Category Archives: Psychedelics

A portrait of late Swiss chemist Albert Hoffman is seen on a collection of LSD blotting papers shown ... [+] during an exhibition entitled "LSD, the 75 Years of a Problem Child" at the Swiss National Library on September 21, 2018 in Bern. - Photo by Fabrice COFFRINI

Some of you may be wonderingWhat is Bicycle Day? On April 19, 1943, the Swiss father of psychedelic medicine Albert Hofmann dropped lysergic acid diethylamide (at 4:20pm, is that a coincidence?) and went on a bike ride, becoming the first human to trip on LSD. As the onset of the psychedelic revolution zooms across the globe at breathtaking speed, this unofficial holiday for psychonauts is an opportunity to reflect on the history of psychedelics and the state of them now.

This day prompts me to think about how different things were when Albert Hofmann accidentally discovered LSD in the 40s, shares DoubleBlind Co-founder Shelby Hartman. At the time, the psychedelic revolution (and shutdown) had not happened, and he could never have dreamt of it: a Swiss scientist looking for an analeptic, a type of stimulant for treating respiratory and circulatory problems, literally fueled a cultural and political paradigm shift decades later. The impact was so destabilizing to the status quo that the government shut it down. It took nearly half a century for institutional science to begin to look at LSD and compounds like it seriously again, Shelby explains. And now, they may be our most promising tool yet for disrupting the current mental health epidemic. How far we've come, and how far we have to go.

The only way to keep up with the momentum of the psychedelics movement is to share dispatches from our community. In this way we can pay respect to the hipstory of this day, how it came to be, and to those who have sacrificed the most to make sure the rest of us can celebrate on our bicycles with the people we love most. Were all incredibly blessed to share in these exceptional times, doing this exceptional work. We can never forget all those who have come before us. We are standing on their shoulders, one and all. Be safe out there, everybody.

Ophelia Chong

Asian Americans for Cannabis Education Founder Ophelia Chongs advocacy is guided by the mission to advocate and offer truthful reflections of the communities that embrace cannabis and psilocybin: In our own ways, we are broken. Psilocybin, 5-MeO-DMT, MDMA, LSD, all allow you to hold your heart and mind outside of your body to heal, to view your trauma in an out of body experience that separates you from your fear, which creates space for the hidden strength you can no longer hold back or deny.

Reggie Harris

California Psychedelic Conference Founder Reggie Harris has created a grassroots gathering designed to showcase the people influencing psychedelic culture and policy, featuring masters of mycology, chemists, medicine workers, underground therapists, policy makers, and psychedelic wellness workers: There would be no psychedelic community without the legacy community, PERIOD. These people have put their lives on the line and built this culture for us to be a part of. In a day and age when we talk about Land Back and Reparations, we have a unique opportunity to structure the psychedelic landscape in a way that will center the people who built this entire thing on their backs, whove been to jail and had their families split up. We should be rewarding them for taking those risks.

Josh Pollack

Bicycle Day SF Producer Josh Pollack has been curating and producing music and art events nationwide since 2006, ranging from intimate club nights to large multi-day camping festivals that aim to evoke creativity and provide a platform of inspiration: I'm honored to help carry the torch for the psychedelic community, especially in the Bay Area with the annual Bicycle Day SF celebration. Its crucial to pay homage and give recognition to the founders of the movement, by providing an event that embodies psychedelic culture, both past and present. The event includes a daytime conference featuring a panel discussion with legends such as Leonard Pickard, Rhoney Stanley, Isaac Abrams, Hamilton Morris, Mountain Girl, Madison Margolin and more, in addition to nighttime festivities which include a full scale art and sensory immersion at The Midway Creative Complex in San Francisco.

Chef Nikki

The High-End Affair Founder & Celebrity Chef Nikki Steward is one of the most sought-after culinary entertainment chefs in the country, and a master in the art of cooking and conversation. Nikki is an advocate for safe and equitable spaces across the plant medicine and psychotherapy community: I believe in creating supportive, community-driven environments when it comes to accessing plant medicine, while also introducing sensible drug policy that allows for treatment, free testing, and access to healing outside of the criminalization frame workings we are so often used to.

Kat Walsh

Kat Walsh is the Creator & Host of Trip On This, a psychedelic podcast exploring trippy stories and expansive thinking. Walshs latest venture is the launch of her second podcast Life With Kat Walsh, a solo podcast centered around the raw, vulnerable nature of the spiritual awakening journey: "For so long I lived my life just going through the motions, filling time with my eyes trained on the weekend escape from the mundane. Then, psychedelics found me and blessed me with a world of beauty and wonder. From that newfound sense of joy, life took on a new vibrancy that led me down a path of purpose, direction, and fulfillment I never knew possible including the creation of my psychedelic podcast. It made me realize that miracles are there for the asking. Psychedelics like LSD and psilocybin have the power to change our minds and in a world where so many minds are stuck in despair, what a gift it is to know there is a rainbow light at the end of the tunnel."

Lulu Tsui

Lulu Tsui, Co-Founder and Chief Experience Officer at On The Revel, applies her vast XD and UX expertise across verticals in the cannabis industry while championing ways to normalize and destigmatize cannabis and entheogens: These psychedelic medicines and healing practices/rituals originated from black, brown, and indigenous communities, but if you look at any psychedelic event, conference, patient waiting room, or psychedelic company's C-suite or board, there are hardly any included or represented. I hope the psychedelic space can start including more black and brown voices in the growth of this industry. Access to mental health and wellness should be accessible to all people.

Dave & James

Farechild Events Founders Dave Tran & James Zachodni curate cool events that enable grassroots networking opportunities between the industrys most influential advocates, brands, and thought leaders for the cannabis industry and beyond. Up next, they are taking their signature experience to Hall of Flowers in Palm Springs on May 4th. The massive hotel takeover High on Life event will connect artisans, retailers, consumers, and everyone in between. Both cannabis and psychedelics have had a huge impact on the way Dave sees the world and lives life, and the that hes building a legal business around entheogens 30 years later is mind blowing and brings everything full circle. Once cannabis broke through the publics consciousness of being something that can help people, James says, It really opened up the doorway for more people to enjoy other mind altering substances without the social stigma.

Jordan Wagman

In The Weeds Podcast Host Jordan Wagman is a James Beard Nominated Chef with a goal to change the world one conversation and meal at a time: In my younger years, specifically leading up to a weekend; the hottest topic wasWhich drug should we take? LSD, mushrooms or stick with cannabis? Truth is, we often indulged in it all simultaneously. Back then, psychedelics were about self exploration and releasing my creative mind. Today, Im thankful for psychedelics and their impact on my mental health. After years struggling with Psoriasis, a debilitating autoimmune disease, I changed my diet, began consuming cannabis, and began microdosing mushrooms, all with the intention of getting healthier. Within 60 days, my change in diet and cannabis consumption led to my Psoriasis improving and losing 30 pounds. Magically, Ive become a much happier person. My new book follows my journey to health and is entitled WILL- How I Found My Health Through Food, available May 2022.

Brooke Burgstahler

Brooke Burgstahler is a Creative, Actress, Founder of Budding Mind, a wellness startup and podcast designed to expand minds and hearts through the exploration of plant medicine, alternative healing, science, and spirituality: I believe that we will remember Ophelia Chong as one of the great mycelium masters of our time. I just had the great honor of interviewing Ohelia on my podcast, and she reminded me that amidst the rising popularity of psychedelics, the most important thing to come from this emerging industry is, very simply, people healing. Decriminalization would be great, a potential marketplace could be cool, but the real purpose of all this effort in normalizing psychedelics and plant medicines is human beings finding inner peace and returning to self love.

Jesus Burrola

Jesus Burrola, Chief Executive Officer of POSIBL, a cultivation that leverages a state-of-art system that uses less to do more, brings the best greenhouse technology and expertise from traditional agriculture into cannabis, and pairs it with the best possible genetics to produce the perfect flower: As we make progress on the stigma of cannabis, the world is opening its eyes to other plant medicines. As with cannabis, entheogens like psilocybin mushrooms are magical with many potential benefits to help those in need, specifically mental health. As many markets struggle with the repercussions of imperfect regulations on cannabis, we should keep those valuable lessons in mind as the psychedelics space potentially evolves into an industry to avoid those same mistakes.

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Bicycle Day: Honoring The Onset Of The Psychedelic Revolution As It Zooms Across The Globe - Forbes

Psilocybin fosters greater connections between different regions of the brain in depressed people, freeing them up from long-held patterns of rumination and excessive self-focus, according to a new study by scientists at UC San Francisco and Imperial College London.

The discovery points toward a general mechanism through which psychedelics may be acting therapeutically on the brain to alleviate depression and possibly other psychiatric conditions that are marked by fixed patterns of thinking.

Depression

Psilocybin

Post-treatment

Scientists analyzed fMRI brain scans from nearly 60 people who had participated in two psilocybin trials. In the first one, all the participants had treatment-resistant depression and knew they were being given psilocybin. In the second one, the participants were depressed but not as severely, and they were not told whether they had been given psilocybin or a placebo that turned out to be escitalopram, an SSRI antidepressant. In addition to the drugs, all the participants received the same type of psychotherapy.

The scans, which were done before and after treatment, showed the psilocybin treatment reduced connections within brain areas that are tightly connected in depression, including the default mode, salience, and executive networks, and increased connections to other regions of the brain that had not been well integrated.

Participants were also less emotionally avoidant and their cognitive functioning got better. The improvement in their depressive symptoms correlated with changes to their brains, and these changes lasted until the study ended three weeks after the second psilocybin dose. No such changes were seen in the brains of those who received escitalopram, suggesting that psilocybin acts differently on the brain than SSRIs.

Psilocybin and other serotonergic psychedelics like ayahuasca affect 5-HT2A receptors, which are plentiful in brain networks that become overactive in depression. One hypothesis is that the drugs briefly disrupt these connections, giving them a chance to reform in new ways in the ensuing days and weeks.

In previous studies we had seen a similar effect in the brain when people were scanned whilst on a psychedelic, but here were seeing it weeks after treatment for depression, which suggests a carry-over of the acute drug action, said Robin Carhart-Harris, PhD, who directs the Neuroscape Psychedelics Division at UCSF and is the senior author of the study, which appears April 11, 2022, in Nature Medicine.

We dont yet know how long the changes in brain activity seen with psilocybin therapy last, and we need to do more research to understand this, said Carhart-Harris, who is the Ralph Metzner Distinguished Professor of Neurology, Psychiatry, and Behavioral Sciences and a member of the UCSF Weill Institute for Neurosciences. We do know that some people relapse, and it may be that after a while their brains revert to the rigid patterns of activity we see in depression.

The authors caution that while these findings are encouraging, patients with depression should not attempt to self-medicate with psilocybin. The trials took place under controlled, clinical conditions, using a regulated dose formulated in a laboratory, and involved extensive psychological support before, during, and after dosing.

But the study points to a mechanism that, if it holds up, may explain both how psilocybin helps to alleviate depression and potentially other debilitating psychiatric conditions.

For the first time we find that psilocybin works differently from conventional antidepressants making the brain more flexible and fluid, and less entrenched in the negative thinking patterns associated with depression, said David Nutt, DM, head of the Imperial Centre for Psychedelic Research. This supports our initial predictions and confirms psilocybin could be a real alternative approach to depression treatments.

Disclosures, as well as the full list of authors and funding are available in the paper.

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Psilocybin Rewires the Brain for People with Depression - University of California, San Francisco

An episode of a CNN show about psychedelic drug treatments sent Spring resident Katy Parr on a quest.

Psychedelic healing was the topic on host Lisa Lings This Is Life series on CNN.

The story centered on three individuals: one who used psilocybin on his own, another who tried ketamine with a psychiatrist and a third who had treatments of methylenedioxymethamphetamine (commonly known as Molly or Ectasy) with the nonprofit Multidisciplinary Association for Psychedelic Studies.

Parr was so intrigued that sometimes the show became too overwhelming to watch.

I had to stop several times and cry, she recalled.

Parr has experienced depressive symptoms since adolescence and began therapy at 25. She has anxiety, major depressive disorder and complex post-traumatic stress disorder.

In the past, Parr has been prescribed several different selective serotonin reuptake inhibitors (SSRIs), a class of drugs used as antidepressants. The experience only set her back, she said.

Therapy, however, has been essential for her treatment. The idea of coupling it with psychedelic healing, as she saw on CNN, seemed promising.

On HoustonChronicle.com: Clinic Field Trip Health brings ketamine-based therapy to depression treatment

Parr called her therapist, who replied, I think youd be an incredible candidate for this.

Chloe Chew gives a tour Friday, March 11, 2022, at Field Trip Health in Houston.

Her therapist was actually in the midst of training with MAPS but not yet able to prescribe anything.

She recommended Field Trip, Parr said. She knew that they had a new office here, right in our backyard.

Field Trip Health Houston at 4310 Westheimer, opened in May. The company, which now has 12 locations globally, launched in Canada in 2019.

Field Trip Health says on its website that clients using ketamine-assisted psychotherapy report 92 percent improvement with anxiety and 89 percent with depression one month after treatment.

Parrs treatment began at the end of September.

During the first psychedelic exploration session, Parr received two small doses of ketamine and was monitored for her reaction.

This appointment sets the stage for the correct dosage moving forward. Its also a time for psychotherapists to gauge how the body will respond to ketamine.

The goal is to get you into a psychedelic space, Parr said. Thats where the healing happens.

She had six more psychedelic explorations, and during each, her dosage increased.

Youre in an enclosed room in a zero-gravity chair that reclines, Parr said. She had a weighted blanket, eye shades and headphones pumping out a curated playlist.

Field Trip Health, photographed Friday, March 11, 2022, in Houston.

Her guide, psychotherapist Bobbie Russell, was in the room and there to help if she picked up on any signs of distress.

The psychedelic explorations are paired with full integration appointments, when Russell and Parr could discuss what happened.

It helped me understand what all of this was about, Parr said.

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She scheduled three weeks with six explorations and three integrations. She went from feeling high at the lower dosages to having a full psychedelic experience later on.

Its almost like youre jerked into a different reality, she said.

The experience was cathartic.

This medicine is bringing you on a journey, Parr said.

Russell was drawn to merging psychedelics with therapy after reading studies of how effective the option has been.

