Ketamine is the first truly new pharmacological approach to treating depression in the past 50 years and could herald a new generation of rapid acting antidepressants, researchers have predicted.
“We haven’t had anything really new for about 50 or 60 years,” said Allan Young, professor of mood disorders at the Institute of Psychiatry, Psychology and Neuroscience at King’s College, London, at a briefing on 12 July at London’s Science Media Centre.
Most of the new launches have been “tinkering with drugs which were really discovered in the ’50s and ’60s,” he explained. “Even the famous Prozac, which came in in the late ’80s, is really just a refinement of the tricyclic antidepressants that came in the ’50s. People say we are still in the age of steam, and we need to go to the next technological advance.”
In the past few years the focus has fallen on ketamine, which is used for pain relief and anaesthesia but is better known for being a horse sedative and a “club drug” that can induce hallucinations and calmness. It has been found to have rapid antidepressant effects and to be effective in many patients with treatment resistant depression.
US clinics increasingly offer IV infusions of ketamine off label, and in March esketamine, a nasal ketamine based drug, was approved by the US Food and Drug Administration for treatment resistant depression,1 at a cost of £32 400 (€36 060; $40 615) per patient per year.
Carlos Zarate, chief of the Experimental Therapeutics and Pathophysiology Branch at the US National Institute of Mental Health, who has been a key figure in the discovery and evaluation of ketamine as an antidepressant, said that one of the main problems with current antidepressants was their speed of onset in terms of antidepressant and anti-suicidal effects.
He explained that it took 10-14 weeks to see significant improvement with monoaminergic based antidepressants. “In my mind that is too slow,” he said. “We are focusing on treatments that can produce results within hours. That is where we are heading with the next generation of antidepressant, and ketamine is now the prototype for future generation antidepressants which will have rapid, robust antidepressant effects—rapid within a few hours.”
Efficacy and tolerability
Zarate said that, besides correcting chemical imbalances of serotonin and norepinephrine, the new generation of ketamine based antidepressants had other effects such as enhancing plasticity and restoring the synapses and dendrite circuits that shrivel in depression.
When ketamine is given to patients it binds to the N-methyl-D-aspartate (NMDA) receptor, causing a series of transient side effects including decreased awareness of the environment, vivid dreams, and problems in communicating. But the half life of ketamine is only two to three hours, so these side effects quickly subside, whereas the therapeutic effects of the drug last seven days or longer.
Zarate’s team is now focusing on the 24 metabolites of ketamine to hone the drug’s efficacy and tolerability. One of these, hydroxynorketamine, has already been shown to have similar antidepressive effects to ketamine in animals, without the side effects, and it is due to be tested in patients this autumn.
“Ketamine may actually be a prodrug for hydroxynorketamine,” said Zarate.
A few dozen patients with treatment resistant depression have been treated with ketamine in UK trials, and the European Medicines Agency and the Medicines and Healthcare Products Regulatory Agency are due to reach a decision on authorising esketamine for marketing in October. If the drug is approved private clinics will be able to provide it. But it would be unlikely to be available through the NHS until at least 2020, if at all, as the National Institute for Health and Care Excellence would need to deem it cost effective.
Rupert McShane, consultant psychiatrist and associate professor at the University of Oxford, said that, as well as the likely high cost of esketamine, patients treated with it must be observed in a clinic for two hours after each administration. This would require substantial clinical time, as esketamine is given twice a week for the first month, once a week for the second month, and once a week or once a fortnight from then on.
McShane also recommended that, if approved, a multidrug registry should be set up to monitor the long term safety and effectiveness of ketamine based drugs. Patients would be asked to input their use of any prescribed ketamine, esketamine, or any other future ketamine based product, as well as any self medication with illicit ketamine.
Ketamine was originally approved by the US Food and Drug Administration (FDA) as an anesthetic, but is increasingly being used to treat mood disorders, such as treatment-resistant depression, anxiety disorders, and post-traumatic stress disorder (PTSD).1,2 Several studies have also found it to be effective for treating suicidal ideation.3,4
“Ketamine can play an important role in the treatment of anxiety disorders,” according to Prakash Masand, MD, co-founder, chairman, and CEO of Centers of Psychiatric Excellence (COPE) (https://www.copepsychiatry.com) and adjunct professor at the Academic Medicine Education Institute, Duke-National University of Singapore Medical School (Duke-NUS).
“Nowadays, people with anxiety disorders are treated either with a generic antidepressant, such as an SSRI (selective serotonin reuptake inhibitor), an SNRI (selective norepinephrine reuptake inhibitor), or a benzodiazepine and if they don’t respond to one of these, they get a trial of another or several more,” Dr Masand said.
However, between 30% and 40% of these patients will not achieve remission, despite 3 or 4 different traditional agents, and even with evidence-based nonpharmacologic therapies, such as cognitive behavioral therapy (CBT) or mentalization-based therapy (MBT), he noted.
“No good current strategies are available for these non-responders, so novel agents are being studied — including ketamine, which is accumulating an evidence base as [being] rapidly effective for an array of anxiety disorders, including social anxiety disorder (SAD) and PTSD,” he said.
How Does Ketamine Work?
A growing body of evidence points to the role of glutamate, a widely distributed excitatory neurotransmitter, in mediating response to stress and the formation of traumatic memories.2 Ketamine is an ionotropic glutamatergic N-methyl-d-aspartate (NMDA) receptor antagonist. Its antidepressant and anti-anxiety effects are presumed to occur through activating synaptic plasticity by increasing brain-derived neutrophic factor translation and secretion and also by inhibiting glycogen synthase kinase-3 and activating mammalian target of rapamycin signaling.5
Brain-derived neutrophic factor plays a role in behavioral responses to classical antidepressants, but the impact on synaptic plasticity may take several weeks to manifest. In contrast, ketamine-mediated synaptic plasticity changes appear to occur within a matter of hours after ketamine administration.5
“The current thinking is that eventually, 6 to 12 weeks after initiating treatment with traditional antidepressants, dendritic growth and increased synaptic connections occur but with ketamine, these can occur within 24 hours of the infusion,” Dr Masand said.
Ketamine and Anxiety: An Increasing Evidence Base
“Ketamine has been studied and shown [to be] effective with an array of anxiety disorders, including SAD, general anxiety disorder (GAD), and PTSD, although the data on its effectiveness in obsessive compulsive disorder (OCD) are more mixed,” Dr Masand observed.
A small study of patients with GAD and/or SAD (n=12) compared 3 ascending ketamine doses to midazolam. Each was given at 1-week intervals, with midazolam counterbalanced in dosing position across patients. Ketamine was found to dose-dependently improve scores on the Fear Questionnaire. Moreover, it’s impact on decreasing theta frequency in the right frontal sites assessed via electroencelphalogram (EEG) was comparable to that of conventional anxiolytics.6
Glue et al evaluated the efficacy and safety of ketamine in 12 patients with refractory GAD and/or SAD who were not currently depressed using an ascending single-dose at weekly intervals study design. Within 1 hour of dosing, patients reported reduced anxiety, which persisted for up to 7 days.7
A continuation of that study evaluated the impact of maintenance treatment ketamine in patients with GAD and/or SAD (n=20) and found that 18 of the 20 patients reported ongoing improvements in social functioning and/or work functioning during maintenance treatment. The researchers concluded that maintenance therapy ”may be a therapeutic alternative for patients with treatment-refractory GAD/SAD.”8
“What is interesting about this study is that the impact of just one infusion lasted for 14 weeks, suggesting that patient[s] with anxiety disorders might have longer maintenance of response than patients with major depression, where the response has been maintained for only one week,” Dr Masand commented.
