Three new articles in European Psychiatry journal

The Effect of 5-HT2A/1a Agonist Treatment On Social Cognition, Empathy, and Social Decision-making
K.H. Preller, T. Pokorny, R. Krähenmann, I. Dziobek, P. Stämpfli, F.X. Vollenweider
European Psychiatry March 28–31, 2015; Volume 30, Supplement 1, Page 22
Social cognition is a crucial factor influencing development, progress, and treatment of psychiatric disorders. However, social cognition skills are insufficiently targeted by current treatment approaches. In particular, patients suffering from depression show an increased negative reaction to social exclusion and deficits in empathy. The 5HT-1A/2A receptor agonist psilocybin has previously been shown to reduce the neural response to negative emotional stimuli. However, it is not known if this extends to negative social interaction and whether 5HT-1A/2A receptor stimulation induces changes in empathy. Given the clear need for improved treatment of socio-cognitive functioning in psychiatric disorders, it is important to better understand the neuronal and neuromodulatory substrates of social cognition.

In a double-blind, randomized, cross-over design we therefore investigated the neural response to ostracism after the acute administration of psilocybin (0.215mg/kg) and placebo in healthy volunteers using fMRI. Furthermore, we assessed cognitive and emotional empathy using the Multifaceted Empathy Test.

The neural response to social exclusion in the ACC – a brain region associated with ‘social pain”- was reduced after psilocybin administration compared to placebo. Furthermore, emotional empathy was enhanced after treatment with psilocybin while no significant differences were found in cognitive empathy.

These results show that the 5HT-1A/2A receptor subtypes play an important role in the modulation of socio-cognitive functioning and therefore may be relevant for the treatment of social cognition deficits in psychiatric disorders. In particular, they may be important for the normalization of empathy deficits and increased negative reaction to social exclusion in depressed patients.

5HT2a Receptors – a New Target for Depression?
D. Nutt
European Psychiatry March 28–31, 2015; Volume 30, Supplement 1, Page 35
Cortical 5HT2A receptors are largely expressed in layer 5 pyramidal neurons and appear to play a pivotal role in brain function in that they gate top-down descending inputs to local cortical microcircuits. There is evidence that they may play a role in depression in that the number of these receptors is increased in some people with depression and the augmenting action of atypical antipsychotics in depression is thought to be – at least in part – due to blockade of these receptors. We have explored this possibility by studying the effects of agonists at these receptors – the psychedelic druds psilocybin and LSD. We found they had profound effects to reduce brain activity particularly in regions that higly express the 5HT2A receptor such as the default mode network [DMN]. As this region is overactive in depression this may explain the improvements in mood that users of psychedelic often report. Based on these findings a study of psilocybin in resistant depression has been funded by the UK MRC and will start in early 2015.

The Effect of Serotonin Receptor Manipulation On Brain Networks and Its Impact On Emotion Regulation
R. Krähenmann
European Psychiatry March 28–31, 2015; Volume 30, Supplement 1, Page 21
Hallucinogenic substances have been used for millenia. Still, the scientific investigation into the effects and mechanisms of classical hallucinogens in humans has only commenced with the discovery of LSD by Albert Hofmann in 1943. In the 1960’s, there were more than a thousand clinical studies that reported promising therapeutic effects of LSD and psilocybin in psychiatric patients. Only recently, however, the neuropharmacological and neurobiological underpinnings of hallucinogenic drugs have undergone systematic investigations. Despite having different chemical structures, classical hallucinogens produce striking similar subjective and behavioral effects in both animals and humans. Activation of the serotonin 2A (5-HT2A) receptor is a core feature in hallucinogenic pharmacology. Recent neuroimaging studies have begun to elucidate the brain mechanisms underlying hallucinogen-induced changes of thought, perception, and mood. Among the many networks involved in hallucinogen-related states of consciousness, the prefrontal cortex and the limbic regions appear to be especially relevant to the putative antidepressant effects of classical hallucinogens. Furthermore, hallucinogens may foster neuroplastic adaptations within cortico-subcortical brain networks. This appears to be a promising mechanism with regard to future clinical studies into the effects of classical hallucinogens in depression and anxiety.

Psilocybin treatment for PTSD: a Clinical Trial protocol

There have been numerous studies published to date that provide an overwhelming rationale for conducting a Clinical Trial utilizing psilocybin to treat PTSD.  Below is a list of PTSD related issues and the recent research that has provided ample evidence to support such a trial and could function effectively as a key aspect in someone's protocol:

PTSD.  There has been a recent animal model study demonstrating the efficacy of low-dose psilocybin in treating PTSD as well as a 1968 case report on a long-standing chronic pain/depression/PTSD patient treated successfully with psilocybin. The animal model study also demonstrated psilocybin's ability to promote hippocampal neurogenesis.