I knew my clients deserved the absolute best treatments we could give them, she said.

Field Trip Health sources ketamine from licensed medical suppliers and employs a trained team of health professionals to support treatment. All treatments are completed with supervision and on-going monitoring to ensure safety.

Russell said the treatment is an option for individuals with depression, anxiety, PTSD or chronic pain.

I want them to know that there is hope, she said.

Many of her clients have treatment-resistant depression. Theyve tried everything, but they dont have symptom reduction, Russell said.

Bobbie Russells shoes sit next to crystals Wednesday, March 16, 2022, at Field Trip Health in Houston.

With ketamine, she has seen a change in her patients. She said that the treatment, which is short term and lasts four to six weeks, is about 80 percent effective.

Its safe, she said. Its medically monitored. Its evidence-based and its effective.

Therapists are also trained to deal with trauma and to work with veterans.

A common concern, Russell said, is that ketamine will be addictive. Another is that the drug alone will treat a symptom. Neither is true, Russell said.

Its the medicine and psychology working together, she said. Its not the drug itself.

Russell said talk therapy sessions help patients integrate the psychedelic experiences to create long-lasting, positive outcomes.

One of the main lenses she uses for therapy is the internal family system, which explores an individuals subpersonalities in order for them to better understand identity.

Russell uses the Pixar film Inside Out to explain the concept. The main character Riley is faced with a move across the country, and her emotions guide her on the journey.

Crystals and coloring books, photographed Friday, March 11, 2022, at Field Trip Health in Houston.

All of these parts of herself have different feelings and ideas of how Riley should react, Russell said. Their views are informed by life experiences. Sometimes, they can be our worst critics, but they are there to guide us and keep us safe.

By building understanding of these aspects, clients can better spot their triggers and guide their own responses.

Pairing the therapy with psychedelics holds immense promise for patients, Russell said.

It empowers them to make informed changes in their behavior and reaction to stress, she said.

For Parr, the internal family systems approach was a game changer.

Its helped a lot with how I speak to myself, like moving past negative self talk, she said.

And when it came to changing her reaction to stress, Parr put that to the test, shortly after completing her treatment with Field Trip Health.

About a week after her last individual session, she went through a divorce. She said the therapy helped her take in stride what, in the past, would have been impossible to handle.

I think this happened at just the right time of my life, Parr said. I was able to accelerate the therapy in that psychedelic space. Out of that session I got so much.

Some clients come into Field Trip Health skeptical about the treatment, Russell said.

Theyve tried everything and dont believe this is going to work, she said. But theyre out of options.

After a month, they return telling a different story, she said.

Bobbie Russell, a social worker, poses for a portrait Wednesday, March 16, 2022, at Field Trip Health in Houston.

Theyll say, For the first time in my life, I dont have crippling anxiety. For the first time, Im not depressed, she said. And that is why I get up every day to go to work. My clients say they feel better.

That doesnt mean they are cured, Russell added. But their baseline is better, she said. They leave treatment with hope, with a renewed view of life and with new skills.

Parr, for instance, said she will face depressive symptoms for the rest of her life. In the past, that realization could make her feel hopeless, like depression was lurking on the horizon.

But the ketamine treatments, in conjunction with her usual therapist, have given her a different outlook.

It helped me focus on the fact that its not always going to be like this, she said. Even when I dont have access to joy in those moments, I know it will be available to me in the future.

She added, The work that Ive done is helping me change my relationship with depression and see it more as a teacher in my life instead of a monster always following me around.

Peyton is a Houston-based freelance writer.

Excerpt from:

Field Trip Health Houston's psychedelic healing with ketamine helps patient with depressive anxiety - Houston Chronicle

Californias K-12 Enrollment Drops Again. We Ask Local Districts What Theyre Seeing

CA School Enrollment 4.13.22

Californias K-12 enrollment has dropped for the fifth year in a row, and the California Department of Education says the trend is projected to continue. When comparing this academic year to the previous one, California public schools lost 110,000 students, a steeper drop than we saw before the pandemic, when declines were driven largely by demographic shifts due to housing affordability. Most California public schools are funded based on enrollment and attendance, so the enrollment drop could have big implications for districts bottom lines.

Today on AirTalk, we discuss these drastic changes to enrollment, whats driving them, and how the trend could possibly be reversed with dean of the USC Rossier School of Education Pedro Noguera, San Bernardino City Unified School District associate superintendent Harold Sullins, and El Monte City School District superintendent Maribel Garcia.

MLB Bets Big On Streaming With Apple TV Deal -- Will It Drive In New Fans Who Turn Into Subscribers?

MLB and Streaming 4.13.22

For decades big money in baseball broadcast rights has been traditional cable television, but now as streamers proliferate, Major League Baseball is stepping up to bat with a major streamer who just won Best Picture at the Oscars and also features one of the most beloved and acclaimed series on streaming TV.

Last month, MLB and Apple TV announced a deal to broadcast a Friday Night Baseball doubleheader on Apple TV. Forbes reported that sources close to the deal said it is worth $85 million a year, and Apple says access to the games is free until June. Major League Baseball also signed a two year deal, per Forbes, to broadcast Sunday games on NBCUniversals streamer, Peacock. For baseball, a sport that desperately needs to reach new fans, its a bet that theyll get more eyeballs on a national scale and that fans will follow their favorite teams onto the streaming platforms. And for the streamers, its a bet that those people following their teams to the platforms will be first-time users of the platforms who turn into subscribers when they begin exploring other content.

Today on AirTalk, Los Angeles Times baseball writer Bill Shaikin calls in to talk about his reporting on why Major League Baseball thinks this will be a win for both the league and the streamers who will now carry games, and why both sides are betting fans will like it too.

Baseballs Rebels: The Dissenters, Radicals, Mavericks And Trailblazers That Changed The Game

Peter Dreier Baseball Book 4.13.22

The history of baseball is rife with stories of people who pushed boundaries, blazed trails and shattered glass ceilings. Jackie Robinson being the first Black man to play in the Majors is probably the most well-known, but the effort to desegregate baseball that led to Jackie even being in a position to make history began well before the Pasadena native first set foot on the diamond for the Brooklyn Dodgers in 1947. And as Occidental College Professor of Politics Peter Dreier writes in his new books Baseball Rebels: The Players, People, and Social Movements That Shook Up the Game and Changed America and Major League Rebels: Baseball Battles over Workers' Rights and American Empire, Jackies story is just one chapter, albeit an incredibly important one, in the history of changemakers in baseball, whose impacts have spanned and still span across labor, gender and sexuality. Just this past week, Rachel Balkovec became the first woman to ever manage an MLB-affiliated team when she won her debut game managing the Tampa Tarpons, a minor league affiliate of the New York Yankees.

Today on AirTalk, Professor Dreier returns to the show to talk about his, both of which explore figures in baseball from players to managers to journalists who challenged the status quo, sometimes at the cost of professional success or even their career. Hell also talk about how we see some of these themes continue to play out in 2022 after Major League Baseballs season hung in the balance for a period of time in February and March during the labor lockout.

Professor Dreier will be talking about his books coming up next week on Tuesday, April 19th, at 6:00 p.m. in a virtual event presented by Vromans Bookstore. Registration is free and you can sign up to receive the link to the virtual discussion here.

Mental Health Week: What One Doctor Says Americas Mental Health System Is Missing, And How To Fix It

Mental Health Healing Books 4.13.22

In 2015, Dr. Thomas Insel, at that time, head of the National Institute of Mental Health, was giving a talk about stem cell studies of neurons in schizophrenia, when the father of a 23-year-old man with schizophrenia stood up and said, Our house is on fire and you're talking about the chemistry of the paint." The interaction changed the trajectory of Insels professional life. In his new book, he argues that while science has made tremendous insights to understand mental illness and develop better tools for diagnosis and treatment, the U.S. mental health system hasnt done enough to help ordinary Americans.

Today on AirTalk, Larry speaks with Dr. Thomas Insel, psychiatrist, neuroscientist and former head of the National Institute of Mental Health about his new book, Healing: Our Path from Mental Illness to Mental Health, and how Americas mental health care systems can pivot to better address the current mental health crisis.

If you or a loved one needs help, call the National Suicide Prevention Lifeline at 1-800-273-8255. Los Angeles County maintains a 24-hour bilingual hotline at 800-854-7771.

Mental Health Week: Magnetic Stimulation, Psychedelics and Tai Chi How Treatments For Anxiety And Depression Are Growing

Mental Health Treatment 4.13.22

For many people, the burdens of mental illness are a daily struggle that the pandemic has only intensified. According to the World Health Organization, during the first year of the pandemic, rates of anxiety and depression increased by 25% worldwide. That is a massive jump. Another study found 33% of adults in the U.S. experienced elevated depressive symptoms during the first year of the pandemic. For decades, those suffering from depression have benefited from SSRIs, selective serotonin reuptake inhibitors, like prozac and zoloft among many others. But taking and prescribing these medications is not that simple. People become treatment-resistant over time, and many mood disorders can be difficult to diagnose, with no biological markers clearly indicating whether someone has bi-polar depression or a substance abuse disorder, for example. This is one of the reasons that researchers have been developing new forms of treatments for anxiety and depression that are non-invasive, long-lasting, and with minimal side-effects.

Today on AirTalk, were joined by geriatric psychiatrist and professor of psychiatry at UCLA Helen Lavretsky, professor of psychiatry at Stanford University and director of the Brain Stimulation Lab Nolan Williams, and professor of psychiatry at Johns Hopkins and researcher at the Johns Hopkins Center for Psychedelic and Consciousness Research, Albert Garcia-Romeu to talk about how mental health treatments are evolving and how they soon might be made more widely available to those in need.

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Mental Health Week: Magnetic Stimulation, Psychedelics and Tai Chi How Treatments For Anxiety And Depression Are Growing - KPCC

Everyone wants a good nights sleep. There are multiple over-the-counter pharmaceuticals for sleep assistance, most with side effects such as dizziness and headaches, and other physical unpleasantries.

Cannabis has seemingly cornered the sleep market for those exploring alternative sleep strategies with a plant-based option, as more CBD and THC products are marketed and sold specifically for help with sleep. For example, Plus Products (OTC: PLPRF) has two products specifically marketed toward aiding sleep with varying levels of THC included.

The thinking is that yes, cannabis will certainly make you sleepy, specifically any indica strain. But is it helpful for your psychological well-being and your sleep/wake cycle? Can you keep taking it for sleep? Data to prove those points is a bit dodgyresearch on sleep and cannabis is in its infancy, one study added, and has yielded mixed results.

While studies indicate that cannabis may hold promise for REM sleep behavior disorder and excessive daytime sleepiness, and may reduce nightmares associated with PTSD, the study of sleep and cannabis has been plagued by error and bias, according to one study, with no hard and fast conclusions drawn except to note that there does not appear to be a consistent effect on total sleep time. These results are consistent with one interpretation that cannabis is typically not beneficial to sleep except among medicinal cannabis users who are identified by the presence of pre-existing sleep interrupting symptoms such as pain, the study concluded.

Another study found that cannabis helped people who had chronic pain issues sleep, but that use of cannabis overtime did not have the same effect. There is even a concern that cannabis consumption is associated with an increased likelihood of developing bipolar disorder, perhaps because of interactions of THC with sleep/wake circadian rhythm cycles.

Sleep disturbance is strongly associated with the development and maintenance of many common psychological disorders, including depression. Researchers have discovered that the need for sleep increases more slowly during wakefulness and so is chronically low in depressed patients. It is unclear whether sleep changes in depression represent disease symptoms or adaptive mechanisms to help handle the depressive state. Acute sleep deprivation oddly enough creates an anti-depressive effect that typically relapses after subsequent sleep occurs, according to research. There is a clear need for a large scale, longitudinal and well-controlled study on the specific effects of cannabinoids on sleep, a study concluded.

Now researchers are looking at psychedelics as a potential aid for sleeping. In a recent study published in Translational Psychiatry in February 2022, electrophysiological recordings were collected from mice to track sleep-wake architecture and cortical activity after psilocin injection. The mice had delayed REM sleep onset, and no long-term changes in sleep-wake quantity were found.

Psilocin-affected mice spent a significant amount of time in their nests, adopting a posture compatible with sleep, but still apparently awake according to electrophysiological measurements. Rest in these animals was frequently disturbed by small body movements, such as stretches and readjustments of posture, and often the eyes remained open even while motionless.

What researchers concluded is that the modulation of REM sleep is a core mechanism of the psychological benefits of psychedelics, although it remains possible that the underlying brain activity of REM sleep is affected in a more subtle way.

Psychedelic drugs such as psilocybin provide a novel approach to studying the basic science of sleep regulation, offering a means to manipulate the content of wakefulness and associated brain dynamics, the February 2022 study concurred. Psychedelic stimulation offers important advantages compared to other manipulations of waking brain activities because of its relative simplicity, physiological validity, translatability to humans, and comprehensibility in terms of the associated conscious experience.

So, bottom line, the jury is out on how helpful psychedelics is for sleep control. Research with psychedelics and sleep essentially is no further along than similar research with cannabis for sleep.

From the clinical perspective, sleep represents an overlooked aspect of physiology to understanding how psychedelic-mediated mechanisms yield psychological benefits, according to the February, 2022 study.

But this study using psilocybin for sleep is just another way that psychedelics are helping scientists understand the full range of its benefits. Although many essential questions remain, a consistent picture of psychedelic biology is gradually forming, carrying the great potential to inform neuroscience in areas spanning basic neurobiology to clinical practice.

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Psychedelics Want To Win Over The Sleep Aid Market - Green Market Report

NEW YORK, April 13, 2022 /PRNewswire/ -- Terran Biosciences ("Terran"), a biotech platform company dedicated to the development of transformational therapeutics for neurological and psychiatric diseases, has entered into an agreement with Blumentech S.L. ("Blumentech") to acquire Blumentech's full patent portfolio and accompanying data,which includes multiple groundbreaking discoveries by the late Dr. Jordi Riba Serrano, a renown ethno-pharmacologist and pioneer of psychedelics research.