A study of patients with anxious and non-anxious bipolar depression (n=21 for both groups) found that both anxious and non-anxious patients with bipolar depression had significant antidepressant responses to ketamine, although the anxious depressed group did not show a clear antidepressant response disadvantage over the non-anxious group.9 “Given that anxiety has been shown to be a predictor of poor treatment response in bipolar depression when traditional treatments are used, our findings suggest the need for further investigations into ketamine’s novel role in the treatment of anxious bipolar depression.,” the investigators concluded.9
An open-label trial of ketamine in 10 patients with treatment-refractory OCD found that ketamine’s effects on OCD symptoms, in contrast to depressive symptoms, did not seem to persist or progress after the acute effects of ketamine had dissipated.10
On the other hand, another randomized controlled trial (RCT) of 15 patients with OCD found that anti-OCD effects from a single intravenous dose of ketamine persisted for more than 1 week in some patients with OCD with constant intrusive thoughts, demonstrating that “a drug affecting glutamate neurotransmission can reduce OCD symptoms without the presence of an [SSRI].”11
In PTSD, there is “mounting evidence for a role of the excitatory neurotransmitter glutamate in stress responsiveness, the formation of traumatic memories, and the pathophysiology of PTSD, raising the possibility of identifying novel glutamatergic interventions for this disorder.”12
One double-blind study demonstrated that infusion of ketamine rapidly and significantly reduces symptom severity in patients with PTSD compared with midazolam.2
Another study found that administration of ketamine immediately after witnessing a traumatic event has been shown to prevent the enhancement of passive avoidance learning in mice.13Ketamine may thus target the mechanisms involved in the consolidation of traumatic memory and may enable the brain to reconsolidate memory and release trauma.14
A case study of a child with PTSD reported remission from behavioral dysregulation after receiving procedural ketamine.15
Drawbacks and Potential Adverse Effects
The main concern regarding the use of ketamine for anxiety disorders is the lack of a road map regarding maintenance, Dr Masand noted.
“At COPE, we have found that roughly 30% to 40% of our patients being treated with ketamine require maintenance infusions, and we highly personalize this approach so that patients can identify early signs of recurrence or relapse and we can devise a treatment schedule to prevent them,” he said.
Some patients continue treatment with pharmacotherapy, including standard antidepressants, benzodiazepines, or a mood stabilizer such as valproate and some patients become more receptive to psychotherapies such as CBT,” he stated.
However, “there is very little data regarding what happens long-term in this patient population.”
“Most side effects are mild and transient,” Dr Masand reported. “Patients must be monitored because of potential increases in blood pressure and pulse.”
Additional adverse events include nausea or vomiting, which are also mild and transient. Patients may be pre-treated with prophylactic anti-nausea medication, such as ondansetron, to pre-empt these symptoms, he said.
Some patients experience dissociation, or an out-of-body experience, which is also usually transient but seen by some patients as “annoying,” he noted. “Dissociative experiences are sometimes seen as a biomarker for insufficient response and suggest that the dose should be increased.”
Providers should be aware that cystitis and lower urinary tract pathologies (eg, detrusor over-activity) have been reported in long-term ketamine users, but typically only at high doses.16
Ketamine’s psychedelic effects make it a” popular recreational drug.”16 At lower doses, the predominant effects are stimulating, and users experience mild dissociation with hallucinations and a distortion of time and space. However, higher doses can induce more severe, schizophrenia-like symptoms and perceptions.16 Although these effects resolve rapidly, long-term use “can cause more pronounced and persistent neuropsychiatric symptoms. For this reason, ketamine should be “used cautiously with other drugs that alter mood and perception, including alcohol, opioids, benzodiazepines and cannabis.”16
“Ketamine for treatment-resistant depression has a robust evidence base and a rapidly-growing evidence base for its use in anxiety disorders,” Dr Masand said.
“Given the gaps in current treatment, this promising agent is occupying a more promising role in treatment of anxiety disorders, such as PTSD. Considering how common PTSD is, ketamine can make an important difference for a large number of people who suffer from this debilitating condition,” he concluded.
First Person Account of Ketamine Therapy: An Interview with Kimberly Palmer
To gain insight into the experience of ketamine treatment in a person with depression and anxiety, Psychiatry Advisor interviewed Kimberly Palmer of Los Angeles, California. Ms Palmer received treatment at the Ketamine Clinics of Los Angeles (https://www.ketamineclinics.com). Ms Palmer works as a program manager for a consulting company where she organizes and runs corporate events for small groups.
Psychiatry Advisor:What made you decide to pursue ketamine treatment?
Ms Palmer:I was raised in an abusive home, and as an adult I had severe major depression, as well as anxiety. I was treated with medications, such as antidepressants, but they had many adverse events and they ended up making me feel like a zombie, so I discontinued them. I managed okay for a while, but then I had another major depressive episode.
I was receiving psychotherapy at the time and it was only moderately helpful — not enough to stop the episode. Fortunately, I knew someone who works at a ketamine clinic. She told me how many patients had been helped by ketamine and I was interested, mostly because the adverse events of ketamine seemed mild and are not long-term.
Psychiatry Advisor: What were your experiences during your infusion?
Ms Palmer: I felt incredible during the infusion. The best way I can describe it is by referring to the movie Avatar, specifically the scene in which the protagonist is walking through a jungle at night for the first time and touching all the plants, which light up with pretty colors—very vivid, colorful, and not linear. There was the sensation of being on a sort of roller coaster, riding through different scenes.
At one point, it felt as though my chair was on a cloud. Then suddenly, the chair disappeared and I was floating on the cloud. It was a wonderful experience.
Psychiatry Advisor: How did the ketamine treatment affect you afterwards?
Ms Palmer: After only one treatment, it was as if a switch had flipped in my brain that allowed me to digest things and move beyond my trauma. Before the infusion, a lot of what was going on with me had to do with self-esteem issues and negative self-talk. These were behaviors learned over many years. After the infusion, the negative self-talk immediately disappeared. All of those thoughts — such as telling myself I am not good enough — that were preventing me from working through emotional issues, were resolved. I was able to start looking at things more objectively rather than taking them personally, and not take on responsibility for other people’s emotions and reactions.
I am currently working with a therapist and a life coach to help me feel more comfortable with communication because I was raised not to ask for things and to put up with anything I’m asked to do. As a result, I have developed a much more positive outlook of myself and the world.
Psychiatry Advisor: How many ketamine treatments have you had?
Ms Palmer: Over a 6-month period I had 6 treatments, which were all very helpful. Then, 6 months after the conclusion of this first series of treatments, some new issues came up, so I received 2 more — one regular 60-minute treatment and one extended 90-minute treatment.
Recently, with the holidays coming up, I decided to pre-empt the effect of some stressors and have another treatment. My most recent infusion took place the day after my father passed away. I noticed that during the infusion, I was able to steer myself away from negative thoughts about that issue. Although I cannot control what visions or experiences I might have, I do have some control over the direction of my thoughts and the after-effects have been positive and helpful.
