John J. Miller, MD

Let me begin with my conclusion: The current clinical use of pharmacogenomic testing in psychiatry to determine a metabolic enzyme’s activity to choose a medication to prescribe is not evidence based.

The history of medicine, and of the edifice of science upon which much of medicine is built, is a never-ending work in progress that involves the continued evolution of hypotheses and rewriting of paradigms as they are disproven and become outdated. In 1869, Dmitri Mendeleev, PhD, a brilliant Russian chemist, submitted the first periodic table of the elements to the scientific community; this was a quantum leap forward in understanding the physical nature of reality. Over the next 25 years, scientists bragged about how the physical nature of reality was finally understood, and all that was left was filling in the gaps.

This paradigm was rocked in 1895 when German physicist Wilhelm Röntgen, PhD, discovered x-rays. This began the new chapter of the electromagnetic spectrum of radiation, which culminated in our understanding of discrete bands with unique properties and energies: radio waves, microwaves, infrared, visible light, ultraviolet, x-rays, and gamma rays. This new science enabled the development of the atomic bomb.

My favorite story about medicine’s changing understanding revolves around the cause of gastric ulcers. When I was in medical school, the etiology was believed to be due to stress and/or spicy foods. In the early 1980s, J. Robin Warren, MBBS, and Barry J. Marshall, MB, BS, AC, FRACP, FRS, FAA, of Australia discovered 

residing in the stomachs of patients with ulcers and gastritis; they eventually confirmed that this bacterium was the etiologic agent for these disorders, and ultimately received the 2005 Nobel Prize in Physiology or Medicine.

 They ultimately transformed the treatment of gastritis by proving antibiotics were an effective treatment in most cases.

Since my college years I have always enjoyed a passion for molecular genetics. In the early 1990s, I reveled in the growing understanding of the cytochrome P450 (CYP450) metabolic enzyme system and the subsequent identification and classification of the 57 human isoforms. In psychiatry, 5 CYP450 enzymes surfaced as significant for many medications: CYP450 1A2, 2C9, 2C19, 2D6, and 3A4. Further research revealed that 2 of these enzymes had significant genetic polymorphisms: CYP2D6 with approximately 100 different alleles, and CYP2C19 with approximately 35 alleles.

With the complete sequencing of the human genome in 2003, the field of pharmacogenomics exploded. Over the ensuing decade, DNA sequencing technology continued to improve, and the varying gene alleles of the CYP450 enzymes, especially CYP450 2C19 and 2D6, could be identified for a 

 This led to the development of pharmacogenetic testing on a commercial scale, with the accompanying message by invested labs that the genetic phenotypic information for metabolic enzymes allowed the psychiatric clinician to make a more informed choice of which antidepressant or antipsychotic would be best for their patient based on the information from the patient’s 2 sequenced genes for each metabolic enzyme.

The Clinical Pharmacogenetics Implementation Consortium was established in 2009 to vet pharmacogenomic data as clinically actionable versus simply interesting.

 Yet this organization and its database has been virtually ignored by commercial labs and clinical prescribers who choose to believe all the results in pharmacogenomic test reports are clinically accurate. For instance, a recent review concluded, “Genotype-assisted forecasts cannot therefore be used with confidence to replace actual phenotype measurements.”

 For a more comprehensive discussion of this current controversy, please see my 

Psychiatric Pharmacogenomic Testing: The Evidence Base

Unfortunately, the anticipated exciting discoveries aimed to better understand and treat human disease as a result of completed sequencing of the human genome never really materialized. Rather, geneticists learned that the sequenced 3 billion base pairs in the human genome was simply a static code. This code contains all of the genetic information to create a complete person, but it served more as data on a computer’s hard drive that needed complex software to decipher, from conception until death.

Over the past 20 years, the exploding field of epigenetics has opened an entirely new chapter in science and has created many more questions than it has answered. We have learned it serves as the software. (Please see my 

When the new field of epigenetics collided with the well-established field of pharmacogenomics, the result was a novel explosion of information and understanding that is helping to shed light on how these fields are intimately interwoven into the human genomics story. In 2013 at the 2nd International Genomic Medicine Conference, it was concluded

Pharmacogenomics deal with various biological factors related to drug metabolism including drug transporters, the contribution of receptors and drug metabolizing enzymes with polymorphisms that affect the drug response in a variety of diseases; all of these parameters are under epigenetic control.