Depression. A recent Lancet Psychiatry article has shown psilocybin to be highly effective for patients with treatment resistant depression.

No serious or unexpected adverse events occurred during the course of the study and all patients demonstrated a reduction in depression severity at 1 week that was sustained in the majority for 3 months. Eight (67%) of the 12 patients achieved complete remission at 1 week and seven patients (58%) continued to meet criteria for response at 3 months, with five of these (42%) still in complete remission. This is quite remarkable since the equivalent remission rate for SSRIs is around 20%. Unlike current anti-depression medications, psilocybin does not have to be given daily, perhaps only once or twice as in this study.

Social isolation/exclusion. Numerous studies have demonstrated improvement of social cognition deficits in various psychiatric disorders after psilocybin administration compared to placebo. Furthermore, emotional empathy was enhanced after treatment with psilocybin as well as a decrease in social exclusion and social stigmatization.

Addictions. A recent pilot study  involving 15 psychiatrically healthy nicotine-dependent smokers (10 males; mean age of 51 years), with a mean of six previous lifetime quit attempts, and smoking a mean of 19 cigarettes per day for a mean of 31 years at intake demonstrated an 80% abstinence at 6-month follow-up. The observed smoking cessation rate substantially exceeds rates commonly reported for other behavioral and/or pharmacological therapies (typically < 35%).

There are currently three Clinical Trials examining psilocybin's ability to help individuals with addiction related disorders.

Existential distress.  To me, this is key.  Existential distress is, in my opinion, what gives rise to PTSD in the first place. When a Warfighter heads out on patrol day after day not knowing if he will return, this creates a definite existential distress.  Why some develop PTSD as a result of this experience and others do not is not known but I suspect levels of pre-existing systemic inflammation may play a key role. A future study will examine psilocybin's ability to decrease inflammation in the brain.

Two recent studies. one performed at NYU, the other at Johns Hopkins that provided psilocybin to cancer patients with life-threatening in an attempt to mitigate their existential distress will soon be published. Preliminary results have been provided by NYU and by Johns Hopkins.  It is reasonable to infer that what is effective for these patients will be effective for those with PTSD as well.

Anger/violence. A recent study from the Journal of Psychopharmacology looked at 302 men ages 17-40 in the criminal justice system. Of the 56 percent of participants who reported using hallucinogens, only 27 percent were arrested for later IPV as opposed to 42 percent of the group who reported no hallucinogen use being arrested for IPV within seven years.

Dr. Peter Hendricks, one of the study authors, commented that "A body of evidence suggests that substances such as psilocybin may have a range of clinical indications," he said. "Although we're attempting to better understand how or why these substances may be beneficial, one explanation is that they can transform people's lives by providing profoundly meaningful spiritual experiences that highlight what matters most. Often, people are struck by the realization that behaving with compassion and kindness toward others is high on the list of what matters."

Suicidal ideations. Two previous studies have demonstrated psilocybin's potential effectiveness in preventing suicides.  A 2013 article in PLoS One used data from over 130,000 individuals drawn from years 2001 to 2004 of the National Survey on Drug Use and Health and demonstrated no significant associations between lifetime use of any psychedelics, lifetime use of specific psychedelics (LSD, psilocybin, mescaline, peyote), or past year use of LSD and increased rate of any of the mental health outcomes. Rather, in several cases psychedelic use was associated with lower rate of mental health problems to include suicide.

A 2015 article from the Journal of Psychopharmacology by researchers from the University of Alabama and Johns Hopkins demonstrated lifetime classic psychedelic use was associated with a significantly reduced odds of past month psychological distress (weighted odds ratio (OR)=0.81 (0.72-0.91)), past year suicidal thinking (weighted OR=0.86 (0.78-0.94)), past year suicidal planning (weighted OR=0.71 (0.54-0.94)), and past year suicide attempt (weighted OR=0.64 (0.46-0.89)), whereas lifetime illicit use of other drugs was largely associated with an increased likelihood of these outcomes.

Anxiety. Numerous studies have demonstrated a decrease in anxiety in those who have taken psilocybin with the proper Set and Setting. One specific 2011 study from UCLA titled Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer demonstrated a significant reduction in anxiety at 1 and 3 months after treatment as measured by the State-Trait Anxiety Inventory and the Beck Depression Inventory revealed an improvement of mood that reached significance at 6 months in 12 adults with advanced-stage cancer and anxiety.

