprietary) Animal
PERIPHERAL FAAH AS A TARGET FOR NOVEL ANALGESICS Endogenous (AE via FAAH inhibitor (URB937)) Animal
THE EFFECT OF VAPORIZED CANNABIS ON NEUROPATHIC PAIN IN SPINAL CORD INJURY Plant (cannabis, vaporized) Human
Psychiatric Disorder
Project Title Cannabinoid Study Model
CANNABIDIOL MODULATION OF ???-9-THC???S PSYCHOTOMIMETIC EFFECTS IN HEALTHY HUMANS Purified (Cannabidiol) Human
CANNABIS, SCHIZOPHRENIA AND REWARD: SELF-MEDICATION AND AGONIST TREATMENT? Synthetic and Plant (Dronabinol & cannabis cigarettes) Human
Seizures
Project Title Cannabinoid Study Model
NEW DRUGS TO ENHANCE ENDOCANNABINOID RESPONSES FOR TREATING EXCITOTOXICITY, PHASE Endogenous (AE via FAAH inhibitors) Animal
SUD, Withdrawal, and Dependence
Project Title Cannabinoid Study Model
CANNABINERGIC MEDICATIONS FOR METHAMPHETAMINE ADDICTION Synthetic (CB1 agonists and antagonists, proprietary) Animal
EFFICACY AND SAFETY OF DRONABINOL (ORAL THC) FOR TREATING CANNABIS DEPENDENCE Synthetic (Dronabinol) Human
EVALUATION OF NOVEL PHARMACOTHERAPIES FOR THE TREATMENT OF OPIOID DEPENDENCE Synthetic (Dronabinol, Nabilone) Human
FAAH-INHIBITOR FOR CANNABIS DEPENDENCE Endogenous (AE via PF-04457845 FAAH inhibitor) Human
MARIJUANA RELAPSE: INFLUENCE OF TOBACCO CESSATION AND VARENICLINE Sythetic (Dronabinol )+/- the noncannabinoid varenicline Human
MEDICATIONS DEVELOPMENT FOR CANNABIS-USE DISORDERS: CLINICAL STUDIES Purified (THC) and non-cannabinoids: Gabapentin & Tiagabine Human
MONOACYLGLYCEROL LIPASE INHIBITORS FOR TREATING OPIOID USE DISORDERS + supplement Endogenous (2-AG via JZL184 MAGL inhibitor) Animal
NABILONE FOR CANNABIS DEPENDENCE: IMAGING AND NEUROPSYCHOLOGICAL PERFORMANCE + supplement Synthetic (Nabilone) Human
NOVEL MEDICATION APPROACHES FOR SUBSTANCE ABUSE Synthetic (Dronabinol, Project 4)+noncannabinoid lofexidine Human
NOVEL MEDICATIONS FOR CANNABIS DEPENDENCE Synthetic (Modify THC and nabilone to create new cannabinoids) Animal
SATIVEX ASSOCIATED WITH BEHAVIOURAL-PREVENTION RELAPSE STRATEGY AS TREATMENT FOR + supplement Purified (Sativex) +/- behavioral therapy Human
STRESS-INDUCED MARIJUANA SELF-ADMINISTRATION: ROLE OF SEX AND OXYTOCIN Plant (cannabis cigarettes) Human
TREATMENT OF CANNABINOID WITHDRAWAL IN RHESUS MONKEYS Purified (THC) and Endogenous (via AEA via FAAH inhibitors) Animal

Ten Things You Didn’t Know About the History of Marijuana

What do Bill Clinton, Sarah Palin, Barack Obama, Justin Bieber, Maya Angelou and well over 100 million Americans all have in common? They’ve all smoked pot. Throughout its history, marijuana has attracted plenty of unexpected users and proponents. And much of the history of greenery is now familiar to us—thanks to CNN and History Channel specials, the burgeoning legalization movement and the popularity of anti-pot propaganda films like Reefer Madness. But even if you’re intimately familiar with the plant in all its forms, we’re willing to wager that some of these facts will surprise you.