Psychiatry Advisor: Did you have any adverse events from the treatments?
Ms Palmer: I had no negative physical effects. I had one mild bad reaction, when I came to the treatment session in an agitated state because I had gotten into a fight with someone right before. I was sad and crying by the time I finished the infusion. But I was in a bad headspace before I even walked into the room. And my experience was not scary, only sad.
Psychiatry Advisor: What impact has your treatment had on your day-to-day life?
Ms Palmer: My depression had interrupted my schooling. I was in school for 3 and a half years and then I hit a roadblock. After the treatments, I was able to complete my studies and graduated with a BA in business administration and management.
My job is stressful. I counterbalance the stress with hobbies like surfing and photography. But there are still stressors, and I have a dog who is reaching the end of life, which is affecting me. The ketamine treatments have helped me to manage those stressors.
Geuris “Jerry” Rivas, a native of New York, was diagnosed with severe obsessive-compulsive disorder when he was 15. Obsessions with organizing and reorganizing the belongings in his bedroom — posters, comic books, videos — took over most of his life.
Forced by germ obsessions to compulsively wash and rewash his hands, he started wearing gloves all day to both protect him from the germs and stop him from washing his hands raw. Now, at 36, OCD symptoms continue to cost him jobs and relationships. He’s managed to turn his organizational skills into a profession — he’s a home organizer and house cleaner — but still he struggles daily with his obsessions.
“It’s caused me a great deal of suffering,” Rivas says. “I’ve tried many, many medications. I’ve wasted so much of my life.”
In 2012, running out of answers, Rivas took part in the first clinical trial to test ketamine as a treatment for OCD. While ketamine is approved by the U.S. Food and Drug Administration as an anesthetic, it is also an illicit party drug known as “Special K,” with hallucinogenic effects and the potential for abuse. Over the past 10 years, dozens of small studies of ketamine’s ability to treat a variety of mood and anxiety disorders have reported remarkable results — including the sudden alleviation of treatment-resistant depression, bipolar disorder and post-traumatic stress disorder. And these effects lasted days, sometimes weeks, after the hallucinogenic effects of the drug wore off.
With a single infusion of the drug, Rivas experienced for two weeks what it was like to live without the compulsions and obsessions that had for years controlled his life.
“I felt like, for the first time, I was able to function like a regular person,” he says.
Pros and cons
Ketamine has brought hope to a psychiatric field desperate to find new treatments for severe OCD, a chronic condition marked by debilitating obsessions and repetitive behaviors. Current treatments, which include antidepressants such as Prozac, can take months to have any effect on the disease, if they work at all.
“Severe OCD takes such a toll on patients,” says Carolyn Rodriguez, MD, PhD, who as a researcher at Columbia University ran the OCD trial. Now an assistant professor of psychiatry and behavioral sciences at Stanford, she has continued to explore the pros and cons of using ketamine to treat OCD. “The constant, intrusive thoughts that something is contaminated, the checking and rechecking, the repetitive behaviors. It interferes with your life, your jobs, your relationships.”
Ketamine was developed in the 1960s and has been used for decades as an anesthetic during surgery. It remains a mystery just how the drug works in the brain, and there are safety concerns. There is evidence from people who take the drug routinely — in much higher doses — that chronic, high-frequency ketamine use may be associated with increased risk of bladder inflammation and cognitive impairment, Rodriguez says. And if taken regularly, it can lead to dependence.
But researchers like Rodriguez are intrigued about the drug’s potential to help them identify a whole new line of medicines for fast-acting treatment of mental health disorders.
“What most excites me about ketamine is that it works in a different way than traditional antidepressants,” Rodriguez says. “Using ketamine, we hope to understand the neurobiology that could lead to safe, fast-acting treatments. I feel that is part of my mission as a physician and researcher.”
‘Right out of a movie’
Rodriguez’s interest in ketamine as a treatment for OCD was sparked about a decade ago when she was starting out as a research scientist at Columbia. A small, placebo-controlled study published in 2006 by a mentor of hers, Carlos Zarate, MD, now chief of the section on neurobiology and treatment of mood disorders at the National Institute of Mental Health, had shown that ketamine induced dramatic improvement in treatment-resistant depression within two hours of infusion. It was a landmark study, drawing attention among the psychiatric community and launching a new field of research into the use of ketamine to treat various mood and anxiety disorders.
“What most excites me about ketamine is that it works in a different way than traditional antidepressants.”
Rodriguez, intent on searching for better, faster treatments for her patients like Rivas with OCD, took note. There was an emerging theory that ketamine affects the levels of the neurotransmitter glutamate in the brain and increasing evidence that glutamate plays a role in OCD symptoms, she says. Perhaps ketamine could help regulate OCD symptoms as well as depression.
In 2013, Rodriguez and colleagues published their results from that first clinical trial of ketamine in OCD patients. The trial randomized 15 patients with OCD to ketamine or placebo.
In those patients who were given ketamine, the effect was immediate. Patients reported dramatic decreases in their obsessive-compulsive symptoms midway through the 40-minute infusion, according to the study. The diminished symptoms lasted throughout the following week in half of the patients. Most striking were comments by the patients quoted in the study: “I tried to have OCD thoughts, but I couldn’t,” said one. Another said, “I feel as if the weight of OCD has been lifted.” A third said, “I don’t have any intrusive thoughts. … This is amazing, unbelievable. This is right out of a movie.” And while nearly all initially had dissociative effects like feelings of unreality, distortions of time or hallucinations, they were gone within two hours after the start of the infusion.
“Carolyn’s study was quite exciting,” Zarate says, adding that there were a number of similar, small but rigorous studies following his 2006 study that found fast-acting results using ketamine to treat bipolar disorder and post-traumatic stress disorder.
“We had no reason to believe that ketamine could wipe out any symptoms of these disorders within hours or days,” he says.
So how does it work?
Virtually all of the antidepressants used in the past 60 years work the same way: by raising levels of serotonin or one or two other neurotransmitters. Ketamine, however, doesn’t affect serotonin levels. Exactly what it does remains unclear.
“There’s a recognition that people like me and others are using the drug to treat patients now. There’s an incredible need for something.”
Since coming to Stanford in 2015, Rodriguez has been funded by the National Institute of Mental Health for a large clinical trial of ketamine’s effects on OCD. This five-year trial aims to follow 90 OCD patients for as long as six months after they’ve been given a dose of ketamine or an alternative drug. Rodriguez and her research team want to observe how ketamine changes participants’ brains, as well as test for side effects.
Ultimately, Rodriguez says, she hopes the study will lead to the discovery of other fast-acting drugs that work in the brain like ketamine but without its addictive potential.
Recent research in the field indicates that the glutamate hypothesis that triggered her pilot study might be further refined.
“Ketamine is a complicated drug that works on many different receptor sites,” she says. “Researchers have fixated on the NMDA receptor, one of the glutamate-type receptors, but it might not be the only receptor bringing benefit.”
In May 2016, researchers from NIMH and the University of Maryland — Zarate among them — published a study conducted in mice showing that a chemical byproduct, or metabolite, created as the body breaks down ketamine might hold the secret to its rapid antidepressant actions. This metabolite, hydroxynorketamine, reversed depressionlike symptoms in mice without triggering any of the anesthetic, dissociative or addictive side effects associated with ketamine, Zarate says.
