Carl Hart grew up in a rough neighborhood in Miami, selling drugs, doing petty crime, and carrying a gun. But he pulled himself out of the "hood" and became a neuroscientist and now teaches psychology and psychiatry at Columbia University.

He is the author of High Price: A Neuroscientist's Journey of Self-Discovery That Challenges Everything You Know About Drugs and Society (2013).

Neuroscientist Carl Hart: Everything You Think You Know About Drugs and Addiction Is Wrong

"The overwhelming majority of drug users don’t have a drug problem.”

September 17, 2014 | By April M. Short

Carl Hart grew up in Miami in what he calls the 'hood, a poor community with high rates of crime and prevalent drug use. He kept a gun in his car, engaged in petty crime and sold drugs. Today Hart is a neuroscientist and associate professor of psychology and psychiatry at Columbia University. He's also an expert on drug addiction. In a TEDMED Talk earlier this month, Hart explained how he went from dealing drugs in the 'hood to studying addiction at one of the world’s top universities. His talk summarizes some of the major themes from his book, High Price: A Neuroscientist's Journey of Self-Discovery That Challenges Everything You Know About Drugs and Society (2013).

Hart said growing up as he did, he came to believe the prevailing assertion that crack cocaine and other drugs were the villains behind crime and poverty. If he could only solve the addiction problem, he thought, he'd be tackling the root of the problem. As Hart came to learn, that is not the reality. Poverty and crime were around long before crack and other drugs appeared on the scene, and the forces at play that keep poor communities poor are insidious and systemic.

“My family, we were poor before drugs entered the picture,” Hart said. “I engaged in petty crime but it had nothing to do with drug addiction. It was about money and status. If you take drugs out of the equation, poverty and crime still exist. It’s not drug addiction causing people to commit crime. It’s other factors.”

One of the biggest factors is the war on drugs and its racist law enforcment policies, which target impoverished, black populations despite the fact that whites and blacks use drugs at similar rates.

“Drug laws are not uniformly enforced across all segments of our society, and this perpetuates the cycle of poverty and crime,” Hart said.

Hart said he first began questioning his thinking when he discovered that drugs like crack and meth are not nearly as addictive as he had been told. He points out in his talk that 80 to 90 percent of people who use illegal drugs are not addicted.

“The overwhelming majority of drug users don’t have a drug problem,” he said.

Hart’s work has revealed some striking truths about drug use and addiction. His research on both crack and meth users have shown that even drug users with serious addictions tend to make surprisingly rational decisions. When given the choice between drugs and money—even a small amount of money such as $5—they will choose the money over the drugs at least half the time. When the sum offered is higher, like $20 to $50, they will almost always choose the money.

As Hart told AlterNet last June, his studies have shown that the pharmacological effects of drugs rarely lead to crime, “but the public conflates these issues regardless.”

“Certainly, we have given thousands of doses of crack cocaine and methamphetamine to people in our lab, and never had any problems with violence or anything like that,” he said. “That tells you it's not the pharmacology of the drug, but some interaction with the environment or environmental conditions, that would probably happen without the drug.”

Hart said his TED Talk was an effort to educate the public about drug myths and bad US drug policy. “Millions of people languish unnecessarily in jails and prisons largely, and still others needlessly die from preventable overdoses, underground market violence and police interactions, due to a misguided approach to drug regulations,” he said. “And no one suffers more than African American men and the poor.”

Watch Hart’s talk below:


April M. Short is an associate editor at AlterNet. Follow her on Twitter @AprilMShort.

Got Tylenol? One Of The Most Dangerous Drugs Is Probably In Your Medicine Cabinet Right Now

This deadly drug, a leading cause of liver failure, is not in our medicine cabinet because I have been arguing to pull Tylenol from the market for years and I make sure we do not have products with that poison in our house.

This comes from Urban Times.

One Of The Most Dangerous Drugs Is Probably In Your Medicine Cabinet Right Now

And you don't even need a prescription to get it.

27th August 2014
Abby Norman

• Got a headache? Pop a Tylenol.
• Pulled a muscle? How about a Tylenol?
• Menstrual cramps, aches and pains, fever, sniffles? There’s a Tylenol for that.

As it is marketed in the United States.
But before you shake the bottle, there are few things you should know…


Other common brands/packaging
Acetaminophen, also known as paracetamol, mapap and any number of combination drugs like Alka Seltzer Cold and Sinus, Nyquil Cold and Flu, Percocet and Excedrin, is a pain reliever and fever reducer. Unlike some pain relieving drugs that get a bad rap for addiction, Tylenol and other acetaminophen-containing drugs are non-opioid. This has made it widely over-the-counter and formulated for infants, children and adults. Tylenol has long been so widely accepted that some people even take it preventatively as part of a medication regimen.

The mechanism of acetaminophen is actually pretty interesting. Essentially, it blocks the enzyme responsible for sending out prostaglandins, the lipid compounds that cause pain when your cells become injured. So, you take a Tylenol, it blocks the enzyme that creates those painful lipids, and boom; relief.

But there’s a catch: it’s incredibly easy to take too much acetaminophen.

There are several reasons for this. One, it’s so widely regarded as “safe” that people often assume they can take higher than the recommended dose without ill-effects and two, it’s found in many more drugs than just Tylenol, making it easy to overdose unintentionally.

The biggest threat of such an overdose is liver damage. For many years, the FDA has known that long term use, even at low doses, has been linked to liver damage, but the extent of the damage was not well understood. Now, the FDA has urged doctors to limit their prescriptions of the drug to help prevent these complications.

The liver is so at-risk because it’s the Brita-filter of our body: anything that you put into your body passes through the liver where “toxins and crap” get filtered out. This is true of everything from compounds in medication to alcohol. The problem with acetaminophen is that when it gets broken down by the liver, one of the compounds it leaves behind, NAPQI, builds up and damages liver cells. The more acetaminophen your liver processes, the more NAPQI gets left behind.

It’s like continuously pouring a tiny bit of muddy water through a coffee filter; it doesn’t take long before the paper is coated with sludge.

The FDA is right to be concerned. Often the early stages of liver damage are hard to diagnose because the symptoms can be very vague; loss of appetite, nausea and maybe a little jaundice eventually. Once a liver is truly damaged, the only option is a liver transplant.

In addition to complicates [coined here first] from toxicity, there is new research that claims that acetaminophen may actually help influenza spread faster. If you’re down and out with the flu and you take acetaminophen to reduce your fever, there are two mechanisms that the study claims help to hasten the spread of the flu: first, the sooner you are fever-free, the sooner you end up back in public interacting with friends, family and co-workers, therefore spreading the illness unwittingly because, since you feel better, you forget you’re still contagious. And secondly, there is research that indicates that acetaminophen use increases the amount of the virus that you shed, meaning you send more infectious particles out into the world when you cough or sneeze. The research isn’t precise, and was done predominantly with mathematical inferences, but it does bring up another important investigation into the overuse of acetaminophen in western medicine.

The big take away?

Overusing Tylenol, either by taking more than the recommended dose or mixing multiple drugs that contain acetaminophen does not carry benefits that outweigh the risk of liver damage. So, you’re better off having a slight headache than popping another Tylenol before that eight hour window is up and putting your liver at risk.