In conclusion, with the possible exception of Ayahuasca, there exists no other known compound that has shown effectiveness with all the various issues manifested in those afflicted by PTSD.  It is less toxic than caffeine, not addicting and has to be given only once or twice. This is an excellent opportunity for the DoD and/or VA to conduct a Clinical Trial utilizing psilocybin to treat PTSD in an attempt to decrease suicides in active duty military and veterans, to take whatever steps necessary to find the best treatment for this debilitating condition.

Magic mushrooms and blueberries: a recipe for treating PTSD

Individuals with PTSD frequently report experiencing social exclusion and social stigmatization. Social isolation will further compound their traumas, whether the nature of their trauma is mental, physical, moral or a combination. Such was especially the case with Veterans returning from the unpopular war in Vietnam.  Unlike the more recent excursion in the Middle East which had much support following the 9/11 atrocities, the Vietnam veterans were subject to significantly more indifference, rejection and criticism.

Now an exciting new study from the University Hospital of Psychiatry Zurich, authors of numerous psilocybin studies and the Institution that gave rise to Carl Jung, whose work had a profound influence on Joseph Campbell, have published an article titled Effects of serotonin 2A/1A receptor stimulation on social exclusion processing (PNAS April 2016).

In their study, the University of Zurich researchers demonstrated that psilocybin had a positive effect on brain regions to include the dorsal anterior cingulate cortex by stimulation of specific serotonin receptors. These findings may be relevant to the normalization of negative social interaction processing in psychiatric disorders characterized by increased rejection sensitivity. Plus this reduction of psychological pain and fear can be of great importance in facilitating the therapist-patient relationship and the psychotherapeutic treatment of formative negative social experiences.

Psilocybin has demonstrated an ability to increase subjective feelings of connection with the environment and other people, which may lead to stronger and more empathetic connections between people. This in turn may help reduce “egocentric bias” and “render negative experiences more bearable,” the authors of the study wrote.

In another recent article (FASEB April 2106) detailed in MedicalXpress and titled Eating blueberries could regulate genetic and biochemical drivers of depression and suicide the benefits of compound(s) in blueberries that help to ameliorate the depression and suicidal tendencies often associated with PTSD is described.  This is good news since available medical treatments offer only limited relief and a Clinical Trial utilizing psilocybin to treat PTSD, which offers the most promise of any known compound, has yet to be initiated.  Johns Hopkins, this is in your ballpark.  Time to hit a homerun.

The researchers from Louisiana State University (LSU), working with animal models, have found that eating blueberries could help to reduce the genetic and biochemical drivers behind depression and suicidal tendencies associated with the disorder. Specifically, eating blueberries increase the expression of the gene SKA2 which is found to be decreased in those with those who are depressed and may show suicidal tendencies. The rat's blueberry diet was equivalent to about two cups per day for a person which, with the present price of blueberries, would be quite expensive.

Previously the researchers found that rats with the PTSD-like experience fed a blueberry-enriched diet showed increased levels of the signaling chemical serotonin in the brain. Psilocybin has a positive effect on the serotonergic system as well so there may be a good synergy here.

It was LSU researchers who were the first to isolate DMT (dimethyltryptamine) from the mammalian pineal gland which I have written about previously.

Of course eating 2 cups of blueberries a day will probably not cure anyone of PTSD but it does help to highlight the importance of diet, along with exercise and stress reduction towards mitigating the effects of PTSD.  But then again, if I ever have the opportunity to be part of a therapeutic session of psilocybin for PTSD, I'll be sure to follow it up with a big bowl of juicy, organic blueberries!

“There are moments when one feels free from one’s own identification with human limitations and inadequacies ... Life and death flow into one, and there is neither evolution nor destiny; only being.” — Albert Einstein

Novel psychopharmacological therapies for psychiatric disorders: psilocybin and MDMA

The article titled Novel psychopharmacological therapies for psychiatric disorders: psilocybin and MDMA was published in The Lancet Psychiatry on 5 April 2016. The article reviews the encouraging use of psilocybin and MDMA (I am personally opposed to the use of MDMA to treat PTSD as discussed below) for various psychiatric disorders and was written by Psychiatrists from UCLA and the University of South Carolina.