Widely admired for his trailblazing work in the space, Dr. Riba was the first to conduct a placebo-controlled study of ayahuasca in 1999, and published extensively on the ability of the molecule DMT to induce neurogenesis. His findings demonstrated novel ways to maintain the therapeutic and neurogenic benefit of psychedelic compounds while also reducing potential side effects and increasing the potential for use across a much wider population of patients.

During his time as a senior researcher at the Sant Pau Biomedical Research Institute in Barcelona, Dr. Riba founded Blumentech in 2017 as a spinout to advance his research and further explore these new possibilities and applications for psychedelics. That same year he was featured alongside Elon Musk and Kamala Harris on Rolling Stone's list of "25 People Shaping the Future," highlighting the visionaries who are "changing (and maybe saving) the world one brilliant idea at a time."

Since Dr. Riba's passing in 2020, his son Marc Riba has stepped in as a director at Blumentech to keep the work moving ahead. "My purpose is to continue my father's legacy. His vision was to use his research to find solutions for the millions of people suffering from mental and neurological illnesses," stated Marc, "Thanks to our great team at Blumentech, led by Gerard de Lucas, we were able to protect and expand my father's intellectual property. Now we are happy to partner with the team at Terran, who we know will be able to ensure his important work continues and take his vision to the next level. We have been impressed by their team, IP, portfolio, and novel approach to the space, and we have faith they will be successful in delivering new therapeutic options to patients in need."

Blumentech's patents further complement Terran's rapidly growing IP portfolio of over 150 patent applications in the psychedelic space, which includes patents on Terran's orally-active DMT compound, a product of Terran's robust medicinal chemistry drug discovery program.

Dr. Sam Clark, CEO of Terran commented "We are honored to partner with Blumentech and advance these assets as quickly as possible. Dr. Riba truly opened the door to this entire field of research, and we hope we too can open doors for patients with these innovative approaches."

The deal also included data and patent rights assigned and licensed from several academic institutions in Spain, including: Fundaci Institut de Recerca de l'Hospital de La Santa Creu i Sant Pau (FIRHSCSP), Universidad Autnoma de Madrid (UAM), State Agency Consejo Superior de Investigaciones Cientificas M.P (CSIC), and Consorcio Centro de Investigacin Biomdica en Red (CIBER).

About Terran Biosciences, Inc.

Terran is a biotech platform company developing a portfolio of therapeutics and technologies for patients with neurological and psychiatric diseases. Backed by a number of life-science and tech investors, Terran has built a CNS-focused, tech-enabled drug development platform, and is rapidly advancing of number of late-stage assets, which include novel psychedelic-based therapeutics.

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Terran Biosciences and Blumentech SL announce the acquisition of a patent portfolio covering the groundbreaking discoveries of prominent psychedelics...

Federally-licensed research lab received additional 56 Research Exemption to acquire psilocybin mushrooms from Nectar Health Sciences Laboratory Division Inc.

VANCOUVER, BC, April 13, 2022 /PRNewswire/ - Delic Holdings Corp ("Delic" or the "Company") (CSE: DELC) (OTCQB: DELCF) (FRA: 6X0), a leader in new medicines and treatments for a modern world, today announced that its subsidiary, Delic Labs, received a Health Canada 56 Research Exemption that will allow scientists to conduct research and perform tests on a number of compounds outside of psychedelic mushrooms, including MDMA, LSD, DMT, mescaline and 2C-B. Additionally, Delic Labs has received a Health Canada 56 exemption to acquire 60 grams of psilocybin mushrooms from Nectar Health Sciences Laboratory Division Inc., a wholly-owned subsidiary of Psilobrain Therapeutics Inc. Delic Labs' latest exemptions enable the Company to develop innovative analytical methods for psychedelic research.

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Last year, the lab also applied for a Dealer's License with the intent of commercializing psilocybin research and associated intellectual property (IP) for medical and research purposes. Securing a Dealer's License to accompany its existing research exemptions would cement Delic Labs' position as the leader in psychedelic safety testing. The Company aims to establish consistent quality control standards as more patients and clinicians incorporate psychedelic compounds into treatment plans.

Delic Labs is the engine of innovation for Delic Corp, conducting research and developing new product lines and IP. The Company's latest foray into psilocybin research reaffirms its commitment to advancing extraction methods, analytical testing and chemical process development.

"Securing our latest Health Canada 56 exemptions allow us to advance our research efforts as we continue to understand the medical applications of psychedelic compounds," said Dr. Markus Roggen, co-founder of Delic Labs. "Psychedelics show tremendous promise as a new class of therapeutics, and Delic Labs is taking extensive measures to establish best practices in developing and manufacturing these potential treatments. We look forward to exploring these novel compounds with the goal of commercializing the research once our Dealer's License is secured."

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Founded by award-winning chemist, Dr. Roggen, and UBC Professor, Dr. Glenn Sammis, Delic Labs supports the psychedelic and cannabis industry with high precision chemical analytics, metabolomic identification and process optimization. Delic Labs is one of a handful of licensed psilocybin research labs in Canada and has an strategic plan to develop a suite of novel compounds and delivery methods for the industry. Delic Labs is also a leading cannabis analytical and research company boasting clients that include some of the largest brands in the world.

About Delic Labs (formerly Complex Biotech Discovery Ventures Ltd.)

Delic Labs is a federally licensed cannabis and psilocybin research laboratory focused on extraction optimization, analytical testing, and process development. Based at the University of British Columbia in Vancouver, Canada and founded by award-winning chemists Dr. Markus Roggen and UBC Professor Dr. Glenn Sammis, Delic Labs uses precision chemical analytics and metabolomics identification to develop IP, produce novel products for patients, and advance the cannabis and psychedelic wellness industries. Part of the Delic Corp family, the leading psychedelic wellness platform, Delic Labs powers innovation and treatment options with an ever-expanding line of unique and high-quality products for markets that allow legal cannabis and psychedelic-based care.

About Delic Corp

Delic is a leader in new medicines and treatments for a modern world, improving access to health benefits across the country and reframing the conversation on psychedelics. The company owns and operates an umbrella of related businesses, including the largest chain of psychedelic wellness clinics in the country, Ketamine Wellness Centers; the only licensed entity by Health Canada to exclusively focus on research and development of psilocybin vaporization technology, Delic Labs; the premier psychedelic wellness event, Meet Delic; and trusted media and e-commerce platforms Reality Sandwich and Delic Radio. Delic is backed by a team of industry and cannabis veterans and a diverse network, whose mission is to provide education, research, high-quality products, and effective treatment options to the masses.

The Canadian Securities Exchange has neither approved nor disapproved the contents of this news release and does not accept responsibility for the adequacy or accuracy of this release.

This news release does not constitute an offer to sell, or a solicitation of an offer to buy, any securities in the United States. The securities have not been and will not be registered under the United States Securities Act of 1933, as amended (the "U.S. Securities Act"), or any state securities laws and may not be offered or sold within the United States unless registered under the U.S. Securities Act and applicable state securities laws or an exemption from such registration is available.

Forward-Looking Information and Statements

This press release contains certain "forward-looking information" within the meaning of applicable Canadian securities legislation and may also contain statements that may constitute "forward-looking statements" within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. Such forward-looking information and forward-looking statements are not representative of historical facts or information or current condition, but instead represent only the Company's beliefs regarding future events, plans or objectives, many of which, by their nature, are inherently uncertain and outside of Delic's control. Generally, such forward-looking information or forward-looking statements can be identified by the use of forward-looking terminology such as "plans", "expects" or "does not expect", "is expected", "budget", "scheduled", "estimates", "forecasts", "intends", "anticipates" or "does not anticipate", or "believes", or variations of such words and phrases or may contain statements that certain actions, events or results "may", "could", "would", "might" or "will be taken", "will continue", "will occur" or "will be achieved". The forward-looking information and forward-looking statements contained herein may include, but are not limited to: information regarding the timing or terms upon which the Transaction will be completed; potential benefits of the Transaction; anticipated continued growth in the health and wellness sector (and, in particular, related to psychedelics); the ability of Delic to successfully achieve business objectives, and expectations for other economic, business, and/or competitive factors.

By identifying such information and statements in this manner, Delic is alerting the reader that such information and statements are subject to known and unknown risks, uncertainties and other factors that may cause the actual results, level of activity, performance or achievements of Delic to be materially different from those expressed or implied by such information and statements. Such risks and other factors may include, but are not limited to: risks and uncertainties relating to the Transaction not closing as planned or at all or on terms and conditions set forth in the Merger Agreement; incorrect assessment of the value and potential benefits of the Transaction; direct and indirect material adverse effects from the COVID-19 pandemic; inability to obtain future financing on suitable terms; failure to obtain required regulatory and other approvals; risks inherent in the psychedelic treatment sector; changes in applicable laws and regulations; and failure to comply with applicable laws and regulations.

In addition, in connection with the forward-looking information and forward-looking statements contained in this press release, Delic has made certain assumptions. These assumptions include, but are not limited to: assumptions as to the time required to negotiate a definite agreement and complete matters related to the Transaction; the ability to consummate the Transaction; the ability of the parties to obtain, in a timely manner, the requisite regulatory, corporate and other third party approvals and the satisfaction of other conditions to the consummation of the Transaction on the proposed terms; the potential impact of the announcement or consummation of the Transaction on relationships, including with regulatory bodies, employees, suppliers, customers and competitors; changes in general economic, business and political conditions, including changes in the financial markets; changes in applicable laws; compliance with extensive government regulation; and the diversion of management time on the Transaction.

Should one or more of these risks, uncertainties or other factors materialize, or should assumptions underlying the forward-looking information or statements prove incorrect, actual results may vary materially from those described herein as intended, planned, anticipated, believed, estimated or expected.

Although Delic believes that the assumptions and factors used in preparing, and the expectations contained in, the forward-looking information and statements are reasonable, undue reliance should not be placed on such information and statements, and no assurance or guarantee can be given that such forward-looking information and statements will prove to be accurate, as actual results and future events could differ materially from those anticipated in such information and statements. The forward-looking information and forward-looking statements contained in this press release are made as of the date of this press release, and Delic does not undertake to update any forward-looking information and/or forward-looking statements that are contained or referenced herein, except in accordance with applicable securities laws. All subsequent written and oral forward- looking information and statements attributable to Delic or persons acting on its behalf is expressly qualified in its entirety by this notice.

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Delic Labs Receives Health Canada 56 Exemption to Conduct Research on MDMA, LSD and Other Psychedelic Compounds - Yahoo Finance

By Natashia Gebre-Zion

In 2018, the Farm Bill removed hemp from the Controlled Substances Act, making hemp and cannabidiol (CBD) legal in all 50 states.

CBD can be found in both body products and in oils; however, one of the biggest uses of CBD is in food and beverage products.

Dr. Sang Park, a senior scientist with the Institute of Cannabis Research at CSU Pueblo, shared his view on using cannabis in food.

Seed oil doesnt have any THC; you dont have to worry about ingesting any THC from seed oil products, he said. It is very clean and safe to use in food production.

One of the biggest debates going on currently, is the health benefits of cannabis products. Dr. Park was another big supporter of these benefits, as he went into detail about different benefits he is seeing with the use of CBD.

[Cannabis] is not synthetic, Its a natural product, Park said. Lets say you have a headache or migraine, you can go to the hospital and they just prescribe medicine, but you dont have to buy that medicine.

You can go to a natural grocery store and grab a CBD-infused medicine and save a lot of money, and its from nature so it doesnt have many of the side effects.

Park said CBD is also a safe alternative for children who are experiencing physical health problems that are impacting their nutrition.

[CBD] is a good alternative medicine for epilepsy patience, if you put some under the tongue then it can stop seizures, Parks said.

He also discussed that CBD is being used to calm the nervous systems. A lot of cancer patients use CBD while they are receiving chemotherapy treatments. Normally, individuals going through chemotherapy, experience nausea and have a hard time keeping their food down. Ultimately, this causes a delayed recovery, because individuals are not getting the nutrition that they need.

CBD-infused products, like this brand of watermelon-flavored water, are growing in popularity at health food stores. [Today photo/Natashia Gebre-Zion]Many parents who have neurodivergent children have turned to CBD products, including food and beverages, as an alternative to Ritalin to assist in calming the nervous system.

CBD works wonders for my son. He has autism (ASD), and it has been a game changer, said Laci Pinckney, a mom from New York. Our son used to take [prescription] medications. He no longer uses any of those.

With the rise of social media, there has been an increase of awareness surrounding alternative medicine, that doesnt just revolve around cannabis, but also psychedelics.

Nathan Sepeda, a research data specialist at The John Hopkins University School of Medicine, discussed how John Hopkins is currently gathering research about psychedelics. Sepeda explained that psychedelics are being tested to help with mental disorders like anxiety, depression and PTSD.

I dont think psychedelics will ever replace traditional medicine, but it will be another tool in the toolkit There are a large portion of people that find that antidepressants dont work, and for those people maybe something like psychedelics will help, Sepeda said.

Parks research surrounding cannabis and CBD is another tool in the toolkit, like Sepeda mentioned. CBD is being used to help with anxiety, depression and physical pain.

Though alternative medicine is a positive alternative, Park did share his concerns with CBD.

Too much is bad, he said. It can cause liver damage, and because people dont know how often to take CBD oil it can cause a lot of abdominal pain.

I have spoken with ER doctors, and they reported that there are a lot of patients screaming because of the abdominal pain, and they are realizing these are the people over-using cannabis products.

Sepeda also shared his concerns with psychedelic research.

In terms of the research, we are really excited about psychedelics and their potential and the different avenues that psychedelics are being tested for, Sepeda said. Some concerns are the narrative that gets adopted by the mainstream. As the narrative is being published more and more, the narrative is shifting and being described as a cure-all, but that is not always the case and there are people who dont experience the benefits. There should be caution about how these treatments are being described.