“Ideally, we’d like to test hydroxynorketamine and possibly other drugs that act on glutamate pathways without ketamine-like side effects as possible alternatives to ketamine in OCD,” Rodriguez says.
Beyond the clubs
Meanwhile, dozens of commercial ketamine clinics have popped up across the country, making treatments available to patients who are searching for help to stop their suffering now. Medical insurance companies usually cover ketamine’s FDA-approved use as an anesthetic but won’t cover its use for other purposes, such as mental health disorders. So patients who have run out of treatment options are paying hundreds of dollars a dose for repeated ketamine infusions.
“The fact that these clinics exist is due to the desperation of patients,” says Rodriguez.
She and other researchers are calling for guidelines to protect patients and more research to learn how to use the drug safely.
“I think it’s a game changer, and it’s here to stay,” says David Feifel, MD, PhD, professor emeritus of psychiatry at UC-San Diego, who studies the effect of ketamine on clinical depression. Feifel began prescribing the drug for patients with treatment-resistant depression in 2010.
“I’ve found it to be very safe,” Feifel says, adding that the American Psychiatric Association this year issued safety guidelines on how to use ketamine clinically for treatment of depression.
“There’s a recognition that people like me and others are using the drug to treat patients now,” he says. “There’s an incredible need for something.”
The drug hasn’t worked for everyone he’s treated, Feifel says, but for many it’s been “life-changing.”
Rodriguez says she understands what motivates the clinicians to prescribe the drug now to patients in dire straits — those who are suicidal or who have tried every possible medication and therapeutic option and continue to suffer each day.
“I see it as a way to treat people whose OCD is very, very severe,” she says. “People who can’t come out of the house, who are suicidal, who have no other options.
“I just don’t like the idea of people being in pain,” Rodriguez adds. “I want to see science translated into treatments now.”
Meanwhile, researchers are learning more about the drug. Janssen Pharmaceutical is testing the efficacy of a version of ketamine, known as esketamine, as a therapy for treatment-resistant depression and for major depressive disorder with imminent risk for suicide. The FDA has fast-tracked both investigations. At Stanford, Alan Schatzberg, MD, a professor of psychiatry and behavioral sciences, along with other faculty including Rodriguez, is studying the mechanism of action for ketamine in treating depression.
Rodriguez is also interested in using ketamine to kick-start a type of cognitive behavioral therapy called exposure and response prevention, an evidence-based psychological treatment designed to help patients overcome OCD. The therapy involves teaching patients with OCD to face anxieties by refraining from ritualizing behaviors, then progressing to more challenging anxieties as they experience success.
Relaxation and other techniques also help patients tolerate their anxiety — for example, postponing the compulsion to wash their hands for at least 30 minutes, then extending that time period.
“My goal isn’t to have people taking ketamine for long periods of time,” Rodriguez says. But perhaps a short-term course of ketamine could provide its own kind of exposure and response prevention by allowing patients to experience that it is possible not to be controlled by their OCD, she says.
Rivas well remembers that infusion of ketamine he received during Rodriguez’s first clinical trial to test the drug. The rush made him feel “like Superman.”
“I felt like my body was bigger, that I was more muscular, that I could tackle anything,” he says. But that feeling only lasted the duration of the 40-minute infusion. His OCD symptoms disappeared immediately and were still gone for two weeks after.
“I was amazed that something like that would work and work so fast,” he says. His OCD symptoms today are still intrusive, but he manages to keep them under control by taking antidepressants and seeing a therapist. Still, each day when he comes home from work, he has to put gloves on before he enters his apartment building, and as soon as he enters his apartment, he must wash his hands.
“It’s a ritual now,” he says. “There has never been a time that I haven’t done that, except those two weeks after the ketamine.”
When he heard that certain private ketamine clinics are now offering the drug as treatment for OCD, he said he understands why patients take the risks and pay the high prices. As more research has become available, he’s begun considering it himself.
“I’ve been suffering through my OCD for so long, I’ve gotten to the point where I’d try anything,” he says.
USING KETAMINE TO TREAT SEVERE MENTAL ILLNESS conversation with Stanford psychiatrist Carolyn Rodriguez, MD, PhD, about how she got interested in the use of ketamine to treat obsessive-compulsive disorder and how she is determined to find out why, in studies, the drug has provided relief from symptoms.
Cannabis use in patients with early psychosis is a risk factor for relapse, a higher number of re-hospitalizations, and longer length of stay (LOS) in hospital, particularly in black male patients, according to study results published in Psychiatry Research.
Marco Colizzi, MD, of the National Institute for Health Research, Biomedical Research Centre, South London and Maudsley NHS Foundation Trust, and the department of psychosis studies, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, United Kingdom, and colleagues, conducted a chart review study at the Early Intervention Inpatient Unit of the South London and Maudsley NHS Foundation Trust, an inpatient facility that specializes in the care of individuals between the age of 18 and 35 experiencing a first episode of psychosis. All consecutive admissions to the facility in 2010 were included in the study. Patients with suspected or known acute substance intoxication or an organic cause for psychosis were excluded. Patients were followed for 6 years after initial inpatient admission. The investigators used negative binomial regressions to test for an effect of baseline cannabis use on the number of hospital readmissions and LOS during the 6-year follow-up period.
The study included 161 patients, 13 of whom (8.1%) had a second admission and 1 (0.6%) had a third within the same calendar year. Males made up 61% of the study population, whites 28%, black Africans/Caribbeans 50.7%, Asians 13.3%, and mixed ancestry 8%. Information on cannabis use was available for 141 of these patients. The researchers noted that 62.4% of patients had a lifetime history of cannabis use, 61.2% were tobacco users, 64.5% alcohol users, and 38.5% stimulant users. Their initial hospitalization lasted an average of 54.3 days, and over the following 6 years patients had an average of 2.2 hospital readmissions for a total of 197.4 days.
The analysis suggested that cannabis use significantly predicts the number of hospital readmissions over the 6-year follow-up period (P =.029). However, a further negative binomial regression that adjusted for the use of other psychoactive substances, as well as sociodemographic and other clinical characteristics at baseline, did not find significance for the effect of cannabis on the number of hospital readmissions (P =.072). A significant effect for cannabis use on LOS over the 6-year follow-up was also found (P =.001), and this remained significant even after adjusting for the use of other psychoactive substances (P =.044).
Other exploratory analyses looked at the effect of gender and ethnicity on the number of hospital readmissions and found a significant interaction between cannabis use and male gender on LOS (P =.034) and between lifetime cannabis use and the number of hospital readmissions over the follow-up period in patients of Afro-Caribbean origin (P =.049).
The investigators suggest that cannabis may have detrimental effects on psychosocial factors such as employment, quality of life, and on physical health, which may affect hospitalizations. They noted as well that experimental studies have shown that the primary psychoactive ingredient in cannabis can induce psychotic symptoms in otherwise healthy individuals.
HealthDay News — Cannabis use is associated with psychosis symptoms (PS) during adolescence, according to a research letter published online June 6 in JAMA Psychiatry.