1. The first known potheads lived in ancient China, circa 2,727 BC. Emperor Shen Nung helpfully compiled an encyclopedic list of drugs and their uses, which includes “ma,” or cannabis. But ancient Chinese weed consumption is indicated by more than just written records: Six years ago, archaeologists on a dig in the Gobi Desert found the world’s oldest pot stash in the grave of a shaman of the Gushi tribe. The purpose of the cannabis was easily identified because the male plant parts, which are less psychoactive, had been removed.

The Chinese certainly weren’t the only ancient culture to enjoy toking. The Greeks and Romans used marijuana, as did the citizens of the Islamic empires. In 1545, Spanish conquistadors introduced it to the New World when they began planting cannabis seed in Chile to be used for fiber.

 

Thomas_Jefferson_by_Rembrandt_Peale,_1800

2. You probably heard that a bunch of the Founding Fathers grew weed, but did you know the details? Technically, you can’t really classify them as pot farmers because they were growing hemp, which is not the same cannabis variety that you’ll find in a joint. Hemp and pot are the same species—cannabis sativa—but the hemp variety has a lower THC content and was useful instead as a source of fiber for those distinguished dudes’ duds.

But debate continues about whether the Founding Fathers actually smoked cannabis in addition to growing it. While many traditional sourcessay there’s no evidence of it, other, less buttoned-down ones—including, predictably, High Times—contend that there is.

One factor that muddies the water and the Internet is an oft-repeated Thomas Jefferson “quote” that experts agree is not legit. Although he was a hemp farmer, Thomas Jefferson never said: “Some of my finest hours have been spent sitting on my back veranda, smoking hemp and observing as far as my eye can see.”

Admittedly, that’s a pretty difficult image to forget.

 

3. Hashish, which is a compressed or purified form of pot resin, became faddish in the mid-1800s, as a result of its prominence in popular novels of the era, including two classics: The Count of Monte Cristo and Arabian Nights, an early English translation of One Thousand and One Nights.

In one scene fit to make any DARE instructor shudder, the Count of Monte Cristo virtually coerces another character into a mind-bending hashish adventure, urging, “Taste the hashish, guest, taste the hashish!”

Arabian Nights meanwhile contains multiple references to hashish, including the story “The Tale of the Hashish Eater.” Both Monte Cristoand Arabian Nights found wide audiences due to their exotic settings, foreign cultures and adventure plots that heightened the allure of the drug described on the pages. Contemporary readers who would never had the opportunity to to Persia could at least cop a little bit of Persia off seafaring vessels from foreign ports.

 

Reefer Madness! Photo via

4. Pot’s reputation began to go south when the first English-language newspaper started in Mexico in the 1890s.Sensationalized stories of marijuana-induced violence gave the drug a bad rap, although pot didn’t really hit the US until after the Mexican Revolution in 1910, when a flood of Mexican immigrants moved north, bringing their favorite weed.

US groups began spreading stories of violence induced by the drug, playing on anti-immigrant sentiment, and referring to the drug by the Mexican-sounding name “marijuana.” This highly racialized propaganda led to widespread fear of the drug, which grew into a panic in the early 1930s when government research “determined” that marijuana-induced criminal acts were “primarily committed by ‘racially inferior’ or underclass communities.”

Interestingly, some of the accounts of violence and crime may not have been entirely fabricated. Just as the myth of the unicorn may have been based on early and inaccurate descriptions of the rhinoceros, the tales may have partly been the result of some confusion regarding plant names. Some media stories of the era conflated marijuana with locoweed, a type of poisonous plant. So it’s just possible that some of the horror stories held a grain of truth—relating to a completely different plant.

 

5. There is no consensus about where the word “marijuana” came from. The word sounds like a Spanish language cognate, but some etymologists trace its origins to China or India. The plant itself originated in Central Asia, and China and India were the first two regions to begin cultivating it.

One theory is that Chinese immigrants brought the phrase ma ren hua—which translates more or less as “hemp seed flowers”—to Mexico, where it became Spanishized into “marijuana.” Another theory is that Angolan slaves brought the Bantu word for cannabis—ma’kaña—to the Americas via Brazil and Spanish-speakers later adapted it. Yet another theory traces the word back to the Semitic rootmrr.