Manufacturer-Funded Research Compromises Patient Care

How interesting to see Forbes run a story on the way Big Pharma is manipulating research to support their drugs, but every effort to expose this dangerous and possibly criminal behavior on the part of these mega-companies is welcome.

How Manufacturer-Funded Research Compromises Patient Care

Robert Pearl, M.D.
7/24/2014
To improve patient care, doctors rely on research and published information.

According to an American Medical News report, professional journals are still the most popular source of up-to-date medical information among doctors.

These medical publications inform physicians on new drugs and treatments, and they contain peer-reviewed studies that both physicians and patients assume are scientifically accurate.

But all too often, research findings aren’t as scientific as they should be. And some are flat-out biased.

Research Studies Confirm Bias In Research

In 2012, the report “Industry sponsorship and research outcome” concluded that studies sponsored by a drug or device company lead to “more favorable results and conclusions” about the products studied than independently sponsored ones.

And a recent study from the Harvard Medical School on plastic surgery outcomes concluded, “Studies authored by groups with conflicts of interest are significantly associated with reporting lower surgical complications and therefore describing positive research findings.”

This was especially true when manufacturer-marketed products were used in the study, according to the study’s abstract.

Perhaps the most damning study comes by way of the National Center for Biotechnology Information.

In it, the authors identified 24 peer-reviewed studies published in highly respected medical journals. Each study compared two different types of suction devices that help wounds heal faster.

One device uses a sponge-type material while the other relies on a gauze-wound interface.

The researchers asked five independent surgeons to read all 24 papers and determine which product was judged as better in each study.

The conclusion: Seven papers seemed to favor the first treatment, 15 favored the second and 2 didn’t reach a definitive judgment.

Now, Here’s The Kicker

Of the 24 studies, 19 were funded by a manufacturer of one of the two devices. Lo and behold, based on determinations made by the independent surgeons, 18 of those 19 papers recommended the product made by the manufacturer who funded the research. Just one manufacturer-funded study was deemed to have a neutral conclusion.

Research advances medicine but conflicts of interest can corrupt outcomes and compromise patient care. (Photo credit: Wikipedia)

From a statistical perspective, this is nearly an impossible outcome.

Flip a coin 19 times and there’s a 1 in 524,288 chance it comes up heads each time.

We might expect that if the two alternative products were relatively equivalent and the research truly unbiased, the product sold by the non-funding company should come out on top about half the time. To have no study go against the funding company yields nearly impossible odds.

And if they are not equivalent, the better product should be identified in nearly all studies, regardless of the source of the researcher’s funding.

There is no way to interpret these results, except to assume the researchers themselves were biased based on who paid for their work.

Biased outcomes like these would raise red flags in any other context. They would have signaled some sort of inappropriate influence. The scientific results would have been rejected by medical journals.

But not under these circumstances.

How Bias Gets By In Medical Research

No manufacturer is foolish enough to demand that investigators reach a specific conclusion in their research. Discovery of such a quid pro quo relationship could result in a major scandal for the company and the termination of the researchers.

The origin of bias in these manufacturer-funded studies may be subconscious, but no less effective.

Researchers and research sponsors interact at events and meetings during the time the work itself is being performance and during subsequent clinical trials.

And social science literature has clearly demonstrated people have a strong desire to reciprocate a gift.

At a minimum, grateful researchers unconsciously want to “return the favor” to their funding organizations.

And given the constant pressure in academia to “publish or perish,” this bias could be more overt as researchers fear losing funding – even if a threat is never explicitly conveyed.

Regardless of the etiology, research bias and skewed results are real when medical companies fund studies on their products. And whether it’s conscious or unconscious, bias is inappropriate in any scientific context.

Curbing Bias In Medical Research
Over the past decades, attempts have been made to limit the inappropriate influence of bias in research.

Today, authors of peer-reviewed articles and presenters at accredited meetings are required to disclose any personal financial benefit from the research. They must also disclose financial dealings with the manufacturer – but not any of the details.

Researchers receiving federally funded grants must register their trials on clinicaltrials.gov and publish their results even when findings don’t favor the funding organization.

The days of sponsors suppressing unfavorable outcomes or helping investigators write their papers before submission are largely behind us.

But as the data demonstrate, today’s system is far from effective at ensuring scientific integrity.

The Negative Consequences of Manufacturer-Funded Research

Physicians rely on published data to determine the best treatment for their patients. When it is contaminated by inappropriate influence, doctors can’t provide the best possible care.

As a result, patients end up with lower quality care, increased complications and higher costs.

Public and private entities could take a number of big steps to curb medical research bias.

For starters, peer-reviewed journals could refuse to publish articles funded by a single company.

If manufacturers wanted to advance medical knowledge, competing drug and device companies could contribute to a common, independent research fund for their particular industry. This would eliminate the manufacturer-researcher relationship from a study’s equation.

Alternatively, a small fee could be added to the sales price of medical devices and drugs to fund independent research. Organizations like the National Institute of Health (NIH) could oversee the distribution of these dollars.

Of course, we should expect manufacturers to resist such changes. After all, drug and device companies aspire to drive product sales, not produce unbiased research.

But the problems created by the current system are far too serious to accept the status quo.

We need to stop hiding our heads in the sand. The data is clear. Change is essential.

~ Dr. Robert Pearl is the CEO of The Permanente Medical Group, a certified plastic and reconstructive surgeon, and Stanford University professor. Follow him on Twitter: @RobertPearlMD.

Peter Gøtzsche - Deadly Medicines and Organised Crime: How Big Pharma Has Corrupted Healthcare

I came across this book kind of by accident yesterday, but it looks to be an important book ("Prescription drugs are the third leading cause of death after heart disease and cancer"). Peter C Gøtzsche is a Professor of Clinical Research Design and Analysis, and Director, The Nordic Cochrane Centre, and Chief Physician, Rigshospitalet and the University of Copenhagen, Denmark. He is highly respected in the field, having published more than 50 papers in "the big five" (BMJ, Lancet, JAMA, Annals of Internal Medicine, and New England Journal of Medicine) and his scientific works have been cited over 10 000 times.

Deadly Medicines and Organised Crime: How Big Pharma Has Corrupted Healthcare (August, 2013), 320 pages; also available as an ebook for the Kindle, here.

Here is the publisher's ad copy for the book, an interview with the author, and a link to a sample chapter.

From the Introduction

'The main reason we take so many drugs is that drug companies don't sell drugs, they sell lies about drugs. This is what makes drugs so different from anything else in life...Virtually everything we know about drugs is what the companies have chosen to tell us and our doctors...the reason patients trust their medicine is that they extrapolate the trust they have in their doctors into the medicines they prescribe. The patients don't realise that, although their doctors may know a lot about diseases and human physiology and psychology, they know very, very little about drugs that hasn't been carefully concocted and dressed up by the drug industry…If you don't think the system is out of control, then please email me and explain why drugs are the third leading cause of death…If such a hugely lethal epidemic had been caused by a new bacterium or a virus, or even one hundredth of it, we would have done everything we could to get it under control.'​

Prescription drugs are the third leading cause of death after heart disease and cancer.