Josiane Bourque, from the University of Montreal, and colleagues examined year-to-year associations between cannabis use and PS over four years among 3,720 adolescents who completed confidential annual surveys from age 13 to 16 years. A multilevel approach was used to test for within-person differences that inform on the extent to which increased cannabis use precedes an increase in PS and vice versa.
The researchers first tested a basic model containing only autoregressive paths, random intercepts, and within-time correlations across variables; this was followed by testing a transactional model that also contained cross-lagged correlations. The transaction model was favored in the Χ²-difference test. Statistically significant positive cross-lagged associations were revealed at every time point from cannabis use to PS reported 12 months later in the transactional model, exceeding the random intercepts of cannabis use and PS. These correlations were similar in size to the autoregressive link between PS from ages 15 to 16. There was a statistically significant association for PS at age 15 years with cannabis use at age 16 years.
“This analysis demonstrates a predominant association at the individual level of cannabis use frequency with increased PS, and not the opposite, in the general population at a developmental stage when both phenomena have their onset,” the authors write.
This analysis demonstrates a predominant association at the individual level of cannabis use frequency with increased PS (psychotic symptoms), and not the opposite, in the general population at a developmental stage when both phenomena have their onset. One limitation was that cannabis use and PS were not confirmed with clinician or collateral reports. However, previous work has shown positive predictive values ranging from 80% to 100% from 3 self-report items to identify interview-verifiable PS.5Furthermore, self-report is the most efficient way to assess substance use when there are no consequences to reporting because collateral reports and biologic measures are not sensitive to the sporadic nature of adolescent substance use.6
Considering that PS are associated with risk for psychosis, as well as nonpsychotic disorders, these results emphasize the need for targeted cannabis use prevention as jurisdictions revise their cannabis regulatory policies. Promoting evidence-based interventions and policies that reduce access to and demand for cannabis among youth could lead to population-based reductions in risk for major psychiatric conditions.
Patients who use medical marijuana may be more likely to use prescription drugs for both medical and nonmedical purposes, according to results published in the Journal of Addiction Medicine.
Previous studies found evidence that medical marijuana use reduces medical and nonmedical prescription drug use, but these new results contradict that hypothesis. The results highlight the need to target medical marijuana users in an effort to reduce nonmedical prescription drug use.
The study used simulations based on logistic regression analyses of data from the 2015 National Survey on Drug Use and Health. The researchers computed associations with adjusted risk ratios controlling for age, sex, race, health status, family income, and living in a state with legalized medical marijuana.
The results indicated that medical marijuana users were significantly more likely to report medical use of prescription drugs in the past 12 months compared with those who did not use medical marijuana (relative risk [RR], 1.62; 95% CI, 1.50-1.74).
People who used medical marijuana were also more likely to report nonmedical use of any prescription drug in the previous 12 months compared with people who did not use medical marijuana (RR, 2.12; 95% CI, 1.67-2.62). This risk was even more pronounced for pain relievers (RR, 1.95; 95% CI, 1.41-2.62), stimulants (RR, 1.86; 95% CI, 1.09-3.02), and tranquilizers (RR, 2.18; 95% CI, 1.45-3.16).
According to data from the Centers for Disease Control and Prevention, deaths from drug overdose have continued to increase in the United States in recent years, with more 600,000 reported from 2000 to 2016.1 Prescription opioids have been identified as a key factor driving this surge; approximately 63% of the 52,404 overdose deaths in 2015 involved an opioid.2
Various strategies have been introduced to address this crisis, including implementation of the CDC Guideline for Prescribing Opioids for Chronic Pain, as well as efforts to improve prescription drug monitoring programs and access to treatment for opioid use disorder. In the ongoing search for solutions, it has been suggested that access to medical cannabis may lead to a reduction in opioid use for pain management.3
n an analysis published in 2014, a 21% reduction in mean annual opioid overdose mortality was found in states with legalized medical cannabis.4 Other findings show that the use of prescriptions for numerous conditions decreased following the legalization of medical cannabis, but the greatest reduction was observed for medications indicated for pain treatment.5
Although these results may seem to support a link between increased access to cannabis and a reduction in prescription opioid use, findings from a study published in 2018 found otherwise (although this investigation focused on cannabis generally rather than legalized medical cannabis).6Researchers at Columbia University Medical Center and the National Institute on Drug Abuse used logistic regression models to analyze data from wave 1 (2001-2002) and wave 2 (2004-2005) of the National Epidemiologic Survey on Alcohol and Related Conditions.
Their analysis of more than 34,000 US adults revealed associations between cannabis use at wave 1 and increased use of nonmedical prescription opioids (odds ratio [OR], 5.78; 95% CI, 4.23-7.90) and opioid use disorder (OR, 7.76, 95% CI, 4.95-12.16) at wave 2, which remained significant after controlling for background characteristics of participants, including age, sex, anxiety or mood disorders, and family history of substance abuse.
Although these results do “not resolve the debate about associations between medical cannabis use, use of prescription opioids, and risks of opioid overdose mortality…. (t)he study is nonetheless an important contribution that balances the state-level analyses with individual level data,” wrote Dennis McCarty, PhD, a professor of public health and preventive medicine at Oregon Health & Science University, in an editorial about the study that appeared in the same issue of the American Journal of Psychiatry.3 He pointed to the large dataset and consistency of participants across waves as strengths of the study, and he cited the dated and self-reported nature of the data, as well as the lack of differentiation between medical and nonmedical cannabis use, as limitations.
“The contrasting associations from the state-level and the person-level analyses should serve as a caution to eager advocates and puzzled policymakers. It is too soon for science to provide deﬁnitive guidance,” added Dr McCarty.
“It is time, therefore, in states where cannabis use is authorized for adults, to build patient registries of cannabis use that link with medical records so that it is feasible to assess morbidity and mortality associated with the frequency, duration, and method [of use],” he wrote.
To further explore the implications of the new findings, Psychiatry Advisor interviewed Mark Olfson, MD, professor of psychiatry at Columbia University Medical Center, who is one of the authors of the study.6
Psychiatry Advisor:What are the top takeaways from your study?
Dr Olfson: As compared with adults who did not smoke marijuana, those who smoked marijuana were found 3 years later to be almost 6 times more likely to misuse prescription opioids and almost 8 times more likely to have an opioid use disorder.Even though [opioid problems did not develop in] most people who smoked marijuana at the start of the study, those who did were at a significantly higher risk [for these problems] developing than were those who did not smoke marijuana. Contrary to some previous reports that were based on population-level patterns, we found that marijuana use tends to increase rather than decrease the risk for prescription opioid use abuse or dependence.
Psychiatry Advisor:What are the overall treatment implications for mental health and pain clinicians?
Dr Olfson: We found that cannabis use, even among adults with moderate or severe pain, was associated with a substantially increased risk for problematic prescription opioid use 3 years later. Although this study was not designed to directly address questions over the appropriate role of medical marijuana in the management of chronic medical pain conditions, the results nevertheless suggest that pain specialists should consider vulnerabilities to addiction when deciding whether to recommend medical marijuana for their patients with persistent pain.
Psychiatry Advisor:What should be the focus of future research in this area?
Dr Olfson: We’re currently working on trying to understand precursors to fatal opioid overdoses. We’re focusing on trying to identify characteristics of patients with non-fatal opioid overdoses who are at the highest short-term risk for overdose death so that more can be done to interrupt this dangerous course by making active efforts to engage them in medication-assisted treatment.