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Experts discuss the intersections of cannabis, health and food - CSU Pueblo Today

Abstract

Psychedelics (serotonergic hallucinogens) are powerful psychoactive substances that alter perception and mood and affect numerous cognitive processes. They are generally considered physiologically safe and do not lead to dependence or addiction. Their origin predates written history, and they were employed by early cultures in many sociocultural and ritual contexts. After the virtually contemporaneous discovery of (5R,8R)-(+)-lysergic acid-N,N-diethylamide (LSD)-25 and the identification of serotonin in the brain, early research focused intensively on the possibility that LSD and other psychedelics had a serotonergic basis for their action. Today there is a consensus that psychedelics are agonists or partial agonists at brain serotonin 5-hydroxytryptamine 2A receptors, with particular importance on those expressed on apical dendrites of neocortical pyramidal cells in layer V. Several useful rodent models have been developed over the years to help unravel the neurochemical correlates of serotonin 5-hydroxytryptamine 2A receptor activation in the brain, and a variety of imaging techniques have been employed to identify key brain areas that are directly affected by psychedelics. Recent and exciting developments in the field have occurred in clinical research, where several double-blind placebo-controlled phase 2 studies of psilocybin-assisted psychotherapy in patients with cancer-related psychosocial distress have demonstrated unprecedented positive relief of anxiety and depression. Two small pilot studies of psilocybin-assisted psychotherapy also have shown positive benefit in treating both alcohol and nicotine addiction. Recently, blood oxygen leveldependent functional magnetic resonance imaging and magnetoencephalography have been employed for in vivo brain imaging in humans after administration of a psychedelic, and results indicate that intravenously administered psilocybin and LSD produce decreases in oscillatory power in areas of the brains default mode network.

I was delighted when the editors invited me to write a review on psychedelics, perhaps a watershed moment, representing a shift in opinion that has been developing for more than 3 decades with respect to research and understanding of psychedelics. When I began my graduate studies in 1969, it was politically correct in scientific circles to refer to these substances only as psychotomimetics, a negative term suggesting that they fostered a mental state resembling psychosis (Hoffer, 1967). Later, as it was realized that these compounds did not provide very realistic models of psychosis or mental illness, it became more correct to refer to them as hallucinogens, again a pejorative term suggesting that they principally produce hallucinations. Yet that is not what they do in most users at ordinary doses, so this term likewise is not particularly descriptive or useful, although it is still widely used and seems to remain the preferred name for these substances in most scientific writing. In addition, the term hallucinogen is often used as a rather broad category to include all kinds of psychoactive molecules, including cannabinoids, ecstasy, dissociative agents, and others.

This review will focus exclusively on the so-called classic serotonergic hallucinogens (psychedelics), which are substances that exert their effects primarily by an agonist (or partial agonist) action on brain serotonin 5-hydroxytryptamine (5-HT) 2A receptors, as discussed later. The discussion will not consider cannabinoids, dissociatives such as ketamine, salvinorin A (a specific opioid agonist), or entactogens such as 3,4-methylenedioxymethamphetamine (MDMA). In certain contexts, all of these and some related agents have been swept into the catchall category hallucinogens. Although they all can produce profound changes in consciousness, they have a different mechanism of action and will not be discussed unless there is a specific reason to do so.

The name psychedelics for these substances was coined by Humphrey Osmond in 1957, connoting that they have a mind-manifesting capability, revealing useful or beneficial properties of the mind (Osmond, 1957). This name has been popular among the lay public for more than 5 decades, but it has generally been frowned upon by the scientific community because it implies that these substances have useful properties. The notion that psychedelics can have beneficial effects has thus far not been embraced in most medical or scientific circles; indeed, federal funding agencies (e.g., the National Institutes of Health National Institute on Drug Abuse and the National Institute of Mental Health) have no mission to support research on potentially useful properties of psychedelics. Yet this term has remained popular with the public and even appears to be gaining popularity. As I intend to show in this discussion, however, the idea that psychedelics may have useful properties is not at all farfetched, and very recent clinical studies have reinforced the belief by many that psychedelics are well worth studying from a number of different perspectives. Indeed, one of the most striking developments in this field has been the initiation and successful completion of a variety of clinical studies of psychedelics in the past 15 years, most of which have been targeted to specific medical indications. As will be discussed later, the results have been, in the main, remarkably positive.

It should be kept in mind that the relative dearth of research on psychedelics in the past half century did not result from a lack of scientific interest, but rather occurred as a consequence of political forces that manifested principally in the United States in the 1960s and 1970s (Grinspoon and Bakalar, 1979). Use of (5R,8R)-(+)-lysergic acid-N,N-diethylamide (LSD) and marijuana by so-called hippies who demonstrated against the Vietnam War during the 1960s created great consternation among authorities and legislative bodies, both at the federal and state levels. Antiwar attitudes and rejection of conventional social norms by adolescents and college students were often perceived by the mainstream culture to be a consequence of drug use; hence, these substances were often believed to be perverting the minds of our youth. Furthermore, the outspoken Harvard University professor and firebrand Timothy Leary encouraged young people to turn on, tune in, and drop out, essentially coaching them to take drugs, discover their true selves, and abandon convention. Such messages did not play well with the mainstream culture, all while the mass media fanned the flames of public hysteria with greatly exaggerated reports of drug-induced insanity, chromosomal damage, attempts to fly, and so forth.

Strict laws were quickly passed. After the passage of the Controlled Substances Act of 1970, LSD and other psychedelics known at the time were placed into the most restrictive category of drugs, Schedule 1. This classification made them virtually impossible to study clinically and effectively ended any significant research into the pharmacology and medical value of psychedelics for more than 3 decades. Nevertheless, there can be no doubt that psychedelics played a substantial role in defining the youth culture of the 1960s and 1970s, with books and essays too numerous to cite being written on this topic. It is believed that more than 30 million people have used LSD, psilocybin, or mescaline (Krebs and Johansen, 2013). One suspects that had LSD never been discovered, the world might look very different today than it does now, for better or worse, depending on ones perspective.

Despite the recreational use of psychedelics, a quote from a book by Grinspoon and Bakalar (1979 Pg 192) needs to be kept in mind:

Many people remember vaguely that LSD and other psychedelic drugs were once used experimentally in psychiatry, but few realize how much and how long they were used. This was not a quickly rejected and forgotten fad. Between 1950 and the mid-1960s there were more than a thousand clinical papers discussing 40,000 patients, several dozen books, and six international conferences on psychedelic drug therapy. It aroused the interest of many psychiatrists who were in no sense cultural rebels or especially radical in their attitudes.

One very important scientific consequence of the discovery of LSD also is often overlooked. The powerful psychologic effect of LSD was accidently discovered in 1943 (Hofmann, 1979a), followed only a decade later in 1953 by the detection of serotonin in the mammalian brain (Twarog and Page, 1953). The presence of the tryptamine moiety within LSD was also quickly seen to be the scaffold for the chemical structure of serotonin ().

Chemical structures of serotonin and LSD.

This recognition led to a proposal only 1 year later by Woolley and Shaw (1954) that mental disturbances caused by lysergic acid diethylamide were to be attributed to an interference with the action of serotonin in the brain. Therefore, one could reasonably argue that the whole field of serotonin neuroscience, and especially the role of serotonin in brain function, was catalyzed by the discovery of LSD! By way of illustration, in 1952, there were only 10 publications in the National Library of Medicine concerning serotonin, nearly all of them dealing with some aspect of its ability to constrict blood vessels. Only 8 years later, in 1960, there were 300 publications on serotonin, 35 of which were now focused on studies of serotonin in the brain. For comparison, in 1960, there were only 197 publications about norepinephrine (NE)/noradrenaline, a neurotransmitter that had been discovered and studied in the mid-1940s. Green (2008) provides an interesting overview of the 19501970 period of intense research activity after the discovery of serotonin in the brain.

There have been numerous recent reviews on this topic, usually titled as hallucinogens, and the reader is encouraged to consult these works for further details (Nichols, 2004; Nichols and Chemel, 2006; Fantegrossi et al., 2008a; Green, 2008; Passie et al., 2008; Winter, 2009; Griffiths and Grob, 2010; Vollenweider and Kometer, 2010; Brandt and Passie, 2012; Beck and Bonnet, 2013; Halberstadt and Geyer, 2013b; Baumeister et al., 2014; Halberstadt, 2014; Tyl et al., 2014). I wrote a comprehensive review on the subject in 2004, so the literature considered for this review will focus primarily, but not exclusively, on the years from 2004 to the present.

Psychedelics are a class of drug that cannot be fully understood without reference to a number of other fields of research, including anthropology, ethnopharmacology, psychiatry, psychology, sociology, and others. This review will focus mostly on pharmacology, both preclinical and clinical, but on occasion reference will be made to aspects of some of those other areas.

Psychedelics may be the oldest class of psychopharmacological agents known to man. Important examples of these substances include a substance used in ancient India known as Soma, which was highly revered and is frequently mentioned in the Rigveda, with numerous Vedic hymns written in praise of Soma (Wasson and Ingalls, 1971). In the ancient village of Eleusis, outside Athens, for more than 2000 years there was an annual all-night secret ceremony that is believed to have involved ingestion of a hallucinogenic brew known as (Wasson et al., 1978). We know almost nothing about the ceremony other than that profound insights about life could be achieved, and it was apparently a treasured once-in-a-lifetime opportunity for any Greek citizen who had not been convicted of murder.

Psilocybin mushrooms were used by the Aztec shaman in healing and in a variety of religious and divinatory rituals. These mushrooms were known as teonanacatl, meaning gods flesh (Ott and Bigwood, 1978; Schultes and Hofmann, 1979). The use of various psychoactive plant materials and substances was common in pre-Columbian Mesoamerican societies, including the Olmec, Zapotec, Maya, and Aztec cultures (Carod-Artal, 2015). In the Bradshaw rock art in the Kimberly region of Australia and in the Sandawe rock art in the Kolo region of Eastern Tanzania, one finds uniquely shared images such as the mushroom head symbol of psilocybin use, suggesting that the two cultures were linked and had shamanic practices that used psychoactive mushrooms (Pettigrew, 2011).

Peyote (Lophophora williamsii) is a small cactus native to the American Southwest and Northern Mexico that has been used for millennia and is consumed as a sacrament during services of the Native American Church. Two peyote samples from a cave on the Rio Grande River in Texas were analyzed and subjected to radiocarbon dating. The average age of the samples, both of which contained mescaline, dated to 37803660 BCE (El-Seedi et al., 2005). This evidence supports the use of peyote by Native North Americans as long ago as 5700 years (Bruhn et al., 2002). Classic psychedelics that have been extensively studied include LSD, shown earlier, mescaline, psilocybin, and N,N-dimethyltryptamine (DMT) ().

Chemical structures of classic psychadelics mescaline, psilocybin, and DMT.

Ayahuasca, also known as yag or hoasca, has a long history of use by natives in the Amazon valley of South America (Dobkin de Rios, 1971; Schultes and Hofmann, 1979). Ayahuasca is a decoction prepared from an admixture of two plants: the pounded bark from Banisteriopsis caapi vines and leaves from Psychotria viridis. The latter contains the hallucinogen DMT, a Schedule 1 controlled substance under U.S. law, and it is generally considered that the psychoactive effects of ayahuasca can be attributed to its DMT content. Although DMT is not orally active, B. caapi contains -carboline alkaloids that inhibit the liver monoamine oxidase (MAO) that normally breaks down DMT; thus, ayahuasca is taken orally as a tea. Its use has been incorporated as a sacrament into the religious practices of two syncretic Brazilian churches [Unio do Vegetal (UDV) and the Santo Daime] that have branches in the United States, with the U.S. Supreme Court rendering a 2006 decision to allow the use of ayahuasca by the UDV under the Religious Freedom Restoration Act.

In view of the widespread historical use of psychedelics as sacraments in a variety of other cultures, Jaffes (1990) definition for the class of psychedelics can perhaps be appreciated: the feature that distinguishes the psychedelic agents from other classes of drug is their capacity reliably to induce states of altered perception, thought, and feeling that are not experienced otherwise except in dreams or at times of religious exaltation. All pharmacologists will recognize that this definition for a class of psychoactive drugs is indeed quite unique!

One of the pioneers of LSD research, the late Daniel X. Freedman, noted that one basic dimension of behavior compellingly revealed in LSD states is portentousness the capacity of the mind to see more than it can tell, to experience more than it can explicate, to believe in and be impressed with more than it can rationally justify, to experience boundlessness and boundaryless events, from the banal to the profound (Freedman, 1968). Freedmans observation is completely consistent with Jaffes definition.

The use of psychedelics as a central feature of many religious practices, as well as the profound and unique psychopharmacological effects suggested by Jaffes definition and the observations of Freedman, surely makes us aware that psychedelics are an exceptional category of mind-altering substances. Indeed, this knowledge prompted Ruck et al. (1979) to coin the word entheogen as a replacement for the terms hallucinogen and psychedelic, both of which they felt had negative connotations. Entheogen is derived from the Greek roots entheos, meaning God (theos) within, and genesthe, meaning to generate. The word entheogen thus essentially refers to a substance or material that generates God or the divine within someone. Although the term entheogen is now seeing fairly wide acceptance within the culture of those who use these substances recreationally, a search of the term in the National Library of Medicine finds only five hits. Although it seems unlikely that the term entheogen will be adopted within the formal scientific community, the reader should realize that in some circles entheogen is generally synonymous with psychedelic. Nonetheless, it should be appreciated that the effects produced by psychedelics are highly dependent on the set (mental expectation) of the user and the setting (environment). A set and setting designed to facilitate a mystical experience will increase the probability of such an occurrence, whereas an unstructured or party-type setting is less likely to lead to a positive outcome.

Studerus et al. (2012) investigated the importance of 24 predictor variables on the acute response to psilocybin and confirmed that nonpharmacological factors play an important role in the effects of psilocybin. Variables examined included age, sex, education, personality traits, drug pre-experience, mental state before drug intake, experimental setting, and drug dose. Their analysis was based on pooled data from 23 controlled experimental studies involving 261 healthy volunteers who had participated in 409 psilocybin administrations over a 19-year period in the authors laboratory. Multiple linear mixed-effects models were fitted for each of 15 response variables. Drug dose was shown to be the most important predictor for all measured response variables, but several nonpharmacological variables significantly contributed to the effects of psilocybin. Specifically, having a high score in the personality trait of absorption, being in an emotionally excitable and active state immediately before drug intake, and having experienced few psychologic problems in past weeks were most strongly associated with pleasant and mystical-type experiences. High emotional excitability, young age, and an experimental setting involving positron emission tomography (PET) most strongly predicted unpleasant and/or anxious reactions to psilocybin. Interestingly, in addition to confirming that nonpharmacological variables play an important role in the effects of psilocybin, an experimental setting involving PET most strongly predicted unpleasant and/or anxious reactions to psilocybin.