In his latest ground-breaking book, Peter Gøtzsche exposes the pharmaceutical industries and their charade of fraudulent behavior, both in research and marketing where the morally repugnant disregard for human lives is the norm. He convincingly draws close comparisons with the tobacco conglomerates, revealing the extraordinary truth behind efforts to confuse and distract the public and their politicians.

The book addresses, in evidence-based detail, an extraordinary system failure caused by widespread crime, corruption, bribery and impotent drug regulation in need of radical reforms.

The author and publisher have no liability or responsibility to any entity regarding loss or damage incurred, or alleged to have incurred, directly or indirectly, by the information contained in this book.

Benefits

• Peter C Gøtzsche reveals how drug companies have hidden the lethal harms of their drugs by fraudulent behaviour, and denials when confronted with the facts.
• Addresses a general system failure caused by widespread crime, corruption and impotent drug regulation in need of radical reforms
• Evidence-based and fully referenced for further investigation of key issues and provides an in-depth level of knowledge in this area.

Sample Chapter

• Free chapter from Deadly Medicines and Organised Crime: How big pharma has corrupted healthcare

Alliance for Natural Health, Exclusive Interview:

• Interview with Dr Peter Gotzsche, author of Deadly Medicines and Organised Crime

We wanted to learn more about this important new book from the author himself. so we put together a list of questions to which Dr Gøtzsche was kind enough to respond by email. The questions and answers are reproduced below with minimal editing by ANH-Intl.

Dr Peter Gøtzsche, author of Deadly Medicines and Organised Crime: How big pharma has corrupted healthcare

ANH-Intl: What do you think is the single biggest threat to the safe practice of medicine that ensures the delivery of the highest quality care and best possible outcomes?

PG: That we have allowed the industry to be its own judge. As long as testing drugs is not a public enterprise, performed by disinterested researchers, we cannot trust what comes out of it.

ANH-Intl: How important are non-pharmaceutical approaches to the combat of escalating rates of major chronic diseases, such as heart disease, cancer, type 2 diabetes and obesity?

PG: Non-pharmaceutical approaches can be more important than drugs. Exercise works equally well for diabetes and depression as drugs and, in contrast to drugs, it has many other beneficial effects. Psychotherapy for depression doesn’t make people dependent on drugs and doesn’t turn transient problems into a chronic disease when people cannot stop taking their drugs. Most important of all, we need to tackle the food industry and ban junk food and junk drinks.

ANH-Intl: What is your opinion of the AllTrials initiative in terms of its potential to significantly improve the objectivity of the medical literature in future?

PG: I have campaigned for access to all data, including the raw data, from research on patients for many years. In 2010, we succeeded in gaining access, for the first time in the world, to unpublished clinical study reports at the European Medicines Agency, which had the effect that the Agency changed its policy from one of extreme secrecy – like the current FDA policy – to one of candid openness. This was to the drug industry’s great chagrin, as its business model hinges on publishing flawed research.

ANH-Intl: Similarly, do you think a sea-change in medical student education is needed to deliver better health outcomes, especially for chronic degenerative diseases?

PG: Yes. There is far too much focus on drugs as the solution to everything and far too little focus on their harms, and the education by necessity builds on flawed research, as this is what gets done and published.

ANH-Intl: Towards the end of your book you state that “What we should do is...identify overdiagnosed and overtreated patients, take patients off most or all of their drugs, and teach them that a life without drugs is possible for most of us.” Can you please explain this a little further? Should the removal of drugs be accompanied with any new modality, and if so which ones might be among the most important?

PG: Removal of drugs should usually not be accompanied by the introduction of other types of treatment. Many patients would gain a better quality of life if their drugs were taken away from them. What we need is to remember Brian McFerrin’s song: “Don’t worry, be happy”. We shall all die, but we should remember to live while we are here without worrying that some day in the future we might get ill. It is daunting how many healthy people are put on drugs that lower blood pressure or cholesterol, and it changes people from healthy citizens to patients who may start worrying about their good health. This can have profound psychological consequences apart from the side effects of the drugs that the patients don’t always realise are side effects, e.g. if they get more tired or depressed after starting antihypertensive therapy or experience problems in their sex life.

ANH-Intl: What can the public and patients do to help redress the situation? Are they effectively disempowered or are there things they can do to help build a more functional healthcare system?

PG: First of all, the public needs to know the extent to which they are being deceived in the current system, e.g. few people know that prescription drugs are the third major killer. If drug testing and drug regulation were effective, this wouldn’t happen.

ANH-Intl: Numerous problems with the medical literature are cited in your book, among them unpublished trials, fiddled statistics, unsuitable comparators and other methodological weaknesses and the preponderance of academic ‘flak’ in the form of weak, industry-sourced publications designed to muddy the waters. Bearing this in mind, what advice would you have for anyone wishing to locate high-quality published data?

PG: There are very little high-quality published data. Neither the drug industry nor publicly employed researchers are particularly willing to share their data with others, which essentially means that science ceases to exist. Scrutiny of data by others is a fundamental aspect of science that moves science forward, but that’s not how it works in healthcare. Most doctors are willing to add their names to articles produced by drug companies, although they are being denied access to the data they and their patients have produced and without which the articles cannot be written. This is corruption of academic integrity and betrayal of the trust patients have in the research enterprise. No self-respecting scientists should publish findings based on data to which they do not have free and full access. 

ANH-Intl: Are there any classes of drug, as opposed to individual products, for which, in your opinion, there is no valid scientific or medical justification for their use in healthcare?

PG: There are several classes of drugs, e.g. cough medicines and anticholinergic drugs for urinary incontinence, where the effect is doubtful but there is no doubt about their harms, which in my opinion means they should be withdrawn from the market. There are many other types of drugs that likely have no effect. All drugs have side effects, and it is therefore difficult to blind placebo-controlled trials effectively. We know that lack of blinding leads to exaggerated views on the effect for subjective outcomes, such as dementia, depression and pain, and it is for this reason that many drugs, which are believed to have minor effects, likely aren't effective at all.

There are also classes of drugs where, although an effect has been demonstrated, their availability likely does more harm than good. I write in my book that, although some psychiatric drugs can be helpful sometimes for some patients, our citizens would be far better off if we removed all the psychotropic drugs from the market, as doctors are unable to handle them. Patients get dependent on them, and if used for more than a few weeks, several drugs will cause even worse disorders than the one that led to starting the drugs. As far as I can see, it is inescapable that their availability does more harm than good.

ANH-Intl: The chapter in your book entitled “Intimidation, violence and threats to protect sales” begins as follows: “It takes great courage to become a whistle-blower. Healthcare is so corrupt that those who expose drug companies’ criminal acts become pariahs.” Have you experienced any blowback since publishing the book?

PG: No, quite the contrary, as people have praised the book. I don't hear from the drug industry of course, but I have seen blunt lies about the book being propagated by drug industry associations and their paid allies among doctors.

Cyberpunk Short Film About An Addictive Drug Called "Mech"

 

Very cool . . . and soon to be a full-length feature film it seems. This comes via io9. This could be a very awesome series for the Sci-Fi network, too.

Must Watch: Cyberpunk Short Film About An Addictive Drug Called Mech

Charlie Jane Anders


It's well worth checking out this five-minute short film, Mech: Human Trials. Not only has it been picked up to become a full-length movie (something there's plenty of scope for), but it's also packing enough excitement and cool ideas into five minutes to keep you rewatching and rewinding.