Whatever its origins, there is some agreement that the first recorded use of a similar term was in a feature called “The American Congo” published in Scribner’s Magazine in 1894. In the article, author John G. Burke used the word “mariguan” to refer to a species of plant included in his description of the flora on the banks of the Rio Grande River between Texas and Mexico.

 

6.  But we do know that the term “pot” entered the lexicon in the 1930s as a shortened form of the Spanish potiguaya, an alcoholic drink in which cannabis buds have been steeped. A literal translation of potiguaya or potacion de guaya is “the drink of grief.”

Other terms are also far easier than “marijuana” to trace. “Ganja,” for example, likely entered the English lexicon in the 1800s when it was borrowed from a similar Hindi word. While words like pot and ganja endured, other terms for cannabis—such as “gage” (17th-century word for a pipe)  and “muggles” (used in the 1920s by the New Orleans jazz crowd)—have sadly fallen by the wayside.

 

Henry Ford's Hemp Car Photo via

7. Henry Ford experimented with the invention of a car that was possibly partially made of hemp. Some pro-pot sites claim that Ford actually developed a hemp-based automobile, but the evidence suggests that they are blowing smoke.

In the early 1940s, Ford developed a plastic car intended to be a lighter, stronger and more affordable alternative to traditional metal vehicles.Newspaper articles stated that the new car was a combination of resin binder and cellulose fiber supposedly drawn from pine fiber, hemp, soybean and ramie. However, The Henry Ford, a museum in Michigan, says that the exact ingredients for the car’s recipe have been lost, so they can’t confirm that hemp was in the mix.

Whether or not Ford’s car contained hemp, current scientists have apparently drawn inspiration from the concept as they work to develop cars made of plant fibers such as hemp and elephant grass.

 

8. Marijuana was initially criminalized by the federal government in an indirect, de facto way: a 1937 tax act. The act set suchhigh taxes on the purchase of weed that it discouraged people from going through the proper legal channels. And because arrest was the penalty for non-compliance, the tax act essentially criminalized marijuana possession.

In 1969, the act was ruled unconstitutional because paying the federal tax required admitting to the possession of something already made illegal by some state laws—and thus violated the right against self-incrimination spelled out in the Fifth Amendment. The following year the law was repealed and replaced with a measure that fully criminalized marijuana. Prior to the federal bans, though, many states had adopted the Uniform Narcotics Drug Act in the early 1930s, which made pot and other drugs illegal under state law.

Today, in a reversal of that situation, marijuana remains illegal on a federal level but two states—Colorado and Washington—legalized recreational use in 2012. More are likely to follow soon.

 

9. Popular urban legend has it that the term “420” is a reference to a 1970s police code, but in fact a group of high school kidscoined the term. In 1971, five California high school students heard about a plot of pot plants whose owner could no longer tend them. Eager to find the green, sticky treasure, the students agreed to meet outside the school at 4:20 pm to look for the plants until they found them. They never did, even after weeks of hunting.

But their fruitless search would be immortalized. Because their school was in Marin County, a counterculture hotspot, and because the treasure hunters had an indirect contact with Grateful Dead member Phil Lesh, the term 420 gradually became a part of drug culture throughout California and then the country.

 

Photo via

10. Alaska effectively legalized marijuana 39 years ago. You might have thought otherwise—especially considering the viral video of Alaskan reporter Charlo Greene quitting on-air last month in order to campaign for marijuana legalization. And policy wonks would insist that pot is technically decriminalized, rather than legalized, in the state. But marijuana in Alaska occupies an interesting legal gray area.

In 1975, the Alaska Supreme Court decided that the state’s constitutional right to privacy protects the right of adults to use and possess small amounts of marijuana in their own homes. However, Alaskan criminal law currently bans the possession of even small amounts of pot. As a result, Alaskans can be charged with possession for having pot in their homes—but technically courts should throw out the charges for amounts under four ounces.

This confusing state of affairs may be cleared up very soon, though: Next month, Alaskans go to the polls to vote on an initiative to officially legalize marijuana for recreational use.

Sourced From