Two instruments have been most widely used to assess the subjective effects of hallucinogenic drugs. The first of these, the Hallucinogen Rating Scale (HRS) was developed by Strassman et al. (1994) during their studies of the intravenous administration of DMT. The HRS was first drafted based on interviews with 19 experienced DMT users and was modified during the early stages of their study. The final version, used for their double-blind study, contained 126 individual items. HRS items were placed into six conceptually coherent clusters: somaesthesia (interoceptive, visceral, and cutaneous/tactile effects), affect (emotional/affective responses), perception (visual, auditory, gustatory, and olfactory experiences), cognition (alteration in thought processes or content), volition (a change in capacity to interact willfully with themselves, the environment, or certain aspects of the experience), and intensity (strength of the various aspects of the experience). Subjects were asked to recall their experiences from the immediately preceding session. Most questions were scored on a 04 scale (0, not at all; 1, slightly; 2, moderately; 3, quite a bit; and 4, extremely).

The second assessment instrument widely used to quantify the subjective effects of hallucinogens is the Abnormal Mental States (APZ) questionnaire, first developed by Dittrich (1994, 1998) to measure altered states of consciousness (ASCs). In a series of 11 experiments using different induction methods in 393 healthy subjects, the hypothesis was tested that ASCs have major dimensions in common, irrespective of their mode of induction. The original version contained 158 items covering a range of phenomena potentially occurring during an ASC. The common denominator of ASCs was described by three primary oblique dimensions, designated as oceanic boundlessness (OSE, later as OBN), dread of ego dissolution (AIA, and later as DED), and visionary restructuralization (VUS, later as VRS). The APZ questionnaire became the international validated standard for the assessment of ASCs and the name was further revised to the OAV scales (Bodmer et al., 1994) and later to the five-dimensional altered states of consciousness (5D-ASC) (Dittrich et al., 2006). Details of the development of the original APZ questionnaire and its further refinements were summarized by Studerus et al. (2010). To overcome a variety of methodological limitations, Studerus et al. (2010) carried out a psychometric evaluation of the OAV and 5D-ASC in a relatively large sample from 43 pooled experimental studies of healthy subjects who had received psilocybin, ketamine, or MDMA. The total sample was composed of 591 drug sessions. After comprehensive and detailed statistical analyses, the authors found that the original OAV scales were multidimensional constructs, and arrived at an improved final model that had 11 factors: experience of unity, spiritual experience, blissful state, insightfulness, disembodiment, impaired control and cognition, anxiety, complex imagery, elementary imagery, audio-visual synesthesia, and changed meaning of percepts. Correlations between the 11 factors and their association with the original OAV scales were presented. The new lower-order scales were proposed to be better suited to assess drug-induced ASCs.

Mechanistically, psychedelics have agonist or partial agonist activity at brain serotonin 5-HT2A receptors. This molecular characterization will be elaborated in some detail later in this review, and aspects of the anatomic and functional importance of this receptor type will also be extensively explored. Discussions over the years with many colleagues working in the pharmaceutical industry have informed me that if upon screening a potential new drug is found to have serotonin 5-HT2A agonist activity, it nearly always signals the end to any further development of that molecule.

A recent study by Turton et al. (2014) reported on the subjective experience of intravenous psilocybin administered during a functional magnetic resonance imaging (fMRI) examination. Fifteen volunteers were administered an intravenous infusion of either placebo or 2 mg psilocybin and were blinded as to whether they would receive placebo or drug for a particular experiment. Drug infusion began 6 minutes after the start of a scan in a magnetic resonance imaging scanner. Subjects completed a visual analog scale rating the intensity of the drug experience at the start of the scan and prior to drug infusion, 5 minutes postinfusion, and 12 minutes postinfusion. All subjects subsequently were interviewed about the drug effects, and interviews were analyzed using interpretative phenomenological analysis, a qualitative method. All subjects reported that the onset of drug effect was very rapid and intense, with a duration of effect lasting 1015 minutes. The investigators identified nine broad categories of phenomenology. Altered somatosensory, visual, auditory, and proprioceptive sensations were reported, with 14 of 15 subjects describing perceptual changes as the primary effect of the drug. Thirteen subjects reported changes in perception of time, either speeding up or slowing down. The report describes a variety of effects on cognition, mood, memory, and spiritual or mystical experiences. Overall, subjects found the experience difficult to describe, yet most found it pleasant and positive.

In a new study by Schmid et al. (2015), LSD (200 g) was administered orally to 16 healthy subjects in a double-blind, randomized, placebo-controlled, crossover study. LSD produced a pronounced alteration in waking consciousness that lasted for 12 hours and included visual hallucinations, audio-visual synesthesia, and positively experienced derealization and depersonalization phenomena. Compared with placebo, LSD increased subjective well-being, happiness, closeness to others, openness, and trust. Increases in blood pressure, heart rate, body temperature, pupil size, plasma cortisol, prolactin, oxytocin, and epinephrine also were measured. On the 5D-ASC scale, LSD produced higher scores than did psilocybin or DMT. The authors also described subjective effects on mood that were similar to those reported for MDMA that might be useful in psychotherapy. No severe acute adverse effects were observed and the effects subsided completely within 72 hours.

In a very recent study by Carhart-Harris et al. (2015a), LSD was shown to enhance responsiveness to suggestion. Their study was prompted by very early reports indicating that LSD increased suggestibility (Sjobergand Hollister, 1965; Middlefell, 1967). Thus, Carhart-Harris et al. (2015a) administered LSD (4080 g, i.v.) to 10 healthy volunteers in a within-subject placebo-controlled design. Suggestibility and cued mental imagery were assessed using the Creative Imagination Scale and a mental imagery test. The two instruments were administered between 110 and 140 minutes after drug infusion, at the peak of the drug effect. Subjects scored significantly higher on the Creative Imagination Scale, but not the mental imagery test after LSD administration, compared with placebo. The magnitude of suggestibility enhancement was positively correlated with the subjects baseline trait conscientiousness. This enhanced suggestibility may have implications for the use of LSD as an adjunct to psychotherapy, but it also indicates that individuals with a high trait conscientiousness are particularly sensitive to the suggestibility-enhancement effect of LSD.

It has been axiomatic among users of psychedelics that music takes on an intensified and more enjoyable quality under the effects of LSD or other psychedelics, yet no modern placebo-controlled study had ever been carried out to confirm that widely held belief. Early studies at the Maryland Psychiatric Research Center found that music was a very effective stimulus and complement to the effect of LSD (Bonny and Pahnke, 1972). Gaston and Eagle (1970) also reported that the presence of music was much preferable to its absence in alcoholic patients undergoing treatment using LSD therapy, both by patient preference and treatment results. Numerous other studies had been reported on the value of music in the context of various shamanic and therapeutic approaches (see references in Kaelen et al., 2015). Very recently, therefore, Kaelen et al. (2015) tested the hypothesis that the emotional response to music is enhanced by LSD. Ten participants were administered placebo or various doses of LSD, including 40, 50, 70, or 80 g, infused intravenously over 3 minutes. They then listened to five different instrumental music tracks on each of two study days: a placebo day followed by an LSD day, separated by 57 days. Music tracks were chosen that produced the highest liking and lowest familiarity by a separate sample of nine participants. The question How emotionally affected were you by the music? was asked immediately after each track and served as the studys primary outcome. The nine-category Geneva Emotional Music Scale (Zentner et al., 2008) was also used. Mean scores for all music stimuli in response to the question how emotionally affected were you by the music? were significantly higher for the LSD condition than for placebo. In addition, all nine factors on the Geneva Emotional Music Scale were scored higher after LSD administration than after placebo. Emotions related to transcendence also were enhanced by LSD. Specific emotions showing the strongest enhancement included wonder, transcendence, tenderness, and power. Furthermore, there was a significant positive relationship between ratings of the intensity of the LSD effect and emotional arousal to music. The results of Zentner et al. (2008) support the hypothesis that LSD enhances music-evoked emotion.

The experimental study of mystical or ecstatic states engendered by psychedelics perhaps began with the so-called Good Friday experiment, carried out at Boston Universitys Marsh Chapel in 1962 by Walter Pahnke as his research for the Ph.D. in religion and society at the Harvard Divinity School. Pahnke (1963) examined the similarities and differences between experiences described by mystics and those induced by psilocybin. On Good Friday in 1962, 20 Christian theological student volunteers attended a 2.5-hour religious service in Boston Universitys Marsh Chapel. The setting and preparation of the subjects was designed to optimize a spiritual or mystical experience. In a double-blind procedure, subjects were given either an oral dose of 30 mg psilocybin, or a 200-mg placebo dose of nicotinic acid, administered in identical capsules. Based on responses to a variety of instruments and questionnaires, subjects who received psilocybin had experiences that were indistinguishable from those experienced by mystics. The experiences were powerful and personally meaningful. Doblin (1991) reported a follow-up to the Pahnke study in 1989 and was able to locate and interview 19 of the original 20 experimental participants. All of the psilocybin subjects felt that the experience had significantly affected their lives in a positive way and they expressed appreciation for having participated in the experiment.

An extension of the Good Friday experiment was recently carried out by Griffiths et al. (2006). The investigators used rigorous double-blind clinical methods to evaluate acute and longer-term effects of psilocybin (30 mg/70 kg) compared with an active comparator compound (40 mg/70 kg methylphenidate). A complex design was used to obscure which treatments were administered from the study participants and the monitors, and the study was designed to minimize adverse effects. Thirty-six healthy volunteers were enrolled, all of whom indicated some participation in regular religious or spiritual activities. Instruments used to assess effects 7 hours after drug administration were the HRS, the Addiction Research Center Inventory, the States of Consciousness questionnaire, and the Mysticism Scale. Seven to 8 weeks after each session, and before any additional session, subjects completed the Persisting Effects Questionnaire, the Mysticism ScaleLifetime, the Spiritual Transcendence Scale, the NEO Personality Inventory, and the Positive and Negative Affect Schedule Expanded Form. Based on measures of mystical experience, 22 of the 36 volunteers had a complete mystical experience after psilocybin administration, whereas only 4 did after the methylphenidate (placebo) sessions. Based on ratings of personal meaningfulness and spiritual experience, 67% of the volunteers rated the psilocybin experience to be either the single most meaningful experience of their lives or among the top five most meaningful experiences in their lives. Based on community observer ratings, psilocybin sessions were associated with significant positive changes in the volunteers behavior and attitudes.

Thus, when psilocybin was administered under structured conditions to well prepared volunteers, it occasioned experiences that had marked similarities to classic mystical experiences, imparting to the participants substantial personal meaning and spiritual significance. The investigators point out that the high value some subjects placed on the psilocybin experience may in part explain the long-term historical use of psychedelics within some cultures for divinatory or religious purposes. Griffiths et al. (2006) conclude with the statement that, The ability to prospectively occasion mystical experiences should permit rigorous scientific investigations about their causes and consequences.

Griffiths et al. (2008) subsequently conducted a 14-month follow-up of the subjects from their earlier study. Subjects were asked to identify in which session they experienced the most pronounced changes in your ordinary mental process. It was found that the 14-month retrospective follow-up ratings for the psilocybin session did not differ significantly from the immediate postsession ratings. Compared with methylphenidate, the psilocybin experience produced significant increases in ratings of positive attitudes, mood, social effects, and behavior at 14 months of follow-up. At the 14-month follow-up, 58% of the 36 volunteers still rated the psilocybin experience as among the five most personally meaningful experiences of their lives and 67% rated it as among the five most spiritually significant experiences of their lives.

A second study using a similar protocol with 18 volunteers examined dose effects of psilocybin, using 0, 5, 10, 20, and 30 mg/70 kg (Griffiths et al., 2011). The percentage of subjects who met the criteria for having a complete mystical-type experience increased with dose. Overall, 72.2% of volunteers had complete mystical experiences at either or both doses of 20 and 30 mg/70 kg. Positive ratings about life, attitudes about self, mood, social effects, and behavior also increased as a function of dose. Ratings at the 14-month follow-up were undiminished compared with ratings at 1 month after the sessions.

MacLean et al. (2011) analyzed the data from the two double-blind controlled studies of psilocybin reported by Griffiths et al. (2006, 2011). In particular, their goal was to use the NEO Personality Inventory to analyze possible personality changes that might have occurred after the high-dose psilocybin sessions in those studies. It is generally believed that personality traits are relatively enduring and that an individuals personality is predominantly stable across the lifespan. Yet evidence also exists that significant life events may dramatically change adult personality (see references in MacLean et al., 2011). The most widely accepted model of personality structure is the five-factor model, which describes five broad domains of personality: neuroticism, extroversion, openness, agreeableness, and conscientiousness (see references in MacLean et al., 2011). The authors suggest that numerous subjective claims of long-term changes after hallucinogen use appear to align with the personality trait of openness, which encompasses aesthetic appreciation and sensitivity, imagination and fantasy, and broad-minded tolerance of others viewpoints and values. Thus, they hypothesize that the mystical experiences reported in the studies by Griffiths et al. might lead to enduring increases in openness. Analysis of personality was assessed 1 to 2 months after a high-dose psilocybin session and again 16 months later to determine the persistence of any personality change(s). Consistent with their hypothesis, a mystical experience after psilocybin administration was significantly correlated with increases in openness. No such effect was seen after methylphenidate treatment. In addition, there were no significant changes in any of the other four personality factors after psilocybin administration. At the 16-month follow-up, openness levels still remained significantly elevated. The authors note that This is the first study to demonstrate changes in personality in healthy adults after an experimentally manipulated discrete event.

Studerus et al. (2011) pooled raw data from eight double-blind placebo-controlled experimental psilocybin studies conducted between 1999 and 2008. The data were analyzed for acute, short- and long-term subjective effects of psilocybin in 110 healthy human subjects who had received between one and four doses of 45315 g/kg psilocybin. Studerus et al. (2011) reported that nearly 40% of the participants in their laboratory studies of psilocybin claimed positive long-term changes in aesthetic experience and in their relationship with the environment (i.e., nature) after their psilocybin sessions. At 816 months after psilocybin sessions, more than 60% of subjects rated the experience as very enriching, and more than 90% described it as enriching to at least a medium degree. These effects occurred despite the fact that no attempt was made in their experiments to optimize conditions for a spiritual or mystical experience, which contrasts with the setting and preparations used in the two Griffiths studies cited above.