In Mech: Human Trials, a mysterious drug not only fixes damage to your body, it makes you stronger and gives you superpowers. But it also slowly takes away your humanity, and turns you into something... else. Here's the official synopsis for the film, written, directed and produced by Patrick Kalyn:

After a serious accident, a man is introduced to a designer street drug promising to restore his ravaged body. Desperate to mend himself, he becomes consumed by the drug - only to discover it is threatening his humanity.

The short film was first teased by an anti-drug PSA over at Don'tDoMech.com, and then posted in its entirety online. And according to The Wrap, IAM Entertainment is already developing the movie as a full-length feature, directed by Kalyn and written by Mike Le, whose script Patient Zero made the Black List of unproduced screenplays in 2013.

[via First Showing]

The Brain: A Secret History - Mind Control

 

I have digging a little into the CIA experiments from the 1950s through the 1970s (Project Bluebird, Project Artichoke, MKULTRA), specifically their work in creating multiple personalities in victims in order to make them into assassins. The reality of these experiments is not in question - they happened and the CIA declassified a lot of the documents (which makes me wonder how bad are the experiments they did not declassify). One of the more compelling books on the subject is Bluebird : Deliberate Creation of Multiple Personality by Psychiatrists (2000) by Colin Ross, M.D.

This research project was inspired by a first person account of similar experiences - I am a skeptic regarding any wide-ranging government mind control efforts, organized and coordinated satanic cult activity, and the creation of very specific and widely seen "alters" that are programmed for very detailed activities in survivors with dissociative identity disorder (formerly known as multiple personality disorder - MPD).

That said, I would be not at all surprised if there are groups organized around pedophilia and child prostitution who use some of these techniques to control and instill fear in the children they victimize.

Moreover, I have little doubt that there are sociopathic gurus, fundamentalist preachers, and other forms of religious or political "leaders" who employ some of these mind control techniques - knowingly or unknowingly - to control their followers and manipulate them into doing what the leader wishes, whether it's financial (Andrew Cohen), sexual (Marc Gafni, Genpo Roshi, and a list of others), or some other objective. 

Anyway, this is the beginning of several posts on this topic.

Here is the description from BBC Four for the original broadcast of the video below:

In a compelling and at times disturbing series, Dr Michael Mosley explores the brutal history of experimental psychology.

To begin, Michael traces the sinister ways this science has been used to try to control our minds. He finds that the pursuit of mind control has led to some truly horrific experiments and left many casualties in its wake. Extraordinary archive captures what happened - scientists systematically change the behaviour of children; law abiding citizens give fatal electric shocks; a gay man has electrodes implanted in his head in an attempt to turn his sexuality.

Michael takes a hallucinogenic drug as part of a controlled experiment to try to understand how its mind-bending properties can change the brain. This is a scientific journey which goes to the very heart of what we hold most dear - our free will, and our ability to control our own destiny.

This is disturbing stuff, but not nearly as much so as the documentary on CIA mind control projects I will post tomorrow.

The Brain: A Secret History

In a compelling and at times disturbing series, Dr Michael Mosley explores the brutal history of experimental psychology.

Mosley embarks on three journeys to understand science's last great frontier - the human mind - as he traces the history of the attempts to understand and manipulate the brain. Experiments on the human mind have led to profound insights into how our brain works - but have also involved great cruelty and posed some terrible ethical dilemmas.

Mind Control. To begin, Michael traces the sinister ways this science has been used to try to control our minds. He finds that the pursuit of mind control has led to some truly horrific experiments and left many casualties in its wake. Extraordinary archive captures what happened - scientists systematically change the behavior of children; law abiding citizens give fatal electric shocks; a gay man has electrodes implanted in his head in an attempt to turn his sexuality.

The other two episodes in the series are on emotions and how we learn about healthy brains by studying broken brains.

Emotions. In this film, Michael investigates how scientists have struggled to understand that most irrational and deeply complex part of our minds - our emotions. Michael meets survivors - both participants and scientists - of some of the key historical experiments. Many of these extraordinary research projects were captured on film - an eight-month-old boy is taught to fear random objects, baby monkeys are given mothers made from wire and cloth, and an adult is deliberately violent before a group of toddlers.

Broken Brains. Dr Michael Mosley concludes his series exploring the brutal history of experimental psychology by looking at how experiments on abnormal brains have revealed the workings of the normal brain. He meets remarkable individuals like Karen, who suffered from a rare condition - alien hand syndrome - which meant that one of her hands constantly attacked her. And Julia, who seems to have recovered from her stroke - until experiments reveal she is unable to recall the name of any object.

Susan C. Hawthorne - ADHD: Time to Change Course

Susan C. Hawthorne is the author of Accidental Intolerance: How We Stigmatize ADHD and How We Can Stop, and is Assistant Professor, Department of Philosophy, St. Catherine University.

In this article from the Oxford University Press blog, Hawthorne questions the current status quo around ADHD and the overuse of pharmaceutical interventions.

Recently, over lunch with a fellow therapist (and like me, a person who in his youth did a fair amount of "reality adjustment"), we were discussing the ADHD issue. We both conclude that if you give ANYONE amphetamines that person will be more focused and get more done. Just because we give the drugs to kids who we think are doing poorly in school and they begin to do better does not even begin to mean they have/had ADHD - it means the amphetamines are working.

And I now return you to the article at hand.

ADHD: time to change course

Posted on Sunday, November 10th, 2013 
By Susan C. Hawthorne

In March 2013, we learned that 11% of US children and teens have received an ADHD diagnosis, an increase of 41% in 10 years. Diagnoses among adults have sharply increased as well. Some ADHD experts welcome this change. They interpret these high rates as signs that much-needed attention is finally being given to people whose biology has been a disadvantage in work, school, and relationships. Other professionals have been taken aback by the current diagnostic rate and its purported repercussions, citing risks such as overprescription of drugs, medicalization of normal behaviors, and drug diversion to street use.

No general uproar has materialized, however. On the contrary, it’s looking like the upward trend will continue. Recent publications explain how to increase screening rates via computerized assessments, and how to hone diagnosis with a new EEG test. Most important, the new diagnostic guidelines in the American Psychiatric Association’s DSM-5 relax the diagnostic criteria, pulling more people, especially adolescents and adults, under the “ADHD” umbrella. The ADHD therapeutics market has responded enthusiastically, predicting high profits from increased diagnostic rates.

Children and their teacher in a classroom

One reason for the lack of outcry might be that people see this as the continuation of a steady trend: same old, same old. Diagnostic rates have been increasing for decades. Another might be the continued sway of the pharmaceutical business. It has effectively hyped the diagnosis for 40 years through targeted medical education; advertising to physicians, patients, and parents; and a smorgasbord of perks for “opinion leaders” and clinicians.

I think, though, that the reason for accepting this status quo involves much more than the drug industry. Basically, a lot of people—and a lot of the social systems in which they participate—like the diagnosis.