Below is the Summary from the 5 April 2016 article in The Lancet Psychiatry:

4-phosphorloxy-N,N-dimethyltryptamine (psilocybin) and methylenedioxymethamfetamine (MDMA), best known for their illegal use as psychedelic drugs, are showing promise as therapeutics in a resurgence of clinical research during the past 10 years. Psilocybin is being tested for alcoholism, smoking cessation, and in patients with advanced cancer with anxiety. MDMA is showing encouraging results as a treatment for refractory post-traumatic stress disorder, social anxiety in autistic adults, and anxiety associated with a life-threatening illness. Both drugs are studied as adjuncts or catalysts to psychotherapy, rather than as stand-alone drug treatments. This model of drug-assisted psychotherapy is a possible alternative to existing pharmacological and psychological treatments in psychiatry. Further research is needed to fully assess the potential of these compounds in the management of these common disorders that are difficult to treat with existing methods.

In a previous post, I mentioned that Jeffrey A. Lieberman, MD, currently chairman of psychiatry at the Columbia University College of Physicians and Surgeons and director of the New York State Psychiatric Institute and former president of the American Psychiatric Association, has endorsed research on psychedelic compounds in a Medscape post (free registration) stating they "need to be studied in an intensive and extensive way". Some passages from Dr. Lieberman's post for those without Medscape access:

• We have had a nearly 50-year hiatus in any serious investigation, except for some heroic investigators at a few universities, primarily in Europe but also in the United States.
• These psychedelic drugs clearly are pharmacologically active, have profound effects, could be useful for therapeutic purposes, and need to be studied in an intensive and extensive way before an informed determination can be made. 
• I believe that the scientific investigation of mind-altering psychedelic drugs in the 1960s and '70s was a truncated but promising avenue of research, and that these medications, these drugs, could have significant value for a variety of indications if studied adequately.

It is obvious that Psychiatry is showing increasing support for the use of psychedelics as therapeutic tools to treat various mental health issues.

The Lancet series of journals has a history dating back to 1823 with The Lancet being ranked second among general medical journals, (with an impact factor of 45), after The New England Journal of Medicine (impact factor of 56) according to the 2014 Journal Citation Reports. Johns Hopkins, which dates back to 1876, has been ranked among the top 10 in US News' Best National Universities Rankings and among the top 20 in a number of international rankings.

I mention both of theses highly regarded institutions due to the newly published Johns Hopkins-Lancet Commission on Public Health and International Drug Policy article and its call for non-violent minor drug offenses including use, possession, and petty sale, to be decriminalized internationally due to the serious detrimental effects on the health, wellbeing and human rights of drug users and the wider public. The article is titled 'Public health and international drug policy' and was published on 2 April 2016 in The Lancet. Authors of this study are from institutions to include Yale University, Columbia University, the UN, Johns Hopkins, UCSF, UCSD, and many prominent international Universities.

The article summary in MedicalXpress concludes:

• A number of countries, mostly in Europe, have decriminalized minor drug offenses with good results, including more ability to reach people with health and social services and better capacity of the police to focus their efforts on high-level trafficking offenses. Drug use, low-level possession and petty sale of drugs should not be subjected to criminal penalties, including prison sentences, and health and social services for drug users should be improved.
• People who use drugs have been shown in many countries to be keen to take advantage of prevention and treatment services, but they are often systematically excluded on the grounds of being thought unworthy or unreliable as patients. Governments should invest in comprehensive HIV, TB and hepatitis C services for people who use drugs. While sexually transmitted HIV is on the decline globally, HIV transmission linked to drug use is increasing. Comprehensive HIV, hepatitis C and TB services should be scaled up in prisons as well as in the community.
• Overdose deaths can be greatly reduced by ensuring that people who use opioids have good access to medication-assisted treatment and by ensuring that people who use drugs or are likely to witness overdoses have access to and are trained in delivering naloxone, a medicine that reverses overdose.
• Increasing numbers of national governments and sub-national jurisdictions (such as US states) are introducing legally regulated markets of cannabis. Governments and research bodies should see these as opportunities for rigorous scientific research and evaluation so best practices for public health and safety can be identified and emulated.
• Over-zealous drug control policies are limiting access to pain medications for legitimate clinical use in too many countries. Governments must find balanced policies for ensuring that people have access to controlled medicines such as opioids for the relief of pain while still impeding non-medical use of these substances.

While the focus of the Lancet article is on narcotics, this drug policy review details the futilities of the current approach to curtailing illicit drug use. Psilocybin is currently classified as a Schedule I drug by the DEA and the FDA based on the following criteria:

1. The drug or other substance has a high potential for abuse.
2. The drug or other substance has no currently accepted medical use in treatment in the United States.
3. There is a lack of accepted safety for use of the drug or other substance under medical supervision

As for the abuse potential, #1 on the list, notice the graph below which clearly shows psilocybin to be relatively free of dependency and toxicity issues.  Also notice how MDMA has a much higher dependency and toxicity potential than psilocybin.  So, let's scratch #1 off the list.  It just should not be there.