Bouso et al. (2012) compared 127 regular ayahuasca users with 115 actively religious controls who did not use ayahuasca. Baseline measurements were taken of general psychologic well-being, mental health, and cognition and the groups were then compared 1 year later to determine whether regular ayahuasca use had an effect on these measurements. Regular ayahuasca users showed lower scores on all psychopathology scales as assessed by the Symptom Checklist 90Revised, as well as on measures of harm avoidance and self-directedness. Participants scored higher on a measure of psychosocial well-being and performed better on the Stroop test (an indicator of resistance to emotional interference) and the Wisconsin Card Sorting Task (a measure of working memory). No evidence of psychologic maladjustment, mental health deterioration, or cognitive impairment was found in the ayahuasca-using group.

Lerner and Lyvers (2006) compared users of psychedelic drugs with users of nonpsychedelic drugs and nonillicit drugusing social drinkers. Samples were drawn from Israel and Australia. Compared with the other two groups, psychedelic drug users scored significantly higher on mystical beliefs (e.g., oneness with God and the universe), life values of spirituality, and concern for others, and scored lower on the value of financial prosperity, irrespective of culture of origin.

Lyvers and Meester (2012) carried out a website survey of 337 adults who used a variety of drugs, including psychedelics. Only about 25% reported spiritual motives for using psychedelics, yet use of high doses of LSD and psilocybin was significantly correlated in a dose-related manner with scores on two well known indices of mystical experiences; use of MDMA, cannabis, cocaine, opiates, or alcohol was not. Thus, even when taken recreationally, psychedelics have the potential to induce mystical experiences.

Quite interestingly, the underlying neuronal basis for mystical/spiritual experiences has recently been the subject of scientific investigation. Kometer et al. (2015) studied the neuronal basis of spiritual experiences and insightfulness after administration of psilocybin to human subjects. They conducted a double-blind, placebo-controlled study and administered psilocybin (170 or 215 g/kg, p.o.) to 50 healthy human volunteers. Electroencephalography (EEG) data were recorded from 64 scalp electrodes. Exact low-resolution brain electromagnetic tomography was applied to compute the three-dimensional intracerebral current density values of the scalp-recorded EEG rhythms. They used lagged phase synchronization, a new measure that can capture nonlinear neuronal relationships to assess dynamic functional connectivity (Pascual-Marqui et al., 2011).

The 11-dimension 5D-ASC questionnaire was used to quantify the subjective psychologic effects of psilocybin, with a particular interest in the spiritual experience subscale, and the related subscales of experience of unity, comprising experience of oneness with the environment and the self, insightfulness, measuring profound insights into life and existence, blissful state, measuring experiences of pleasure, inner peace, and love. Voxel-wise product-moment correlations between current source density in the psilocybin condition and the 11-dimension 5D-ASC subscale scores were computed by regression analysis.

Psilocybin significantly increased scores of all subscales on the 5D-ASC but significantly decreased current source density of oscillations in all frequency bands up to 20 Hz (eyes-closed condition) or up to 30 Hz (eyes-open condition). There was a significant and consistent psilocybin-induced reduction of current source density across low frequency bands (<20 Hz) in the posterior cingulate cortex (PCC) and the retrosplenial cortex (RSC). Psilocybin decreased the current source density of neuronal 1.5- to 2.0-Hz oscillations within a neural network comprising the PCC, anterior cingulate cortex (ACC), and parahippocampal regions. The intensity of psilocybin-induced spiritual experience and insightfulness correlated with the lagged phase synchronization of 1.5-to 2.0-Hz oscillations between the RSC, parahippocampus, and lateral orbitofrontal area.

The extent of lagged phase synchronization within a network of deep cortical structures strongly and positively correlated with score on the insightfulness subscale of the 5D-ASC and spiritual experiences subscales of the 5D-ASC during the eyes-closed condition. Lagged phase synchronization of 1.5- to 4-Hz oscillations within a network comprising the RSC, parahippocampus, and lateral orbitofrontal area was associated with spiritual experiences and insightfulness.

These findings of Kometer et al. (2015) provide further evidence that decreased ongoing oscillations below 20 Hz, particularly / oscillations, may be a common mechanism of action of psychedelics. The decrease in lower frequency oscillations was found to be localized within an extended network that included the PCC, RSC, ACC, and parahippocampal regions, a network that strongly overlaps with the default mode network (DMN). Thus, psilocybin may modulate default mode functions by decreasing ongoing lower frequency oscillations within this network.

Lower frequency oscillations, particularly in the range, mediate rhythmic cortical inhibition of neuronal ensembles (see references in Kometer et al., 2015). The marked decrease in lower frequency oscillations observed in this study may indicate that psilocybin induces a shift of the resting excitation/inhibition balance toward excitation, which would be expected to disrupt the ordinary temporal structure of neuronal processes within the extended DMN.

Lagged phase synchronization was strongly associated with the psilocybin-induced state of consciousness, supporting the view that neural integration, rather than activity, underlies the state of consciousness. Scores of the spiritual experiences subscale of the 5D-ASC questionnaire were also associated with increased lagged phase synchronization of oscillations between parahippocampal regions and the RSC. Kometer et al., (2015) speculate that the neuronal network processes they identified may constitute a crucial pathway that can be modulated by serotonergic receptors to regulate mental health, a conclusion that would be consistent with some of the potential positive mental health outcomes discussed earlier in this section.

For decades, the media have largely portrayed psychedelics as extremely dangerous drugs; in fact, the classic serotoninergic psychedelics are generally considered very physiologically safe, certainly compared with opiates and psychostimulants. Jaffe (1985) stated, In man, deaths attributable to direct effects of LSD are unknown, and this statement remains true even today. Nonetheless, despite the relative physiologic safety of psychedelics, they can lead to serious psychologic consequences. In addition, as will be discussed later, some of the newer highly potent synthetic phenethylamine hallucinogens have proven to be unexpectedly toxic. This section will detail studies indicating that psychedelics can be safely used under supervision, and that few documented serious adverse effects occur even after recreational use. The discussion will then turn to some generally recognized adverse reactions, followed by case reports of some more serious and even fatal reactions to psychedelics. It should be emphasized that these latter fatalities, which are rare, have occurred after use of newer synthetic phenethylamine compounds, and not as a result of ingestion of LSD, psilocybin, mescaline, or DMT.

Analysis of early published reports on adverse reactions and long-term negative sequelae induced by classic psychedelics failed to identify significant adverse events; if long-term adverse effects from repeated use did occur, they were subtle or nonsignificant (Strassman, 1984; Halpern and Pope, 1999). Their reviews were based on reports from supervised clinical studies using pure drugs, so the same conclusions might not apply to recreational use of drugs with unknown identities or purity.

These substances do not lead to addiction or dependence and are not considered to be reinforcing (O'Brien, 2001). This is understandable when one realizes that the serotonergic hallucinogens do not have direct effects on brain dopaminergic systems, a pharmacology that appears essential for nearly all drugs that can engender dependence. Attempts to train animals to self-administer hallucinogens, an animal model that can predict abuse liability, have generally been unsuccessful.

Using 20012004 data drawn from the National Survey on Drug Use and Health (NSDUH), Krebs and Johansen (2013) recently evaluated possible associations between lifetime use of psychedelics and current mental health in the U.S. adult population. In a large sample of respondents, 13.4% reported lifetime psychedelic use. No significant associations were found between lifetime use of any psychedelic or past-year use of LSD and increased rate of any mental health outcome. Surprisingly, in several cases, use of psychedelics was associated with a lower mental health problem rate.

A statewide survey of the adult population in Colorado sought to determine whether psychedelic use was correlated with the lifetime risk of panic attacks (Bonn-Miller et al., 2007). No association was found between psychedelic use and panic attacks, but psychedelic abuse and dependence were significantly related to an increased lifetime risk of panic attacks. It should be noted that in this study, however, phencyclidine (PCP) was included in their survey as a psychedelic, and this substance, in contrast with the classic serotonergic psychedelics, can cause dependence.

Peyote (L. williamsii) is a small cactus that grows in the Southwestern United States and Northern Mexico. It contains the psychedelic compound mescaline and has been used for centuries by Native American populations in rituals and ceremonies. Mescaline is also found in the San Pedro and Peruvian Torch cacti, and these have also been used ceremonially. Although peyote is classified as a Schedule 1 controlled substance, members of the Native American Church have a legal exemption to use it in their religious services. Halpern et al. (2005) compared 61 Navajo Native American Church members who regularly ingested peyote with 79 individuals reporting minimal use of peyote, alcohol, or other substances. Cognitive function was assessed using the Rand Mental Health Inventory and 10 standard neuropsychological tests of memory and attentional/executive functions. The peyote-using group showed no significant deficits on the Rand Mental Health Inventory or on any of the 10 other tests used. For the peyote-using group, total lifetime peyote exposure was not associated with neuropsychological performance.

By contrast, recreational use of peyote has led to adverse events, although peyote exposures reported to poison control centers are relatively rare compared with other drugs of abuse. In 2007, for example, only 116 peyote or mescaline exposures were reported to U.S. poison control centers out of more than 2.4 million total drug exposures (Bronstein et al., 2008). Carstairs and Cantrell (2010) retrospectively reviewed the California Poison Control System electronic database between the years 1997 and 2008 for reports of cases involving adverse reactions to peyote or mescaline ingestion when it was the sole intoxicating agent. A total of 31 cases were identified that met their inclusion criteria. Life-threatening symptoms did not occur, and most exposures were associated with only mild to moderate clinical effects, which most commonly included tachycardia and central nervous system (CNS) effects. Symptoms typically resolved within 24 hours or less and did not usually require anything more than supportive measures or sedation. One case of a prolonged peyote-induced psychosis was reported by Lu et al. (2004), in which the psychosis resolved after sleep. The case involved a 54-year-old Native American man with no prior history of psychosis. He drank peyote juice during a healing ceremony and within a few hours became convinced that he was hunted by animal spirits. He was unable to sleep for 2 weeks, at which time he developed visual and auditory hallucinations of the spirits and became increasingly depressed. He was persuaded to enter a hospital, where he received trazodone to help him sleep. He fell asleep and slept for 15 hours, which led to complete resolution of his psychotic symptoms. The authors speculated that his psychosis was a result of his prolonged sleep deprivation.

Hasler et al. (2004) studied eight subjects given either placebo or 45, 115, 215, or 315 g/kg psilocybin (a very low, low medium, or high dose, respectively). Instruments used to assess psilocybin effects included the 5D-ASC, the Frankfurt Attention Inventory (FAIR), and the Adjective Mood Rating Scale (AMRS). Several physiologic and plasma hormones were also measured. Psilocybin dose-dependently increased all measures on the 5D-ASC. The medium and high doses of psilocybin led to a 50% reduction in performance on the FAIR test. The only scores that were increased on the AMRS were general inactivation, emotional excitability, and dreaminess. Hasler et al. (2004) found no evidence that psilocybin is hazardous with respect to somatic health.

Bouso et al. (2015) used magnetic resonance imaging to examine potential differences in cortical thickness in 22 Spanish regular users of ayahuasca, compared with 22 matched controls. Inclusion criterion for ayahuasca users was that they had used it at least 50 times in the 2 previous years. Subjects also were assessed using three neuropsychological tests, including the two-back test to assess working memory, the Wisconsin Card Sorting Test to assess executive function, and a switching task to assess set shifting. Personality was also assessed by self-report using the Spanish version of the Temperament and Character InventoryRevised questionnaire. Ayahuasca users scored significantly better than controls on several variables derived from the neuropsychological tests. No increased psychopathology or worse neuropsychological performance was observed in the ayahuasca group, consistent with findings reported earlier by Grob et al. (1996) for ayahuasca users who were members of the Brazilian church, the UDV. Indeed, ayahuasca users scored significantly better than controls on harm avoidance, and its subscale anticipatory worry, and significantly higher on self-transcendence. Cortical thinning was found for six brain areas in the ayahuasca group: the middle frontal gyrus, the inferior frontal gyrus, the precuneus, the superior frontal gyrus, and the PCC. By contrast, cortical thickening was seen in the precentral gyrus and the ACC. Correlation analysis revealed that lifetime use of ayahuasca was inversely correlated to cortical thickness in the PCC.

Although there is a general public perception that psychedelic drugs are dangerous, from a physiologic standpoint they are in fact one of the safest known classes of CNS drugs. They do not cause addiction, and no overdose deaths have occurred after ingestion of typical doses of LSD, psilocybin, or mescaline. Cohen (1967) and Jaffe (1985) have both stated that death due to direct LSD toxicity is unknown. Indeed, recreational users who have consumed massive doses of LSD have survived. For example, eight individuals who believed they had cocaine accidentally insufflated an extremely high dose of LSD. Their plasma LSD levels were reported as between 1000 and 7000 g/100 ml (recall that a typical total oral dose of LSD might be 100200 g). These individuals all became comatose, with hyperthermia, vomiting, light gastric bleeding, and respiratory problems. With hospital treatment, however, all eight survived and without apparent residual effects (Klock et al., 1974).

Although the classic psychedelics have not been directly responsible for causing death, the judgment of users is certainly impaired while under the influence of these drugs. This is a particular concern when hallucinogens are used in unsupervised settings. Users may believe that they are invincible or possess superpowers and may do things they would not normally consider, such as believing they can fly (Reynolds and Jindrich, 1985), jumping from buildings (Keeler and Reifler, 1967), or incurring severe ocular damage by prolonged staring at the sun (Schatz and Mendelblatt, 1973; Fuller, 1976).

Studerus et al. (2010) analyzed acute, short-, and long-term subjective effects of psilocybin in healthy humans. Again, using pooled raw data from eight double-blind placebo-controlled experimental studies conducted between 1999 and 2008, their analysis included 110 healthy subjects who had received between one and four oral doses of psilocybin (45315 g/kg body weight). Psilocybin dose-dependently induced profound changes in mood, perception, thought, and self-experience, but most subjects described the experience as pleasurable, enriching, and nonthreatening. Acute adverse reactions were characterized by strong dysphoria and/or anxiety/panic, but occurred only at the two highest doses of psilocybin in a relatively small number of subjects. All acute adverse drug reactions were successfully managed through interpersonal support and did not require psychopharmacological intervention. Follow-up questionnaires indicated no subsequent drug abuse, persisting perception disorders, prolonged psychosis, or other long-term impairment of functioning in any of the subjects. The results indicate that the administration of modest psilocybin doses to healthy, high-functioning, and well prepared subjects in the context of a carefully monitored research environment carries an acceptable level of risk.