Young adults who used cannabis 2 to 3 times per week were shown to be at increased risk for hypomania at age 22 to 23 years, according to the results of a recent study published in Schizophrenia Bulletin.
Participants from a UK birth cohort were assessed for frequency of cannabis use at age 17. In this study, cannabis use 2 to 3 times per week was considered frequent use. At age 22 to 23 years, participants responded to a postal survey that included the Hypomania Checklist Questionnaire-32 to evaluate manic symptoms.
Information about depression symptoms, psychotic symptoms, childhood abuse, and substance use were collected at various times throughout the participants’ lives. The association among these variables, hypomania, and cannabis use were assessed using path analysis.
After adjustment, frequent cannabis use was associated with subsequent hypomania (odds ratio [OR] 2.21). Weekly cannabis use (OR 2.87) was more strongly associated with hypomania compared with any cannabis use (OR 1.82).
In path analysis, cannabis use correlated well with subsequent hypomania after controlling for all pathways. Depression and psychotic symptoms did not mediate the association between hypomania and cannabis use. The association of subsequent hypomania with gender and childhood abuse were significantly mediated by cannabis use.
The study authors concluded that, “adolescent cannabis use is an independent risk factor for future hypomania, and the nature of the associations found is suggestive of a causal link, [al]though the gold standard for inferring causality of course remains intervention.”
After controlling for predisposing factors, frequent cannabis use was shown to be associated with an increased risk for major depressive disorder (MDD) and suicidal ideation, according to a recent twin study published in Lancet Psychiatry.
In this retrospective analysis, same-sex twin pairs (n=13,896; 6181 monozygotic and 7805 dizygotic) from the Australian Twin Registry were evaluated for associations between cannabis use patterns and MDD, suicidal ideation, and suicide plans or attempts. Samples were broken down into 1992 through 1993 (sample 1), 1996 through 2000 (sample 2), and 2005 through 2009 (sample 3). Association analyses were done in the full sample as well as in pairs of twins discordant for cannabis use at a single time point.
Cannabis use was highest in sample 3 (69.0%, n=2275/3299) followed by sample 2 (59.8%, n=3741/6255) and sample 1 (30.4%, n=1345/4432). Among cannabis users, early use (prior to 18 years for sample 1 and prior to 17 years for samples 2 and 3) and frequent use (≥100 times) were found in 21.3% and 15.9% of sample 1, 23.1% and 27.9% of sample 2, and 37.7% and 21.9% of sample 3.
Suicidal ideation was noted in 24.9% of sample 1, 26.3% of sample 2, and 26.2% of sample 3. MDD was found in 20.3% of sample 1, 28.3% of sample 2, and 24.7% of sample 3. After adjusting for covariates including sex, age, early alcohol or nicotine use, early dysphoric or anhedonic mood, conduct disorder, and childhood sexual abuse, monozygotic twins who used cannabis frequently had a higher risk for MDD (odds ratio [OR]: 1.98, 95% confidence interval [CI]: 1.11-3.53) and suicidal ideation (OR: 2.47, CI: 1.19-5.10) compared with the monozygotic twins who used cannabis less frequently.
After adjustment, early cannabis use was not significantly associated with MDD or suicidal thoughts and behaviors within monozygotic twins (OR: 1.17-2.00) but was within dizygotic twins (OR: 2.23-6.50). According to study authors, this may be indicative of shared genetic factors contributing to the association.
The study authors concluded that they were “unable to exclude the possibility that frequent cannabis use might increase risks for MDD and suicidal ideation, independent of shared predisposing influences.” They noted the importance of understanding this potential susceptibility, particularly “against the backdrop of evidence supporting a role of the endocannabinoid system in mood regulation.”
Frequent cannabis users enrolled in a Medication-Assisted Treatment for opioid addiction exhibit greater associations between pain and negative affects (anxiety and depression) compared with less-frequent users, according to findings from a study published in Addictive Behaviors.
Investigators sought to determine whether frequency of cannabis use had an effect on the relationship between pain and depression and/or anxiety in 150 participants treated for opioid use disorder with Medication-Assisted Treatment. The most frequent mental health diagnoses in the patient cohort were major depression (36.7%), bipolar disease (20.0%), and generalized anxiety (17.3%).
Levels of anxiety, depression, and pain were similar in study participants who had used cannabis in the last month and in nonusers. A positive relationship between depression and pain intensity was established in individuals reporting cannabis use for a period of 1 to 2 days (P =.01; 95% CI, 0.04-0.28), 20 to 29 days (P <.001; 95% CI, 0.24-0.60), and 30 days (P <.001; 95% CI, 0.26-0.70) in the last month.
The frequency of cannabis use was found to moderate the relationship between anxiety and pain intensity in participants using cannabis in the last month for 1 to 2 days (P =.003; 95% CI, 0.11-0.35), 20 to 29 days (P <.001; 95% CI, 0.28-0.66), and 30 days (P <.001; 95% CI, 0.29-0.76). The relationship between anxiety and pain intensity was found to increase with the frequency of cannabis use.
Because this cross-sectional study relied on self-reported data for cannabis use frequency, the investigators note it does not establish a causal relationship between the frequency of cannabis use and the association between pain and negative affect.
This study shows that frequent cannabis use among patients receiving Medication-Assisted Treatment “may be interfering with patients’ ability to disentangle symptoms of pain and emotional distress,” underscoring “an important discrepancy between patients’ positive beliefs about the role of cannabis in symptom managementand the more complicated detrimental influence cannabis may have on symptom entanglement.”
A study published in Molecular Psychiatryindicates a likely causal relationship between cannabis use and increased risk for schizophrenia.1
The study, conducted by researchers from the Department of Internal Medicine at the University Hospital of Lausanne in Switzerland, built on already existing studies depicting a positive, dose-dependent association between cannabis use and schizophrenia risk, particularly in younger populations.2
“[A]ny causal link between cannabis use and psychotic disorders remains controversial as observational findings can always be hampered by confounding…and/or reverse causality bias,” Julian Vaucher, MD, and colleagues wrote. “Moreover, cannabis use is strongly associated with tobacco consumption and…smoking could confound the link between cannabis and schizophrenia.”
To assess causality, the researchers opted to use a genetic approach. Using genetic and self-report data on lifetime use of cannabis and a lifetime diagnosis of schizophrenia from 34,241 cases and 45,604 controls from populations of predominantly European descent, they tested the robustness of the relationship between lifetime cannabis use and schizophrenia while controlling for 10 genotypes that have been weakly associated with lifetime use of cannabis in genome-wide association studies.
They learned that the association between lifetime cannabis use and schizophrenia persisted for most of the 10 genotypes. The pooled estimate of the association for these 10 genotypes (OR, 1.37; 95% CI, 1.09-1.67) was different from the null value, and it did not differ from the pooled estimate of the relationship in epidemiological studies (OR, 1.43; 95% CI, 1.19-1.67). They also found that these relationships persisted after controlling for genetic associations between cigarette and cannabis smoking, making it unlikely that cigarette smoking was a potential confounding variable.