• Teachers and education administrators like it: Within the strained education system, it addresses needs of overworked teachers and overcrowded classrooms.
• Physicians and medical insurers like it: It’s a win-win in the medical system because the diagnosis (in the predominant interpretation as a biological dysfunction in individuals) falls in physicians’ purview; current care is quick and easy, often consisting only of a prescription.
• Clinical scientists like it: Research dollars flow toward it because the diagnosis—hence the fruits of research—promises to solve problems.
• And of course parents and adult diagnosees, who typically self-refer, like it: The short-term effects of medication help with behavior issues they deal with, and the promise of long-term effectiveness gives them hope. (Never mind that long-term effectiveness has not yet been demonstrated.)

If so many people like the diagnosis, what’s the problem? The much-discussed worry that we are overusing psychotropics, especially in children, is worth reconsidering. But two other issues also need to be aired

The first is that the continued reliance on ADHD as a research category puts clinical science in a rut—repeatedly studying ADHD and non-ADHD groups assumes that ADHD is a relevant and important category. More research should question that assumption. Investigating other hypotheses opens avenues of research that might better address clinical needs, as well as leading to more knowledge about mental health and illness.

The second issue is the stigmatization of those who are diagnosed as having ADHD. Years of research has shown that ADHD diagnosis correlates with multiple life choices and outcomes generally considered negative, such as increased rates of accidents, substance abuse, poor relationships, low educational and work achievement, and higher medical and education expenses. Drawing attention to “ADHD” as a contributor to these life tracks puts the blame on supposed biological facts about the individuals. Then, despite efforts to spin attitudes toward compassion for these (putatively) inborn circumstances, the opposite often occurs. The correlation between ADHD diagnosis and negatively perceived life tracks instead provides a medically and scientifically justified target for social disapproval—that is, ADHD-diagnosed people are stereotyped and stigmatized. Alternatives suggest that the biological claims are at best incomplete, and that social circumstances require investigation and intervention as well.

For these reasons, I think that it is time for new directions. More specifically, it is time to reassess clinical and research needs, and to find new ways to address both without relying on the “ADHD” catch-all. However, arguments pointing to evidence of progress via the current direction and arguments favoring the vested interests in the status quo—economic, educational, medical, scientific, and personal—weigh in the opposite direction.

Should we change course? I welcome your ideas.

Susan C. Hawthorne, author of Accidental Intolerance: How We Stigmatize ADHD and How We Can Stop, is Assistant Professor, Department of Philosophy, St. Catherine University.

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Image credit: Children in a classroom by Michael Anderson, National Cancer Institute. Public domain via Wikimedia Commons.

Use of cannabis by adolescents in key developmental periods increases vulnerability to psychiatric disease and overlaps with biological changes in the endocannabinoid system. The endocannabinoid system is involved in a LOT of biological functions, including memory, appetite, energy balance and metabolism, stress response, immune function, multiple sclerosis, female reproduction, autonomic nervous system, analgesia, thermo-regulation, and sleep

Adolescence is associated with an increased incidence of psychiatric illness, and exposure to cannabis during this developmental window strongly predicts subsequent development of mood disorders, addictive disorders, and schizophrenia (A). Components of the endocannabinoid system appear as early as embryonic life, but maximal CB₁R mRNA expression occurs during adolescence.

When people advocate for legalizing marijuana and tout its healing benefits, most seem to ignore that there are years and years of research linking marijuana use, especially in adolescents and teens, to increased risk for mental illness and psychotic episodes.

The other thing that advocates of marijuana legalization overlook, or are ignorant of, is the tremendous increase in THC levels relative to CBD (cannabidiol), a trend that makes for a greater high and a greater risk and negative side effects. The black market has bred marijuana to be higher in THC and lower in CBD.

Medical marijuana, on the other hand, at least in San Francisco, is being bred for a higher CBD level and a lower THC level. From Wikipedia:

Cannabidiol (CBD) is one of at least 85 cannabinoids found in cannabis.[3] It is a major constituent of the plant, second to tetrahydrocannabinol (THC), and represents up to 40% in its extracts.[4] Compared with THC, cannabidiol is not psychoactive in healthy individuals, and is considered to have a wider scope of medical applications than THC,[5] including to epilepsy,[6] multiple sclerosis spasms,[7] anxiety disorders, bipolar disorder,[5] schizophrenia,[8] nausea, convulsion and inflammation, as well as inhibiting cancer cell growth.[9] There is some preclinical evidence from studies in animals that suggests CBD may modestly reduce the clearance of THC from the body by interfering with its metabolism.[10][11][12] Cannabidiol has displayed sedative effects in animal tests.[13] Other research indicates that CBD increases alertness.[14] CBD has been shown to reduce growth of aggressive human breast cancer cells in vitro, and to reduce their invasiveness.[15]

Anyway, this article offers pretty solid evidence for the risks in allowing adolescents and teens to smoke marijuana, which would likely be prohibited if and when marijuana becomes widely legal. Still, kids are going to smoke weed just like kids are going to drink their parents' beer.

Cannabis use during adolescent development: Susceptibility to psychiatric illness

Benjamin Chadwick [1], Michael L. Miller [1], and Yasmin L. Hurd [1,2,3]

1. Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
2. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
3. James J. Peters VA Medical Center, Bronx, NY, USA

ABSTRACT

Cannabis use is increasingly pervasive among adolescents today, even more common than cigarette smoking. The evolving policy surrounding the legalization of cannabis reaffirms the need to understand the relationship between cannabis exposure early in life and psychiatric illnesses. cannabis contains psychoactive components, notably Δ9-tetrahydrocannabinol (THC), that interfere with the brain’s endogenous endocannabinoid system, which is critically involved in both pre- and post-natal neurodevelopment. Consequently, THC and related compounds could potentially usurp normal adolescent neurodevelopment, shifting the brain’s developmental trajectory toward a disease-vulnerable state, predisposing early cannabis users to motivational, affective, and psychotic disorders. Numerous human studies, including prospective longitudinal studies, demonstrate that early cannabis use is associated with major depressive disorder and drug addiction. A strong association between schizophrenia and cannabis use is also apparent, especially when considering genetic factors that interact with this environmental exposure. These human studies set a foundation for carefully controlled animal studies which demonstrate similar patterns following early cannabinoid exposure. Given the vulnerable nature of adolescent neurodevelopment and the persistent changes that follow early cannabis exposure, the experimental findings outlined should be carefully considered by policymakers. In order to fully address the growing issues of psychiatric illnesses and to ensure a healthy future, measures should be taken to reduce cannabis use among teens.

Full Citation: 
Chadwick B, Miller ML and Hurd YL. (2013, Oct 14). Cannabis use during adolescent development: susceptibility to psychiatric illness. Frontiers in Psychiatry: Addictive Disorders and Behavioral Dyscontrol, 4:129. doi: 10.3389/fpsyt.2013.00129

Introduction

Cannabis sativa is grown worldwide for its production of Δ9-tetrahydrocannabinol (THC), a psychoactive compound found in the recreational drugs marijuana and hashish. The pervasiveness of this drug worldwide, along with its relatively low lethality, has led many to believe that it is of little harm. Indeed, the use of cannabis currently exceeds that of tobacco smoking among adolescents in the United States (1) (Figure 1). Whether cannabis is harmless, and without significant physiological or mental health impact, is actively debated. Unfortunately, these discussions are often not guided by evidence-based data. Research focused on the relationship between cannabis and mental health is thus important especially considering that psychiatric illnesses are complex disorders with multiple factors contributing to vulnerability and eventual expression of the illness. Based on the accruing data to date outlined in this review, developmental cannabis exposure is an important contributing factor to psychiatric vulnerability (Figure 2A).