The recent resurgence of interest in the clinical uses of psychedelics led Johnson et al. (2008) to propose appropriate procedures for using them in clinical practice. The guidelines they outline have certain parallels with ritual uses of hallucinogens by older indigenous cultures. In particular, Johnson et al. (2008) cite the need for structured use (expressed as ritual in indigenous use) and restrictions on use, including the need for guidance and appreciation of the powerful psychologic effects of hallucinogens (expressed as reverence in indigenous use). Psychedelic administration in humans results in a unique profile of effects and potential adverse reactions that need to be appropriately addressed to maximize safety. The primary safety concerns with psychedelics are largely psychologic rather than physiologic in nature. Somatic effects vary but are relatively insignificant, even at doses that elicit powerful psychologic effects. The proposed guidelines extend and complement the recommendations of Fischman and Johanson (1998) for high-dose hallucinogen research. The guidelines include 1) the presence of two monitors with some medical knowledge, knowledge of ASCs, and a degree of clinical sensitivity; 2) a physical environment that is safe, aesthetically pleasing, and comfortable; 3) careful subject preparation, including several meetings to establish rapport and trust with the monitors; 4) a detailed consent form and explanations of the study procedures, detailed discussions about the range of potential experiences, and time of onset and duration of the effects; and 5) an available physician in the event of an untoward medical reaction. Anyone contemplating carrying out a clinical research program with a psychedelic is strongly encouraged to read the detailed guidelines presented by Johnson et al. (2008).

Krebs and Johansen (2013) evaluated any association between lifetime use of psychedelics and current mental health in the adult population. Data were analyzed for 20012004 for 130,152 randomly selected NSDUH respondents; 21,967 respondents (13.4% weighted) reported lifetime psychedelic use. The authors found no significant association between lifetime use of any psychedelic and increased rate of any mental health outcomes. Indeed, they discovered that psychedelic use was associated with a lower rate of mental health problems in several cases. Johansen and Krebs (2015) subsequently analyzed a new data set of 135,095 randomly selected U.S. adults that included 19,299 users of psychedelics. Data were from the NSDUH for 20082011. As in their earlier study, the authors found no significant associations between lifetime use of psychedelics and increased likelihood of past-year serious psychologic distress, mental health treatment, depression, anxiety, or suicidal thoughts, plans, or attempts. Johansen and Krebs (2015) failed to find any evidence that use of psychedelics is an independent risk factor for mental health problems. Indeed, they report that lifetime use of psychedelics was associated with decreased inpatient psychiatric treatment.

Hendricks et al. (2014) analyzed data from 20022007 for 25,622 individuals charged with a felony in the Southeastern United States and under community corrections supervision in the Treatment Accountability for Safer Communities program, which is a case management intervention program for individuals with a history of substance involvement. The authors examined relationships between any hallucinogen use disorder (versus no hallucinogen use disorder) and all available sociodemographic and psychosocial variables. They report that any hallucinogen use disorder was associated with a decreased probability of supervision failure. They note the contrast with any cannabis, cocaine, alcohol, opiate, or amphetamine use disorder, each of which was associated with an increased probability of supervision failure. Their results suggest that hallucinogens may promote alcohol and other drug abstinence and prosocial behavior in a population with high rates of recidivism.

In a more recent report by Hendricks et al. (2015), the authors evaluated any relationship between use of a classic psychedelic and psychologic distress and suicidality among more than 190,000 U.S. respondents pooled from the NSDUH for 20082012. Lifetime use of a psychedelic was associated with significantly reduced odds of past-month psychologic distress, past-year suicidal thinking, past-year suicidal planning, or past-year suicide attempt. By contrast, lifetime use of other illicit drugs was associated with an increased likelihood of these outcomes. The authors suggest that classic psychedelics may hold promise in the prevention of suicide. These findings are consistent with the surveys of Krebs and Johansen (2013) and Johansen and Krebs (2015); in all three studies, the authors suggest that their data are not compatible with the highly restricted legal status of psychedelics and that more extensive clinical research is warranted.

Use of high doses of psychedelics can lead to vascular problems because the 5-HT2A receptor is associated with vascular smooth muscle contraction, platelet aggregation, thrombus formation, and coronary artery spasms (Nagatomo et al., 2004). Acute vasoconstriction caused by serotonin is usually shared by activation of 5-HT1B and 5-HT2A receptors; however, in intracranial arteries, only the 5-HT1B receptor mediates constriction (Kaumann and Levy, 2006). Both 5-HT2A and 5-HT1B receptors can mediate coronary artery spasm. 5-HT2A receptors also constrict the portal venous system, including esophageal collaterals in cirrhosis. Data from studies by Ootsuka et al. (2004) suggest that spinal 5-HT2A receptors contribute to sympathetically induced cutaneous vasoconstriction regulated by the raphe/parapyramidal neurons in the brainstem.

Balkov (2005) reports a fatal and nonfatal overdose after ingestion of the psychedelic phenethylamine 2,5-dimethoxy-4-bromoamphetamine (DOB) by two male individuals. Gas chromatographymass spectrometry was used to detect the presence of DOB in both gastric and urine samples of the two men. Although one subject survived, the other suffered convulsions and metabolic acidosis and died 6 days after admission.

Psilocybin, when administered in a controlled setting, has frequently been reported to cause transient, delayed headache, with incidence, duration, and severity increased in a dose-related manner (Johnson et al., 2012). Bickel et al. (2005) reported the case of a 25-year-old hepatitis Cinfected man, who presented with severe rhabdomyolysis and acute renal failure after Psilocybe mushroom ingestion. He later developed encephalopathy with cortical blindness. Respiratory and cardiovascular support, mechanical ventilation, continuous venovenous hemodialysis, and corticosteroid treatment led to improvement and the patient recovered completely over several months.

Psilocin was identified in the urine of a subject who was investigated for driving under the influence (Tiscione and Miller, 2006). The subject apparently did not exhibit any response to the crash of his automobile, seemingly unaware of the severity of his situation or immediate surroundings.

Although very rare, there have been reports of rhabdomyolysis after ingestion of LSD (Berrens et al., 2010). A newer tryptamine, 5-methoxy-N,N-diisopropyltryptamine (foxy) also produced rhabdomyolysis and transient acute renal failure in an otherwise healthy 23-year-old man (Alatrash et al., 2006).

Although many ergot alkaloids are known to produce vasospasm, especially after chronic use, LSD has rarely been associated with this adverse effect. Nevertheless, Raval et al. (2008) reported on a 19-year-old woman who experienced severe lower-extremity ischemia related to a single use of LSD 3 days prior to presentation. After intra-arterial nitroglycerin and verapamil failed, balloon percutaneous transluminal angioplasty therapy led to rapid clinical improvement in lower-extremity perfusion. As of the date of the report, the patient had not required a major amputation.

Sunness (2004) described a 15-year-old female patient with a 2-year history of afterimages and photophobia after a history of drug use that included LSD, marijuana, and other illicit drugs. She had discontinued LSD 1 year prior to examination. Although the author connected her visual problems with her prior LSD use, it is not at all clear from the report that her LSD use was the cause of her visual problem.

Bernhard and Ulrich (2009) reported a case of cortical blindness in a 15-year-old girl. She had headache and nausea 5 days after taking LSD and suddenly developed complete blindness in both eyes. The blindness persisted for 48 hours. Over the next 3 months, the subject had three more episodes of complete blindness that lasted 1236 hours, with no visual disturbances between episodes. The authors suggested that the temporary blindness might be a correlate of flashbacks caused by LSD.

Toxicity also has been noted for several of the so-called designer drugs. For example, Jovel et al. (2014) reported the case of a healthy young male individual who ingested 5-methoxy-N,N-diallytryptamine, one of the emerging new tryptamine-type research chemicals. The patient was admitted with extreme agitation, tachycardia, diaphoresis, and combativeness that required physical restraint and intravenous sedation, but the patient did recover.

Andreasen et al. (2009) reported a fatality involving the potent synthetic psychedelic phenethylamine compound 1-(8-bromobenzo[1,2-b; 4,5-b]difuran-4-yl)-2-aminopropane, known commonly as Bromo-Dragonfly. An 18-year-old woman was found dead after ingesting 1 ml of a hallucinogenic liquid. She and her boyfriend had ingested it between 10 and 11 PM on the previous evening and then they both fell asleep. On awakening at 5 AM the next morning, the womans boyfriend discovered that she was dead. Autopsy findings 3 days after her death included edema of the lungs, slight edema of the brain, spleen enlargement, irritation of the mucous membrane in the stomach, and ischemic changes in the kidneys. Her femoral blood concentration of the drug was 4.7 g/kg. The bottle containing the hallucinogenic liquid was recovered and analyzed by ultraperformance liquid chromatography time-of-flight mass spectrometry, high-performance liquid chromatography diode array detection, 1H nuclear magnetic resonance, and 13C nuclear magnetic resonance and found to contain a solution of almost pure Bromo-Dragonfly. Based on the solution concentration and the amount of solution consumed, it was estimated that she had ingested approximately 700 g. Although that would seem to be a relatively small dose, no other drugs were discovered in her system, including the absence of ethanol.

It is often difficult to establish whether the drug is pure or has been coingested with other unknown drugs of unknown purity. For example, Ovaska et al. (2008) reported a case of sympathomimetic toxicity in a patient who was reported to have ingested 2,5-dimethoxy-4-chloroamphetamine (DOC), yet toxicological screening showed the patient had ingested both DOC and MDMA.

Data for 2005 to 2006 from the Texas Poison Control Centers were reviewed for mushroom exposures (Barbee et al., 2009). There were a total of 742 exposures, which were all acute and intentional. Of those, 59 individuals were admitted to a hospital, with 17 requiring admission to a critical care unit. Nonetheless, only 10 of the admissions that were identified involved psilocybin. Of all of the admissions, major toxic reactions were uncommon, with no deaths reported.

One adverse effect of hallucinogen use, particularly associated with LSD use, is hallucinogen persisting perception disorder (HPPD). This term has displaced an earlier somewhat more nonspecific one known as flashbacks, which was a re-experiencing of one or more of the perceptual effects induced by a hallucinogen at some later time, after the acute drug effects had worn off. HPPD is composed of afterimages, perception of movement in peripheral visual fields, blurring of small patterns, halo effects, and macro- and micropsia long after the drug has been used.

The Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV), Text Revision lists the following three criteria for HPPD: A) re-experiencing, after the use of a hallucinogen, of one or more of the perceptual symptoms that were experienced while intoxicated with the hallucinogen; B) the symptoms in criterion A cause clinically significant distress or impairment in social, occupational, or other important areas of functioning; and C) the symptoms are not due to a general medical condition and are not better accounted for by another mental disorder.

Halpern and Pope (2003) noted that when LSD was used in a therapeutic or research setting, HPPD appeared less frequently than when LSD was used recreationally. The authors concluded, however, that some individuals, especially users of LSD, can experience a long-lasting HPPD syndrome with symptoms of persistent perceptual abnormalities reminiscent of acute intoxication. Nevertheless, the incidence of HPPD is very small given the many tens of millions of persons who have taken LSD, most often in a recreational setting. Litjens et al. (2014) provided a recent comprehensive review on the subject of HPPD. The actual incidence of HPPD is not known and depends on the prevalence of use in different countries, but epidemiologic information is scarce.

Hermle et al. (2008) reviewed MEDLINE data for 19972007, searching for reports of hallucinogen-induced psychosis, flashbacks, and HPPD. The authors reported that adolescent intoxication with psychedelic drugs rarely produced acute psychotic syndromes, further stating that The clinical relevance of flashback phenomena as a post-hallucinogenic psychiatric disorder has to be disputed.

Although LSD was most widely used and therefore has led to the greatest number of HPPD cases, it is clear that other hallucinogens also can evoke the syndrome. For example, Espiard et al. (2005) reported HPPD in an 18-year-old man after mixed intoxication with psilocybin and cannabis. The symptoms persisted for more than 8 months. Ikeda et al. (2005) reported flashbacks after use of 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT) by a 35-year-old man without a previous psychiatric history. He had used the substance six or seven times over 5 months but discontinued it after he had a bad trip, with anxiety, palpitations, auditory oversensitiveness, and visual distortions. Treatment with oral risperidone ameliorated his symptoms. Another case study described a 33-year-old woman who developed HPPD after LSD use for a year. Although treatment with antidepressants and risperidone did not ameliorate her symptoms, treatment with the antiseizure drug lamotrigine almost completely abolished her visual disturbances (Hermle et al., 2012).

Although the classic serotonergic hallucinogens are not recognized to be particularly toxic, a new class of substituted phenethylamines with toxic properties has recently become very popular as recreational drugs (Nikolaou et al., 2014). Unfortunately, there are now several reports of hospitalizations and fatalities attributed to these compounds (Poklis et al., 2013, 2014; Rose et al., 2013; Nikolaou et al., 2014; Tang et al., 2014; Walterscheid et al., 2014), but it is not clear whether deaths resulted from ingestion of lethal amounts of pure bulk drug or whether the drug has some inherent toxicity that is not normally associated with other psychedelics.

Suzuki et al. (2015) provided a comprehensive literature review of toxicities associated with NBOMe ingestion. The most common adverse reactions were agitation (including aggressiveness), tachycardia, and hypertension, with seizures reported in 40% of the patients. In the 20 individual cases they reviewed, 3 (15%) were fatalities.

The most potent of these new recreational chemicals are shown in , with potency increasing going from X = H to X = I.