Because this Mendelian randomization used genotypic data to simulate the effects of conducting a randomized controlled trial, it confirmed the hypothesis that cannabis use is likely to increase the risk for schizophrenia. “As cannabis is the leading drug of misuse, this finding is timely to draw attention to the potential mental health consequences of cannabis use and to provide more robust scientific evidence to inform the public health debate on cannabis legalization,” the authors wrote.
BACKGROUND: One of the major mechanisms for terminating the actions of the endocannabinoid anandamide is
hydrolysis by fatty acid amide hydrolase (FAAH), and inhibitors of the enzyme were suggested as potential treatment
for human cannabis dependence. However, the status of brain FAAH in cannabis use disorder is unknown.
METHODS: Brain FAAH binding was measured with positron emission tomography and [11C]CURB in 22 healthy
control subjects and ten chronic cannabis users during early abstinence. The FAAH genetic polymorphism
(rs324420) and blood, urine, and hair levels of cannabinoids and metabolites were determined.
RESULTS: In cannabis users, FAAH binding was significantly lower by 14%–20% across the brain regions examined
than in matched control subjects (overall Cohen’s d 5 0.96). Lower binding was negatively correlated with
cannabinoid concentrations in blood and urine and was associated with higher trait impulsiveness.
CONCLUSIONS: Lower FAAH binding levels in the brain may be a consequence of chronic and recent cannabis
exposure and could contribute to cannabis withdrawal. This effect should be considered in the development of novel
treatment strategies for cannabis use disorder that target FAAH and endocannabinoids. Further studies are needed
to examine possible changes in FAAH binding during prolonged cannabis abstinence and whether lower FAAH
binding predates drug use.
Associations between cannabis use and psychotic outcomes are consistently reported, but establishing causality from observational designs can be problematic. We review the evidence from longitudinal studies that have examined this relationship and discuss the epidemiologic evidence for and against interpreting the findings as causal. We also review the evidence identifying groups at particularly high risk of developing psychosis from using cannabis. Overall, evidence from epidemiologic studies provides strong enough evidence to warrant a public health message that cannabis use can increase the risk of psychotic disorders. However, further studies are required to determine the magnitude of this effect, to determine the effect of different strains of cannabis on risk, and to identify high-risk groups particularly susceptible to the effects of cannabis on psychosis. We also discuss complementary epidemiologic methods that can help address these questions.
The past few decades have seen a marked change in the composition of commonly smoked cannabis. These
changes primarily involve an increase of the psychoactive compound Δ9
-tetrahydrocannabinol (THC) and a decrease
of the potentially therapeutic compound cannabidiol (CBD). This altered composition of cannabis may be linked to
persistent neuroanatomic alterations typically seen in regular cannabis users. In this review, we summarize recent
findings from human structural neuroimaging investigations. We examine whether neuroanatomic alterations are 1)
consistently observed in samples of regular cannabis users, particularly in cannabinoid receptor–high areas, which
are vulnerable to the effects of high circulating levels of THC, and 2) associated either with greater levels of cannabis
use (e.g., higher dosage, longer duration, and earlier age of onset) or with distinct cannabinoid compounds (i.e., THC
and CBD). Across the 31 studies selected for inclusion in this review, neuroanatomic alterations emerged across
regions that are high in cannabinoid receptors (i.e., hippocampus, prefrontal cortex, amygdala, cerebellum). Greater
dose and earlier age of onset were associated with these alterations. Preliminary evidence shows that THC exacerbates, whereas CBD protects from, such harmful effects.Methodologic differences in the quantification of
levels of cannabis use prevent accurate assessment of cannabis exposure and direct comparison of findings across
studies. Consequently, the field lacks large “consortium-style” data sets that can be used to develop reliable
neurobiological models of cannabis-related harm, recovery, and protection. To move the field forward, we encourage
a coordinated approach and suggest the urgent development of consensus-based guidelines to accurately and
comprehensively quantify cannabis use and exposure in human studies.
The reviewed literature demonstrates that regular exposure to
cannabis is associated with neuroanatomic alterations in
several brain regions, most consistently within the hippocampus
(reduced volumes and gray matter density, altered
shape), followed by the amygdala and striatum, orbitofrontal PFC alterations. These trends (i.e., hippocampal volumetric
reduction) were previously observed (47), although there is
now increasing evidence for alteration within other regions
(i.e., striatum, orbitofrontal cortx, parietal cortex, insular cortex,
cerebellum). There was also preliminary evidence that neuroanatomic
alterations within the hippocampus, cerebellum,
prefrontal, and lingual regions were associated with THC and
CBD levels specifically, suggestive of an adverse effect of THC
and a protective effect of CBD (from THC-related damage).Neuroanatomic abnormalities were most reliably found in
regions that have a high concentration of cannabinoid type 1
receptors, to which THC binds to exert its psychoactive
effects (31). Cannabis plants that are typically used for drug
production have high levels of THC (17%–20%) (73) but low
levels of CBD (1). According to preclinical findings, THC
accumulates in neurons (74) and with chronic exposure
becomes neurotoxic (18). Neuroanatomic abnormalities may
result from the adverse effects of direct and chronic exposure
to high levels of THC found in commonly available “street”
cannabis. Although CBD may be neuroprotective (24,25) and
mitigate the adverse effects of THC (47,85), it is seldom found
in high levels (1). As one of the regions of highest density of cannabinoid type 1 receptors (3), damage to the hippocampus may be related to THC-induced neurotoxicity.
Cannabis use has been associated with impaired cognition during acute intoxication as well as in the unintoxicated state in long-term users. However, the evidence has been mixed and contested, and no
systematic reviews of the literature on neuropsychological task-based measures of cognition have been conducted in an attempt to synthesize the findings. We systematically review the empirical research published in the past decade (from January 2004 to February 2015) on acute and chronic effects of cannabis and
cannabinoids and on persistence or recovery after abstinence. We summarize the findings into the major categories of the cognitive domains investigated, considering sample characteristics and associations with various cannabis use parameters. Verbal learning and memory and attention are most consistently impaired by acute and chronic exposure to cannabis. Psychomotor function is most affected during acute intoxication, with some evidence for persistence in chronic users and after cessation of use. Impaired verbal memory, attention, and some executive functions may persist after prolonged abstinence, but persistence or recovery across all cognitive domains remains underresearched. Associations between poorer performance and a range
of cannabis use parameters, including a younger age of onset, are frequently reported. Little further evidence has emerged for the development of tolerance to the acutely impairing effects of cannabis. Evidence for potential protection from harmful effects by cannabidiol continues to increase but is not definitive. In light of
increasing trends toward legalization of cannabis, the knowledge gained from this body of research needs to be incorporated into strategies to minimize harm.
Cross-sectional studies report persistent impairing effects
on some aspects of attention, verbal and working memory,
and psychomotor speed in adolescents abstinent for 28 days
(65) and 35 days (67), but not on other aspects of these and
other cognitive domains. Poor performance was associated
with lifetime cannabis exposure (65) or an earlier age of use
onset in adolescents with 30 days of abstinence (95) and
predicted relapse to cannabis use during a 1-year follow-up
(95). Even after 53 days of abstinence, adolescents showed impaired working memory and risk taking(85). Young adults
abstinent for up to 4 weeks showed poorer verbal fluency
relative to control subjects (119) and nonsignificantly poorer
performance on a gambling task, associated with prior quantity
of weekly cannabis use (127). Older adults abstinent for
.28 days were impaired on executive function and information processing but not attention and working memory (57). Lyons
et al. (64) argued that their study of monozygotic twins,
discordant for cannabis use with .12 months abstinence,
provides evidence against long-term effects of cannabis on
cognition, despite finding impaired performance on block
design tests and trends toward poorer long delay and cued
verbal recall and poorer finger tapping performance in the
Epidemiological studies show that cannabis use is associated with a higher risk of developing psychosis.