It turns out that epigenetic modifications due to environmental factors, life stress, disease states, and epigenetic heritability play a significant role on the ultimate expression of a particular gene and will determine that gene’s phenotype—not the unchanging gene’s DNA sequence that pharmacogenomic testing reports use to determine a patient’s putative phenotype. These epigenetic modifications include DNA methylation of the gene’s promoter sequence, the addition of various chemical structures (such as the covalent addition of an acetyl or methyl group) to histones, and noncoding microRNAs.

Epigenetics and Gene Production Plasticity

It is well established in humans that, throughout the course of an individual’s life, numerous events, environmental conditions, and processes can reversibly add or remove methyl groups from a gene’s promoter sequence. The more methyl groups that are added, the more gene expression is shut down, even to the point that the gene expression can be turned off. Later, the methyl groups can be removed from the promoter sequence and, as they are, the gene will start to be transcribed once again. Histone modifications can serve to increase access to a gene to increase its gene product expression, or to further hide the gene from the transcription machinery. Finally, microRNAs can neutralize a posttranscriptional mRNA gene product effectively 

One group used mice to test their hypothesis that epigenetic gene regulation of CYP450 enzymes involved in drug metabolism could explain the reduced liver function in aging that increases the risk of adverse drug reactions. The authors initially reviewed the literature on epigenome-wide studies of human blood, and they determined that CYP450 2E1 demonstrates the most epigenetic changes with age in humans. Mouse livers from mice aged 4 to 32 months were assayed for clearance of chlorzoxazone—a CYP2E1 specific probe—and compared the clearance with epigenetic changes in mouse CYP2E1 gene with age. They concluded that 

 in mice may influence hepatic drug metabolism function.

If pharmacogenomic testing accurately predicted the functional phenotype of CYP450 and other metabolic enzymes, it would be of great value for the practicing clinician. However, our current understanding of the unchanging DNA sequence of our personal 3 billion base pair genome does not translate into a fixed and unchanging phenotype based on the genotype.

 provided strong evidence that an individual’s functional phenotype at any point in time can be quite different from what the DNA genetic sequence genotype would predict. In their study, patients on venlafaxine extended release (ER) were genotyped for CYP2D6 by traditional pharmacogenomic testing. After up to 8 weeks on venlafaxine ER, patients were phenotyped for CYP2D6 by the established protocol of serum drug level ratios of O-desmethylvenlafaxine and venlafaxine. With this assay, CYP2D6 poor metabolizer phenotype was defined as O-desmethylvenlafaxine to venlafaxine ratio of less than 1.

Although only 4% (35/900) of patients were genotypic CYP2D6 poor metabolizers, 27% (243/900) were phenotypic CYP2D6 poor metabolizers based on the serum level assay. The authors concluded that phenoconversion to CYP2D6 poor metabolizer status occurred in 209 of 865 individuals (24%) with a simultaneous pharmacogenomic test documenting them as CYP2D6 non–poor metabolizer genotype.

Many possibilities exist to explain this discrepancy. The list of putative causes of this dramatic phenoconversion from non-poor metabolizer to poor metabolizer is beyond the scope of this editorial. However, it is entirely possible that epigenetic changes to the individual’s 2 CYP450 2D6 genes may explain some of these phenoconversions. From our current understanding of epigenetic processes on the stable and unchanging DNA genome, the promoter sequence of an individual’s 2 CYP450 2D6 genes could have been highly methylated, hence decreasing gene production of the enzyme CYP450 2D6. For another individual, histone modifications could be decreasing transcription access to these same genes. Additionally, one person may have triggered excessive production of microRNA that neutralized and effectively eliminated the mRNA transcription product that would have otherwise been further processed into a CYP450 2D6 enzyme.

As medicine and science continue to evolve and our hypotheses continue to get refined and updated, more surprises most certainly await us. The collision of epigenetics with pharmacogenomics has once again humbled us.

is medical director, Brain Health, Exeter, New Hampshire; Editor in Chief,

; staff psychiatrist, Seacoast Mental Health Center, Exeter; Consulting Psychiatrist, Exeter Hospital, Exeter; Consulting Psychiatrist, Insight Meditation Society, Barre, Massachusetts.

1. Allen P. What’s the story H. pylori?. Lancet. 2001;357(9257):694.

2. de Leon J, Susce MT, Johnson M, et al. DNA microarray technology in the clinical environment: the AmpliChip CYP450 test for CYP2D6 and CYP2C19 genotyping. CNS Spectr. 2009;14(1):19-34.

3. Relling MV, Klein TE, Gammal RS, Whirl-Carrillo M, Hoffman JM, Caudle KE. The Clinical Pharmacogenetics Implementation Consortium: 10 Years Later. Clin Pharmacol Ther. 2020;107(1):171-175.