For purposes of law enforcement the iodo compound (X = I; 25I-NBOMe) is presently considered by the U.S. Drug Enforcement Administration to be an analog of 2C-I [2-(4-iodo-2,5-dimethoxy)aminoethane], which is currently a Schedule 1 controlled substance. The procedure to classify 25I-NBOMe as a Schedule 1 substance has been initiated and it has been placed temporarily into Schedule 1 (Drug Enforcement Administration, 2013). Global interest in these compounds and closely related analogs has attracted increasing interest. For example, the European Monitoring Centre for Drugs and Drug Addiction has received a range of notifications from European Union member states about analytically confirmed nonfatal and fatal intoxications associated with 25I-NBOMe. This was followed by a risk assessment conducted by the European Monitoring Centre for Drugs and Drug Addiction Scientific Committee to assess health and social risks associated with the iodo analog (European Monitoring Centre for Drugs and Drug Addiction, 2014). In addition, the World Health Organizations Expert Committee on Drug Dependence reviewed the status of a range of new substances for its 36th meeting in June 2014, which included 25I-NBOMe and its 4-bromo and 4-chloro analogs (World Health Organization, 2014).

In the mouse head-twitch assay, 25I-NBOMe and a related analog were extremely potent in inducing this behavior, which was blocked by preadministration of the selective 5-HT2A antagonist M100907 [(R)-(+)-a-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-pipidinemethanol] (Halberstadt and Geyer, 2014). As discussed in the section on mouse models later in this review, the mouse head twitch has shown a high correlation with human psychedelic activity.

A relatively large series of 48 NBOMe-type compounds has been evaluated for affinity and function at 5-HT2 family receptors (Hansen et al., 2014). Their work was directed toward development of potential radioligands for in vivo PET imaging of 5-HT2A receptors that would be selective over 5-HT2C receptors. One compound was discovered that had approximately 100-fold selectivity for both affinity and function at the 5-HT2A versus 5-HT2C receptor. Their high affinity and relative selectivity for the 5-HT2A receptor has made some of these compounds useful as agonist ligands for in vivo PET imaging (Ettrup et al., 2010; Finnema et al., 2014).

Curiously, the NBOMe-type compounds do not appear to be orally active and are typically administered bucally, or by nasal insufflation. Their potency is so high that they are often distributed on blotter papers and marketed as being LSD. Users place the blotters against their gums to effect absorption. One hypothesis put forward to explain the lack of oral activity for these highly active compounds is a significant first-pass metabolic effect (Leth-Petersen et al., 2014). In that study, the microsomal stability of 11 phenethylamines and their N-benzylated congeners was studied using human liver microsomes. It was found that the N-benzylated compounds had a much higher intrinsic clearance than did the simple phenethylamines, and the authors hypothesized that their low hepatic stability was the reason for their lack of oral activity.

Stellpflug et al. (2014) reported a clinical case of a nonfatal overdose with 25I-NBOMe. They identified a major metabolite of the compound in the urine that had a concentration 80-fold higher than the parent drug. The subjects urine was treated with -glucuronidase and then analyzed using ultraperformance liquid chromatography electrospray ionization plus tandem mass spectrometry to identify a major metabolite with a mass that was one methyl group lower than the parent compound. Comparison of the full fragmentation pattern was then assessed and concluded to be an O-demethylated metabolite at the 2- or 5-position of the trisubstituted ring, but the investigators were not able to determine which position had been metabolized. They detected two other very minor metabolites that also appeared to be O-demethylated. The concentration of the unmetabolized parent 25I-NBOMe in the urine was 7.5 ng/ml, whereas the desmethyl metabolite was 600 ng/ml. This metabolite and the two other minor metabolites were not present in the urine in the absence of prior enzymatic treatment, indicating that they were all glucuronidated.

Most recently, Leth-Petersen et al. (2015) identified the basis for the high first-pass effect of NBOMe compounds and the likely basis for their inactivity after oral administration. Using in vivo studies in pigs, they determined that the 5-methoxy of the trisubstituted phenyl ring is rapidly O-demethylated. After intravenous administration of 25B-NBOMe [N-(2-[11C]methoxybenzyl)-2,5-dimethoxy-4-bromophenethylamine (Cimbi-36)] to a pig, analysis revealed that plasma levels of the parent drug rapidly declined, with a new metabolite rapidly appearing and accumulating in plasma. At the 30-minute mark, there was more than twice as much of this metabolite present in plasma as there was of the parent compound. This metabolite was definitively identified as the 5-O-glucuronide using liquid chromatography/mass spectrometry and chemical synthesis. Evidently, the highly hydrophobic nature of the N-benzyl phenethylamines readily targets them to the mixed function oxidases in the endoplasmic reticulum, where they are efficiently 5-O-demethylated and then very quickly glucuronidated.

Stanislov Grof characterized LSD as a powerful nonspecific amplifier of the unconscious (Grof, 1975). This empirical observation was based on his personal supervision of more than a thousand clinical administrations of LSD. Barr et al. (1972) also stated that the phenomena induced by LSD cannot be predicted or understood in purely pharmacological terms; the personality of the drug taker plays an enormous and critical role in determining how much effect there will be and of what particular type.

However, until we understand the fundamental nature of consciousness and its underlying neuronal substrates, as well as the unconscious, it will not be possible to scientifically test Grofs hypothesis. What can be discussed are the findings that point to involvement of specific receptors in certain brain areas that lead to the overt effects of psychedelics. In addition, recent brain scanning technologies, including PET, fMRI, EEG, magnetoencephalography (MEG), and pharmacological magnetic resonance imaging (phMRI), have also allowed the identification of key brain areas that must be involved in the actions of psychedelics.

One should keep in mind that the effects of psychedelics are highly variable and are not necessarily dose dependent. At low doses of LSD (e.g., <100 g), sensory and cognitive processes may be distorted and altered but the user generally remains aware that the effects are attributable to having ingested the drug. For the purposes of clinical investigations, such doses allow the use of various questionnaires, instruments, and interviews to determine the intensity and qualitative aspects of the drug effect. Even lower doses of LSD are popular for recreational use or group events in which the user wishes to remain in contact with their surroundings.

By contrast, high doses have a greater propensity to transport the user to an alternate reality, where they lose contact with their everyday environment. These occasions are often described as peak experiences, transcendent, or mystical and are profoundly altered states of consciousness. Users may feel that they have transcended time and space or encountered their concept of God, or they may feel that they have encountered otherworldly beings, feelings of being at one with the universe, reliving past memories, and so forth. With respect to medical value, this state of consciousness is most closely associated with dramatic therapeutic improvement. Although this phenomenon is more likely to occur after high doses of psychedelics, it can occur at nearly any dose if the set and setting have been optimized to promote such an ASC. These experiences are often characterized as among the most meaningful of the subjects life (e.g., see Griffiths et al., 2006) and can lead to persisting positive effects on attitudes, mood, and behavior.

It was only a decade after the discovery of the remarkable psychopharmacology of LSD that the presence of serotonin was demonstrated in the mammalian brain (Twarog and Page, 1953). A comparison of the chemical structures of LSD and serotonin (shown earlier) led to early hypotheses that the action of LSD was due to an interaction with serotonin systems in the brain. Ten years after the discovery of LSD, Gaddum (1953) reported that LSD antagonized the action of serotonin in peripheral tissues. Only 1 year later, Gaddum and Hameed (1954) and Woolley and Shaw (1954) independently proposed that the effects of LSD might result from serotonin receptor blockade in the CNS. Shaw and Woolley (1956) later modified their hypothesis to include the possibility that LSD might mimic the actions of serotonin. Numerous studies in the subsequent decade examined the possibility that LSD blocked the actions of serotonin, but it was a concept that proved untenable. It was clear, however, that LSD did have a potent effect on brain serotonin systems, elevating whole brain serotonin content (Freedman, 1961) and reducing brain levels of the major metabolite of serotonin, 5-hydroxyindole acetic acid (Rosecrans et al., 1967).

Ultimately, Andn et al. (1968) suggested that LSD might have direct agonist actions at serotonin receptors in the brain. Subsequently, studies from numerous laboratories provided support for that idea, with an initial focus on serotonin 5-HT1A receptors (see discussion in Nichols, 2004). When serotonin receptorselective antagonists became available, it was Glennon et al. (1983, 1984) who demonstrated in a rat drug discrimination model that the 5-HT2 antagonists ketanserin and pirenperone blocked the discriminative cue of a psychedelic. Further studies in numerous laboratories over the next 2 decades, primarily with rodents, then focused attention on the 5-HT2A receptor as the primary target for psychedelics. Agonist or partial agonist activity at the serotonin 5-HT2A receptor was ultimately concluded to be a necessary pharmacology for psychedelic effects, but it may not be sufficient to explain all of the qualitative differences between different drugs. As Ray (2010) pointed out, different molecules may also have significant affinity for other types of brain receptors.

The first definitive experiment pointing to the central role of the 5-HT2A receptor for the action of psychedelics in humans came from a clinical study by Vollenweider et al. (1998), who showed that the effects of psilocybin were blocked by the 5-HT2A receptorselective antagonist ketanserin or the atypical antipsychotic risperidone but were enhanced by the dopamine antagonist and typical antipsychotic haloperidol. These data provided the first evidence that psilocybin-induced effects in humans were due to 5-HT2A receptor activation. Subsequently, Vollenweider and colleagues have carried out several additional clinical studies, discussed later, of various aspects of the action of psilocybin and have shown that ketanserin can block most of those effects.

Kometer et al. (2012) carried out a randomized, double-blind study in 17 healthy human subjects. On 4 separate days, subjects received placebo, psilocybin (215 g/kg), the 5-HT2A antagonist ketanserin (50 mg, p.o.), or psilocybin plus ketanserin. Mood states were assessed, and behavioral and event-related potential measurements were used to quantify facial emotional recognition and goal-directed behavior toward emotional cues. Psilocybin was found to enhance positive mood and attenuate negative facial expression recognition. Furthermore, psilocybin increased goal-directed behavior toward positive compared with negative cues, facilitated positive but inhibited negative sequential emotional effects, and valence-dependently attenuated the P300 component. Ketanserin given alone had no effect but blocked the psilocybin-induced mood enhancement and decreased recognition of negative facial expression. This study demonstrated that psilocybin shifts the emotional bias across various psychologic domains and that activation of 5-HT2A receptors is central in mood regulation and emotional face recognition in healthy subjects. The authors suggest that their findings have implications not only for the pathophysiology of dysfunctional emotional biases, but they may also provide a framework to delineate the mechanisms underlying psilocybins putative antidepressant effects.

Quednow et al. (2012) investigated the role of 5-HT2A receptors in automatic (sensorimotor gating) and controlled (Stroop interference) inhibition processes in a model psychosis approach using psilocybin (260 g/kg) in 16 healthy humans pretreated either with the 5-HT2Aselective receptor antagonist ketanserin (40 mg) or placebo, using a placebo-controlled, crossover, counterbalanced, and double-blind design. They found that psilocybin-induced deficits in automatic and controlled inhibition were significantly attenuated by ketanserin. They also replicated their previous findings that most of the subjective hallucinogenic effects of psilocybin were abolished by ketanserin.

Kometer et al. (2013) assessed the effects of psilocybin (215 g/kg) on both oscillations that regulate cortical excitability and early visual evoked P1 and N170 potentials in 16 healthy human subjects. They employed a double-blind, placebo-controlled, within-subject, randomized design. Psilocybin generally significantly increased 5D-ASC scores after placebo pretreatment, but not after ketanserin pretreatment. Psilocybin strongly decreased both prestimulus parieto-occipatal power and decreased N170 potentials associated with the appearance of visual perceptual alterations, including visual hallucinations. Preadministration of the 5-HT2A antagonist ketanserin (50 mg) blocked all of these effects. The authors conclude that 5-HT2A receptor activation by psilocybin profoundly modulates the neurophysiological and phenomenological indices of visual processing. They further propose that 5-HT2A receptor activation may induce a processing mode in which stimulus-driven cortical excitation is overwhelmed by spontaneous neuronal excitation through modulation of oscillations.

Indirect evidence for a role of 5-HT2A receptors in mediating psychedelic-induced hallucinations comes from a study by Huot et al. (2010). In that study, [3H]ketanserin binding was used to compare 5-HT2A receptor density in postmortem brains of patients with Parkinsons disease (PD) who experienced visual hallucinations with the brains of PD patients who did not experience hallucinations. Six brains from patients with idiopathic PD who experienced visual hallucinations were compared with six PD patients without visual hallucinations and five healthy, age-matched controls. In PD patients with visual hallucinations, [3H]ketanserin binding was increased 45.6% in inferolateral temporal cortex compared with PD patients who did not have visual hallucinations. The authors suggest that increased 5-HT2A density in the inferolateral temporal cortex may be the basis for visual hallucinations in PD patients and that 5HT2A antagonists may alleviate this symptom.

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Psychedelics - PMC

Psychedelics (serotonergic hallucinogens) are powerful psychoactive substances that alter perception and mood and affect numerous cognitive processes. They are generally considered physiologically safe and do not lead to dependence or addiction. Their origin predates written history, and they were employed by early cultures in many sociocultural and ritual contexts. After the virtually contemporaneous discovery of (5R,8R)-(+)-lysergic acid-N,N-diethylamide (LSD)-25 and the identification of serotonin in the brain, early research focused intensively on the possibility that LSD and other psychedelics had a serotonergic basis for their action. Today there is a consensus that psychedelics are agonists or partial agonists at brain serotonin 5-hydroxytryptamine 2A receptors, with particular importance on those expressed on apical dendrites of neocortical pyramidal cells in layer V. Several useful rodent models have been developed over the years to help unravel the neurochemical correlates of serotonin 5-hydroxytryptamine 2A receptor activation in the brain, and a variety of imaging techniques have been employed to identify key brain areas that are directly affected by psychedelics. Recent and exciting developments in the field have occurred in clinical research, where several double-blind placebo-controlled phase 2 studies of psilocybin-assisted psychotherapy in patients with cancer-related psychosocial distress have demonstrated unprecedented positive relief of anxiety and depression. Two small pilot studies of psilocybin-assisted psychotherapy also have shown positive benefit in treating both alcohol and nicotine addiction. Recently, blood oxygen level-dependent functional magnetic resonance imaging and magnetoencephalography have been employed for in vivo brain imaging in humans after administration of a psychedelic, and results indicate that intravenously administered psilocybin and LSD produce decreases in oscillatory power in areas of the brain's default mode network.

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Psychedelics - PubMed