Data source is Gable, R. S. (2006). Acute toxicity of drugs versus regulatory status. In J. M. Fish (Ed.), Drugs and Society: U.S. Public Policy, pp.149-162, Lanham, MD: Rowman & Littlefield Publishers

Psilocybin, besides being less toxic than caffeine and lacking in dependency potential, has shown profound potential in treating addiction problems.  A small pilot study at Johns Hopkins enabled 12 of 15 (80%) subjects to remain tobacco free for 6 months.  Prescription medications such as Chantix, the most potent aid for smoking cessation, have a success rate of about 35% at six months. There are currently 2 other Clinical Trials utilizing psilocybin to treat addiction disorders: one for alcohol dependence and one for cocaine addiction.

As stated in the Lancet Psychiatry study that led off this post, psilocybin has shown encouraging potential for treating various mental health issues.  One of the most profound potentials of psilocybin is in treating the existential distress experienced by cancer patients or anyone with a life threatening diagnosis or having faced life threatening experiences (PTSD). So let's scratch #2 of the list as well.

As for #3, lack of accepted safety for use under medical supervision, all of the recent well-controlled, ethical Clinical Trials completed and ongoing have not shown any serious adverse effects.  So, lets take #3 off the list as well.  Where does that leave us now?

In my opinion, there should be a class-action lawsuit against the DEA and FDA forcing them to take hallucinogens off the Schedule 1 status to enable more ethical research to proceed for psilocybin.  

In an interview with John Ehrlichman, advisor to US President Richard Nixon, Ehrlichman explains that the War on Drugs was not to protect the American public but was ‘really about’ hurting ‘the antiwar Left, and black people’, and openly admits, ‘Did we know we were lying about the drugs? Of course we did’ (Baum, 2012).  We can now see how this policy was not to protect the American Public and in fact has hurt us. A recent (5-13-2016) article in Medical Daily titled 'The War on Drugs May Have Misrepresented Psychedelics; Here's Why That Matters' by Stephanie Kossman does an excellent job addressing this issue.

My objection above to the use of MDMA is first of a philosophical nature.  MDMA is synthetic. Psilocybin is natural and has a history of use for spiritual growth going back thousands of years. Second, MDMA displays an unacceptable degree of toxicity that psilocybin does not have.

My review of the research literature shows there are at least as many reasons not to use MDMA for PTSD as there are for its use.  By running a trial for PTSD using MDMA instead of psilocybin researchers are settling for use of an inferior compound with high levels of toxicity and dependence issues over psilocybin. I'm certain many researchers in the field share the same sentiments but are unwilling to speak up.

A case in point is the April 2016 publication of two articles, one involving psilocybin, the other MDMA.

In the article titled Meta-analysis of molecular imaging of serotonin transporters in ecstasy/polydrug users, researchers found that ecstasy users demonstrated significant reductions serotonin in the brain. which can impact appropriate emotional reactions to situations. They also noted that the effects on the serotonin system may underlie the cognitive deficits observed in ecstasy users.  MDMA is a drug that should be given a second look before using it in any Clinical Trials due to its neurotoxicity.

One the other hand, the April 2016 psilocybin study, Effects of serotonin 2A/1A receptor stimulation on social exclusion processing, has been given positive reviews by the media and demonstrates a keen applicability for treating PTSD.  It appears as though researchers have bet on the wrong horse so far in that there is are Clinical Trials using MDMA in the treatment of PTSD but none for psilocybin.

It is possible the MDMA researcher's goal leans more towards finding a use for MDMA than in finding the best treatment for PTSD which is unfortunate.

Prominent institutions such as Johns Hopkins have discussed using psilocybin in a Clinical Trial to treat PTSD but have yet to act on this idea.  In my opinion, the reason for this inaction is twofold. First, they realize MDMA is already involved in a Clinical Trial to treat PTSD and they do not want to step on those researcher's toes or to have two controversial trials treating PTSD.

The second reason is that, to my knowledge, none of the primary players in psilocybin research are military veterans.  I could be mistaken about this but have seen no mentions in the many CVs I've perused online to indicate such an association. If they had military experience, it would serve as an impetus to head in that direction. They should keep in mind that their right to perform their current research depends on the freedom we are currently enjoying in our society, a freedom many have died for.

If we are not careful, the current path of overpopulation and environmental destruction (Nature 6 April 2016) we are on could very soon put great stress on our way of life. Psilocybin may help us navigate our way out of this mess by contributing to a society with more openness and is less egocentric.