FIGURE 1

Figure 1. Cannabis consumption is widespread in adolescents. Prevalence of this drug’s intake exceeds other illicit drug’s in eighth through twelfth graders in the USA (A), and it recently surpassed cigarette use (B). Graphs based on data adapted from Johnston et al. (1)(A,B).
 
FIGURE 2

 

Figure 2. Developmental cannabis increases vulnerability to psychiatric disease and overlaps with ontogenic changes in the endocannabinoid system. Adolescence is associated with an increased incidence of psychiatric illness, and exposure to cannabis (arrow head) during this developmental window strongly predicts subsequent development of mood disorders, addictive disorders, and schizophrenia (A). Components of the endocannabinoid system appear as early as embryonic life, but maximal CNR1 mRNA expression occurs during adolescence (B). (Green line = cannabis-exposed and gray line = unexposed individuals.)

Cannabis and Developmental Pattern of Use

Psychiatric illnesses are developmental in nature – the 12-month prevalence of any psychiatric illness is ∼40% in adolescents (2), but ∼25% in adults (3) – making it significantly germane to the strong developmental pattern of cannabis use. A plethora of studies and national surveys monitored the patterns of cannabis use in multiple ethnic and geographic populations worldwide. In the United States, cannabis use is highly prevalent during adolescence (Figure 1), the developmental period when most people initiate use. There are over 6000 first-time cannabis users per day in the US, over 60% of which are under the age of 18 (4). Approximately 34–45% of ninth through twelfth graders reported cannabis use at least once in their lifetime and the pattern of subsequent use appears more or less intermittent with 23% of 12 graders reporting use in the past month (1, 5, 6). Data from wave I–III of the National Longitudinal Study for Adolescent Health recapitulate this pattern of wide spread yet occasional use in adolescents. While the majority of teens have infrequent use, still a significant percentage, 6.6%, report daily use. Determining the long-term impact of occasional and heavy cannabis use during active periods of brain development, such as adolescence, is of critical importance. To provide such insights, data garnered from epidemiological and experimental studies is reviewed in this article. The emerging evidence strongly suggests that cannabis exposure during adolescence increases an adult’s individual vulnerability to drug addiction and schizophrenia and may also produce long-lasting effects on anxiety and mood disorders.

Endocannabinoid System

The psychoactive effects of cannabis, principally mediated by THC, occur via its interaction with the endocannabinoid system, which regulates numerous biological processes involved in development and neuroplasticity. The endocannabinoid system consists of lipid-derived ligands, receptors, and enzymes that orchestrate intercellular communication and intracellular metabolism. The most characterized endocannabinoid ligands – or endocannabinoids (eCBs) – include 2-AG and anandamide, which are presumably synthesized via phospholipase-mediated pathways. At least two G-protein coupled receptors, referred to as cannabinoid receptor-1 (CB₁R) and -2 (CB₂R), interact with these ligands. Additionally, recent evidence suggests that eCBs bind to ligand-gated channels, particularly TRPV1. In regard to the ligands, eCBs are synthesized from membranous precursors and immediately diffuse to nearby cannabinoid receptors, classically expressed on pre-synaptic terminals. Following these events, co-expressed enzymes, such as monoacylglycerol lipase (MGLL), α-β-hydrolase domain 6 (ABHD6), and fatty acid amide hydrolase (FAAH), degrade the ligand to terminate its signal (7, 8). Tightly regulated biosynthetic and degradative pathways ensure proper signaling throughout development, and the correct function of these processes depends on the temporal and spatial patterning of this system. Exogenously consumed cannabis produces supraphysiological effects at eCB-targeted receptors and thus usurp the normal endocannabinoid system (9).

The endocannabinoid system is critical for neurodevelopment and as such is present in early development, and maintains expression throughout life (Figure 2B), exhibiting a broad spatial distribution to regulate synaptic plasticity (10, 11). The CB₁R is found in numerous central nervous system structures as early as the eleventh embryonic day, and throughout the embryonic period this receptor is expressed in subcortical and cortical regions (12). In cortical projection neurons, CB₁R and local eCBs facilitate the fasciculation of descending efferents and thalamic afferents, orchestrating the tight coupling of these two tracts (13). During adolescence, the endocannabinoid system still facilitates neurodevelopment through its intricate involvement in neuroplasticity and synaptic function. Receptor levels of CB₁R in the prefrontal cortex and striatum fluctuate during adolescence depending on the specific brain region. For instance, there is a rapid, sustained increase in cannabinoid receptor binding during adolescence, particularly in the striatum, that is substantially reduced (by half) in early adulthood (14). In addition, the expression of the CB₁R gene (Cnr1) is highest during adolescence and gradually decreases by adulthood with the greatest decreases observed in limbic-related cortical regions such as the cingulate, prelimbic, and infralimbic cortices (15). Concomitant to developmental changes in the CB₁R, levels of anandamide and 2-AG, as well as FAAH enzymatic activity, fluctuate throughout adolescence in a region- and time-specific manner (16, 17). The distinct changes in CB₁R and other components of the eCB system during adolescence, some of which occur during a narrow time window, suggest that certain phases during this dynamic ontogenic period may incur different sensitivity to cannabis exposure. These observations highlight the fact that despite significant studies of CB₁R in the adult brain, there are still gaps of knowledge as to the role of CB₁R and the endocannabinoid system in the extensive pruning and development that is evident throughout adolescence.
 

Addiction Vulnerability

A gateway drug hypothesis had long been proposed implying that adolescent cannabis use predisposes individuals to use other illicit drugs as adults, thereby increasing their vulnerability to substance use disorders (18) (Figure 2A). Although, the term “gateway” has sometimes been misinterpreted to imply that all individuals who use cannabis will directly abuse other drugs, this original hypothesis by Kandel (18) conducted on cohorts of high school students suggested that cannabis use is a critical illicit drug, intermediate in the transition from legal substance use (i.e., cigarettes and alcohol) to illicit drug use (i.e., heroin, amphetamines, and LSD). Over a quarter of individuals who progressed to illicit drug use had previous experience with marijuana while only 2–3% of legal drug users without marijuana experience progressed to illicit drug use. Subsequent longitudinal studies that tracked younger adolescents found that early cannabis use positively predicted cocaine and alcohol use across a 1-year period (19). Additional evidence that early-life cannabis consumption increases cocaine use later in life is supported by studies representing broad demographic populations (20), suggesting that these findings are likely generalizable.

Prospective longitudinal studies have also offered compelling evidence in support of the gateway drug hypothesis. A landmark 25 year-long study conducted on a birth cohort from New Zealand assessed associations between age of onset, and frequency of cannabis use, with the use and/or dependence of other substances (21). Even after controlling for a number of confounding variables, such as socio-economic background, other illicit substance use, family functioning, child abuse, and personality traits, early cannabis use was still significantly associated with subsequent drug abuse and dependence. Additionally this effect was age-related such that the association between cannabis use and the development of drug abuse and dependence declined with increasing age of initiation. An important strength of this study was that data collection extended beyond self-reports, and included parental interviews, medical records, psychometric assessment, and teacher reports. Twin-studies, which control for potential confounds such as genetics and shared environmental influences, have also confirmed that early adolescent onset of cannabis use increases the likelihood of developing drug dependence later in life (22).