Only a small proportion of cannabis users go on to develop psychosis.
Risk factors include heavy cannabis use in young age, genetic vulnerability and environmental stress.
Cannabis acts as a component cause of psychosis.
However, the strongest evidence that cannabis use may have a causal association with schizophrenia comes from longitudinal studies of large representative samples of the population who have been followed up to see if cannabis users are at higher risk of developing schizophrenia. The earliest such evidence came from a 15-year prospective study of cannabis use and schizophrenia by who examined around 50,000 Swedish conscripts. They found that those who had tried cannabis by age 18 were 2.4 times more likely to be diagnosed with schizophrenia 15 years later than those who had notand the risk of this diagnosis increased to around six times with higher frequency of cannabis use. The risks were substantially reduced but still significant after statistical adjustment for variables that were related to the risk of developing schizophrenia.
Evidence has accumulated over the past several decades suggesting that both exocannabinoids and endocannabinoids play a role in the pathophysiology of schizophrenia. The current article presents evidence suggesting that one of the mechanisms whereby cannabinoids induce psychosis is through the alteration in synchronized neural oscillations. Neural oscillations, particularly in the gamma (30–80 Hz) and theta (4–7 Hz) ranges, are disrupted in schizophrenia and are involved in various areas of perceptual and cognitive function. Regarding cannabinoids, preclinical evidence from slice and local field potential recordings has shown that central cannabinoid receptor (cannabinoid receptor type 1) agonists decrease the power of neural oscillations, particularly in the gamma and theta bands. Further, the administration of cannabinoids during critical stages of neural development has been shown to disrupt the brain’s ability to generate synchronized neural oscillations in adulthood. In humans, studies examining the effects of chronic cannabis use (utilizing electroencephalography) have shown abnormalities in neural oscillations in a pattern similar to those observed in schizophrenia. Finally, recent studies in humans have also shown disruptions in neural oscillations after the acute administration of delta-9-tetrahydrocannabinol, the primary psychoactive constituent in cannabis. Taken together, these data suggest that both acute and chronic cannabinoids can disrupt the ability of the brain to generate synchronized oscillations at functionally relevant frequencies. Hence, this may represent one of the primary mechanisms whereby cannabinoids induce disruptions in attention, working memory, sensory-motor integration, and many other psychosis-related behavioral effects
Penetrating any developing neural system with external
stimuli leads to functional alterations. The endocannabinoid
system is an evolutionarily conserved signaling network that
guides critical aspects of brain development (185). In this
review, we highlighted human and rodent data to show that
prenatal exposure to CB1R agonists impacts neuronal development,
leading to altered neurotransmitter and neuronal
circuit settings. While ensuing neuroanatomical changes and
behavioral consequences in the offspring are evident, the
intriguing question remains why some neuropsychiatric diseases
evoked by adult or adolescent marijuana consumption
do not manifest in offspring with prenatal drug exposure. The
quasi-absence of epileptiform activities or schizophrenia
symptoms in children with maternal cannabis use does not
only highlight differences in endocannabinoid function in
adult versus the fetal brain but demonstrates the need for
further mechanistic studies to dissect molecular and cellular
determinants of cannabinoid action.
This review discussed data from basic and clinical neuroscience
in relation to cannabis use and brain development.
Nevertheless, the impact of cannabis use on the dependence/
use of drugs considered more harmful later in life was only
briefly touched upon here. Almost all of those who tried
cocaine and heroin first used alcohol, tobacco, and cannabis
(186), and regular cannabis users are most likely to later use
heroin and cocaine (187) with an earlier age of cannabis use
onset being a further risk factor (186). Thus, social complexity
specifics must be considered when concluding on the actual
danger of cannabis use for the development of neuropsychiatric
The regular use of cannabis during adolescence is of particular concern because use by this age group seems to be
associated with an increased likelihood of deleterious consequences, as reported by several epidemiologic studies.
However, despite their unquestionable value, epidemiologic data are inconclusive. Modeling the adolescent phase in
animals appears to be a useful approach to investigate the impact of cannabis use on the adolescent brain. In these
models, adolescent cannabinoid exposure has been reported to cause long-term impairment in specific components of learning and memory and to have differential effects on anxiety, social behavior, and depressive-like signs. These findings suggest that it may represent, per se or in association with other hits, a risk factor for developing psychotic like symptoms in adulthood. The neurobiological bases of this association include the induction of alterations in the maturational events of the endocannabinoid system occurring in the adolescent brain. Alterations in theendocannabinoid system may profoundly dysregulate developmental processes in some neurotransmitter systems, such as gamma-aminobutyric acid and glutamate, mainly in the cortex. The resulting picture strongly resembles the one present in schizophrenic patients, highlighting the translational value of this experimental approach
The past decade has witnessed a number of societal and political changes that have raised critical questions about
the long-term impact of marijuana (Cannabis sativa) that are especially important given the prevalence of its abuse
and that potential long-term effects still largely lack scientific data. Disturbances of the epigenome have generally
been hypothesized as the molecular machinery underlying the persistent, often tissue-specific transcriptional and
behavioral effects of cannabinoids that have been observed within one’s lifetime and even into the subsequent
generation. Here, we provide an overview of the current published scientific literature that has examined epigenetic
effects of cannabinoids. Though mechanistic insights about the epigenome remain sparse, accumulating data in humans and animal models have begun to reveal aberrant epigenetic modifications in brain and the periphery linked to cannabis exposure. Expansion of such knowledge and causal molecular relationships could help provide novel
targets for future therapeutic interventions.
Between January 1, 1995, and December 31, 2014, 38,681 samples of cannabis preparations were
received and analyzed. The data showed that although the number of marijuana samples seized over the last 4 years
has declined, the number of sinsemilla samples has increased. Overall, the potency of illicit cannabis plant material
has consistently increased over time since 1995 from 4% in 1995 to 12% in 2014. The cannabidiol content has
decreased on average from .28% in 2001 to ,.15% in 2014, resulting in a change in the ratio of Δ9 -tetrahydrocannabinol to cannabidiol from 14 times in 1995 to 80 times in 2014.
There is a shift in the production of illicit cannabis plant material from regular marijuana to sinsemilla. This increase in potency poses higher risk of cannabis use, particularly among adolescents.
Intravenous Ketamine is proving to be a tremendous treatment for intractable depression as well as chronic pain. About half the patients treated respond positively with results lasting up to a week in most of the responders.
It has emerged as a treatment option for a variety of chronic pain conditions including fibromyalgia, small fiber neuropathy, Complex Regional Pain Syndrome (CRPS), Reflex Sympathetic Dystrophy (RSD) and psychiatric conditions including depression, Post Traumatic Stress Disorder (PTSD), suicidal ideation, and Obsessive-Compulsive Disorder (OCD).