One concern with human epidemiological studies is the inability to distinguish between casual and purely associative relationships. This is highlighted by a common-factor modeling study which suggests that correlations between cannabis and illicit drugs were principally attributed to other factors, namely an individual’s opportunity for and propensity to use drugs (23). Therefore, it has been argued that the transition from cannabis use to other drugs is not causal but is simply an expected sequence engaged by individuals that would normally go on to use other illicit drugs. Moreover, many teens who routinely smoke cannabis also use other drugs (e.g., alcohol and tobacco). While sequential transitions and the co-abuse of other drugs during such times could potentially contribute to enhance psychiatric risk, it is impossible to ignore the growing body of evidence that suggest a significant contribution of early adolescence cannabis specifically to the propensity to develop substance abuse disorders later in life even when controlling for other substances (21, 22) (Figure 3).

FIGURE 3

Figure 3. Cannabis use is associated with progression to use other illicit substances in humans. Twin-studies illustrate that cannabis users have an increased risk of developing substance abuse disorder compared to their discordant twin. Graph based on data adapted from Lynskey et al. (22) (A). Cross-sectional studies reveal that earlier and more frequent cannabis use further increases this risk. Graph based on data adapted from Fergusson et al. (21) (B).

Animal studies allow the possibility to directly test the causal relationship between adolescent cannabinoid exposure and subsequent risk for drug addiction, independent of subject-specific factors that confound human investigations. Although a weakness of animal studies is that they do not mimic the complex nature of psychiatric disorder, specific phenotypes relevant to such disorders can be examined. In contrast to most psychiatric disorders, modeling addiction in animals is very predictive of the human condition through the use of self-administration paradigms wherein animals control their own drug intake. Under such conditions, adolescent exposure to THC reliably increases heroin self-administration (24, 25). In a similar investigation, performed in slightly older rats (approximately late adolescence), THC pre-exposure increased heroin self-administration when the contingency for heroin was fixed, but not when the work necessary to acquire heroin was progressively increased (26). Such findings imply that adolescent THC exposure increases the hedonic, but not motivational, aspects of heroin-seeking. Limited animal investigations have examined the sensitivity of early THC exposure to other “heavy” drugs of abuse such as cocaine, but the existing studies to date do highlight the generally enhancing effects of adolescent cannabinoid exposure on future drug-seeking behaviors, and experimentally support the gateway drug hypothesis.

Animal studies also provide specific insights about discrete neurobiological disturbances associated with developmental cannabinoid exposure. For example, adolescent THC increases inhibitory G-protein coupled signaling in the rodent midbrain, which by modulating dopaminergic projections, enhances mesolimbic dopamine, all adaptations strongly associated with enhanced reward (24). In addition, adolescent THC exposure increased mu opioid receptor function in the nucleus accumbens, a brain region central to reward and motivated behaviors, and these receptor impairments directly correlated to heroin intake (24). Moreover, increased gene expression of proenkephalin, an opioid neuropeptide that directly modulates heroin self-administration behavior, is also induced in the nucleus accumbens of adult rats with adolescent THC exposure (25). Enhanced cocaine self-administration has also been observed in female rats as a consequence of early-life exposure to the cannabinoid agonist CP-55,940 which was associated with altered striatal dopamine transporter binding in adulthood (27), and this transporter’s disturbance is highly implicated in addiction-related behaviors. Together these and other accumulating evidence in the literature emphasize that adolescent cannabinoids persistently change mesolimbic brain regions of the adult that sufficiently predict future self-administration behavior, a phenotype relevant to drug addiction vulnerability.
 

Negative Affect and Anxiety

Another major question regarding the impact of adolescent cannabis relates to its role in negative affective disorders, such as major depressive disorder (MDD), which are increasingly burdensome worldwide. While equivocal, several longitudinal studies demonstrate an association between MDD and early-life exposure to cannabis. A large multi-cohort longitudinal investigation that examined the effects of adolescent cannabis use on depression and anxiety showed that frequent adolescent cannabis use increased depression and anxiety in early adulthood (28). Furthermore measures of depression and anxiety during adolescence did not predict cannabis use in young adults suggesting that this relationship was not simply due to premorbid differences. Similarly, while individuals who used cannabis during early teens did not differ in depression, suicidal ideation, or suicide attempts during adolescence, by early adulthood these individuals had significantly higher incidence of suicidal ideation and suicide attempts (29). A consistent observation was reported in another large longitudinal investigation, which found that adults with early cannabis use had increased suicidal behaviors (30). Altogether these findings emphasize the important contribution of early cannabis exposure to MDD and suicidal ideation. Importantly, accumulating evidence also implies that both adolescent exposure and the continued use during adulthood are required for these associations (31, 32) suggesting that disease may be mitigated with cannabis cessation.

It is important to note that although most studies to date imply an association of early cannabis with negative affective disorders, the longitudinal cohort investigation by Harder et al. (33) did not find any difference in depression or anxiety either during early adolescence or at the last follow-up in adulthood. This inconsistency may be due to the study’s lenient definition of a “cannabis user,” which included any participant who ever smoked cannabis prior to age 17 (∼50% population). Although additional studies are needed to understand the long-term causative effects of adolescent cannabis on negative affect, a preponderance of the evidence accrued thus far strongly suggests a correlation between these two factors.

Future longitudinal studies are clearly still needed to examine the contribution of the developmental period of onset and cessation of cannabis to the risk of negative affect. In addition, in vivo neuroimaging in humans can also offer much needed neurobiological insights. Evidence already exists demonstrating volumetric impairments in the amygdala, a brain region central to affective and addictive disorders, in cannabis users during early (34), and late (35) adolescence. Similarly, structural changes in the hippocampus, which is linked to depression (36), has been reported in individuals with cannabis use during late adolescence (35, 37).

The use of animal models has also helped to fill gaps of knowledge regarding the direct link between early-life cannabis use and negative affect and anxiety. Such experimental studies have demonstrated that early exposure to cannabinoids directly leads to dysregulation of emotional processes and induces depressive-like phenotypes later in life. For instance, escalating doses of THC to adolescent rats decreases sucrose preference, a measure of anhedonia (38). Other behavioral strategies such as the forced-swim test used to measure depression-related symptoms also reveal a pro-depressive phenotype directly associated with adolescent THC (39), although these effects generally appear stronger in females (38, 40). These findings suggest that adolescent cannabinoid exposure could affect the liability to mood disorders later in life, and the potential gender differences may relate in those well-documented in human depression.

Altered anxiety-like behavior as a consequence of adolescent cannabinoid exposure is also apparent in experimental animals though the relationship is not straightforward per se. Anxiogenesis or anxiolysis has been reported depending on the period of cannabinoid exposure and the specific task used to model anxiety. For example, chronic exposure to cannabinoid agonists – such as THC, CP-55,940, or WIN-55,212-2 – during mid- to late-adolescence, increases social anxiety as measured with a social recognition task (41–44). Other measurements of stress that do not rely on social interaction, such as the open-field and elevated plus-maze tests, indicate varying degrees of anxiolysis, not anxiogenesis (41, 45, 46). These anxiolytic effects were observed after mid- to late-adolescent exposure, whereas earlier, pre-pubertal exposures (PND 15–40) were anxiogenic (47). Consistent with the notion of critical periods, persistent alterations in anxiety almost exclusively occur after early-life exposure and not in animals exposed as adults (39).

Few animal experimental studies have specifically focused on examining neurobiological mechanisms associated with regulation of emotion in association with adolescent cannabinoid exposure. Of the studies, Page et al. (48) demonstrated that administration of the cannabinoid agonist WIN-55,212-2 to adolescents, as compared to adult rats, more profoundly and persistently disrupted cells in the locus coeruleus, a midbrain region that contains noradrenergic neurons and is implicated with depression and anxiety. Similarly, adolescent animals treated with WIN-55,212-2 exhibit altered midbrain neuronal firing characteristics that were not observed in adult-exposed rats (39). Specifically, the cannabinoid treatment resulted in hyperactivity of the noradrenergic neurons concomitant with hypoactivity of serotonergic cells (39). Such neuroadaptations would be predictive of enhanced anxiety and depression-like behavior as a consequence of early cannabinoid exposure.
 

Schizophrenia and Schizoaffective Disorders

Although a small fraction of teens that use cannabis develop schizoaffective disorders, a number of epidemiological studies repeatedly demonstrate elevated risk to develop these psychiatric disorders in association with early-life cannabis use. Longitudinal studies assessing the relationship between early-life cannabis exposure and schizotypal personality disorder demonstrated that early adolescent use increases adulthood symptomatology (49). Moreover, the presence and severity of schizophrenic endophenotypes, such as psychotic symptoms and prepulse inhibition, were predicted by adolescent cannabis use (50, 51).

The first longitudinal studies demonstrating an association between cannabis use before adulthood and schizophrenia were conducted in Swedish conscripts (52, 53) Although no information was known about the individuals before conscription, subjects reporting previous cannabis use at the time of conscription were significantly more likely to be diagnosed with schizophrenia later in life. These findings were replicated in multiple studies emphasizing the reproducible relationship between adolescent cannabis use and increased schizophrenia symptoms in adulthood (54, 55).

Although it is challenging to model schizophrenia in animals, phenotypes related to this disorder may be studied. Animals exposed to cannabinoids during adolescence demonstrate increased schizoaffective-like phenotypes, such as impaired sensorimotor gating, which, similar to humans, results in decreased prepulse inhibition (45). Consistent with the notion that developmental cannabinoids induce a schizophrenia-like phenotype, acute administration of the anti-psychotic haloperidol normalized prepulse inhibition in the cannabinoid-exposed rats (47).

Since not all cannabis users develop schizophrenia, early cannabis use likely interacts with other factors to facilitate the emergence of this disease (56). Accumulating data in recent years highlight that the association between early cannabis exposure and vulnerability to schizophrenia is related to individual genetics. Pioneering studies by Caspi et al. (57) demonstrated that the relationship between adolescent cannabis use and schizophreniform disorder, as well as the presence of various psychotic symptoms, was attributable to the presence of a functional polymorphism in the catechol-O-methyltransferase (COMT) gene. This enzyme degrades catecholamines, such as dopamine, and this functional variant (COMTvaline158) catabolizes this neurotransmitter more rapidly than the methionine allele (58). In cannabis users, schizophreniform disorder is predominantly observed in persons with at least one copy of the polymorphic COMT gene (59–61). Moreover, clinical laboratory experiments show that THC’s acute psychotomimetic effects are moderated by this COMT SNP with THC-induced psychotic-like experiences and cognitive impairments being more pronounced in individuals with the valine158 allele (62). Animal models also confirm a link between the genetic disturbance of COMT and developmental cannabis such that adolescent THC exposure in transgenic mice lacking endogenous COMT synergistically impacts behaviors relevant to schizophrenia (63). Overall, these human and animals studies highlight the significant association between early cannabis exposure and schizophrenia, supporting the so-called two-hit hypothesis which posits that both genetics and early environmental factors enhance individual risk to psychiatric illnesses.

Phytocannabinoids and Psychiatric Vulnerability

It is important to emphasize that while most studies focused on THC to understand the long-term impact of cannabis, the plant produces at least 70 cannabinoids (64). To date the most studied phytocannabinoid aside from THC is cannabidiol (CBD), the second major constituent of the cannabis plant. Interestingly, in contrast to THC, CBD appears to have more protective effects relevant to addiction, cognition, and negative affect. For example, CBD inhibits drug-seeking behavior associated with heroin-relapse in rats (65), reduces cigarette intake (66), and inhibits morphine reward (67). It also has anti-psychotic properties (68, 69) and reduces anxiety behavior in rodents (70) and humans (66). Most of these investigations, however, were carried out in adults. No published study to date has examined CBD in relation to adolescent development and subsequent behavioral consequences in later life. As such, it remains to be explored whether the potential positive effects of CBD on brain function seen in adults would also be evident with adolescent exposure. One intriguing consideration about CBD relevant to the developing brain is that cannabis plants today ingested by teens are grown for high THC, but low CBD content (71). This significant change in the THC:CBD ratio could reduce a normally apparent protective constituent of cannabis. The fact that so little is known about CBD and the developing brain highlights the need for research about this and other phytocannabinoids to more fully understand the impact of cannabis to psychiatric vulnerability.

Conclusion

The high prevalence of cannabis use among teens and the increasing number of states in the USA that legalize cannabis for both medicinal and recreational purposes are concerning given the surprisingly limited information known about the impact of cannabis on the developing brain and individual susceptibility. Though a causative relationship cannot be determined between marijuana’s glamorization and its increasing use in teenagers, important lessons can be learned from the major inroads made in reducing cigarette use in youths such as interventions through campaigns that made smoking less socially accepted. Based on the current evidence available from human and animal models, it is evident that cannabis use during adolescent development increases risk of psychiatric diseases such as drug addiction and schizoaffective disorders with genetic interactions. No convincing data exist to support one “common cause” that exclusively predicts which individuals using cannabis as teens will progress to addiction and psychiatric disorders later in life versus those who do not. Psychiatric diseases, such as those discussed in this review, are complex and multifactorial. Indeed, the complex transition from early cannabis use to subsequent psychiatric illness involves multiple factors such as genetics, environment, time period of initiation and duration of cannabis use, underlying psychiatric pathology that preceded drug use, and combined use of other psychoactive drugs. Whether the early onset of cannabis use relates to preexisting pathology that is then exacerbated by the drug is still debated. Additionally, it remains uncertain whether there exist specific critical windows of vulnerability during different phases of adolescent development relevant to the long-term trajectory of risk in adulthood. Longitudinal investigations, making use of neuroimaging and genetics, alongside concurrent studies in animal models are needed to fully elucidate molecular mechanisms that could provide novel treatment interventions for individuals with psychiatric disease and comorbid adolescent cannabis use.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References available at the Frontiers site