4. Waring RH. Cytochrome P450: genotype to phenotype. Xenobiotica. 2020;50(1):9-18.

5. Rasool M, Malik A, Naseer MI, et al. The role of epigenetics in personalized medicine: challenges and opportunities. BMC Medical Genomics. 2015;8(suppl 1):S5.

6. Zanger UM, Klein K, Thomas M, et al. Genetics, epigenetics, and regulation of drug-metabolizing cytochrome P450 enzymes. Clin Pharmacol Ther. 2014;95(3):258-261.

7. Kronfol MM, Jahr FM, Dozmorov MG, et al. DNA methylation and histone acetylation changes to cytochrome P450 2E1 regulation in normal aging and impact on rates of drug metabolism in the liver. GeroScience. 2020;42(3):819-832.

8. Preskorn SH, Kane CP, et al. CYP450 2D6 phenoconversion is common in patients being treated for depression: implications for personalized medicine. J Clin Psychiatry. 2013;74(6):614-621. ❒

Articles

The history of medicine is a never-ending work in progress. What is the next chapter in the psychiatry and genetics story? 

Epigenetics Collide With Pharmacogenomics

I never met my paternal grandfather. We share the same name, hair pattern, and interests, and I am told we have similar personality characteristics. He died, aged 56 years, from small cell lung carcinoma before I was born. I treasure the stories shared by my father about him, as well as his diary from his tour of France and Germany in 

My grandfather had volunteered to go to the European front as long as he did not have to kill anyone, and so he served on the front lines as a medic in the American Expeditionary Forces, Third Division. He experienced the brutal trench warfare we have all seen dramatized in movies. My grandfather was gassed by the Germans on several occasions, and he returned home with no hair on his body. The secondhand stories shared by my father included horrific wartime events typical of WWI.

I reread my grandfather’s diary as I began writing this editorial, and I was particularly struck by his entry on September 11, 1918. Previously I had never noticed the date.

“At 1 AM the great drive opened up. A heavy barrage was thrown up. Some jamey believe me. The flashes were seen very clearly. Barrage kept up till mid-day. Big naval guns, booming near here jarring doors open and rattling things in general. We were all kind of nervous at first but this gradually wore off. Patients began coming in and we were rushed to death, working day and night. Stories came from the front of different attacks. Lots of gassed. We gave our beds up to patients and slept on ground.”

Juxtaposed with my grandfather’s entry, the following is from my grandmother’s diary, written shortly after my grandfather had returned home from the war.

“Ah! If I could only make you see my darling when he came home to me. The lovely generous body, fit and solid, the same ruddy complexion (the army called him ruddy) and those beautiful blue clear eyes but for all that –The boy who went away was so calm, sunny and sure that everything nice was just around the next corner and the man who came home to me –uncertain, afraid of a sudden noise and timid of the dark in a building. So many days under fire without relief and exposure had left their tragic mark.”

20th anniversary of the 9/11 terrorist attacks

 on the World Trade Center and the Pentagon, as well as the resulting tragedy when the airplane crashed into a field in Pennsylvania. When the attacks began, I was on the phone with a patient, who was in a convenience store with a television on. As we were talking, he informed me that an airplane had just crashed into the World Trade Center. Turning on my TV, I was horrified to see the smoke pouring out of the first hit building. It was surreal to watch a second airplane crash into the second building with the backdrop of a crystal-clear blue sky.

Watching with confusion, helplessness, and disbelief, that horror was greatly amplified as both the World Trade Center buildings collapsed. As I reflect on 

 had on me, watching on a TV screen, I cannot imagine the intensity of emotions and the traumatic assault for those who were present as the terrorist attacks unfolded. Numerous books and documentaries have archived this event and its ongoing traumatic impact on countless individuals.

Sadly, this day of gruesome attacks, as well as all the pain and suffering they have caused, is but one of countless traumatic events that have been perpetrated on humanity over millennia: some by nature, others by accident, but many by people intentionally inflicting death, pain, suffering, and unimaginable loss on other people. During the brief history of our own country, we have already had our share: the Civil War, World War I and II, the Korean, Vietnam, and Gulf wars, and the Capitol insurrection on January 6, 2021, to name a few.

Some traumatic events occur over decades, affecting specific populations. During the colonization of North and South America by different European countries, the indigenous populations were unapologetically nearly exterminated through genocide. As the United States grew as an economic power after obtaining its independence from Great Britain, Africans were captured in their native lands, enslaved without individual rights, and transported in squalid conditions to become the property of landowners and others. What followed were centuries of forced labor, separation of families, torture of the worse kind, and murder without consequence. During World War II, Japanese Americans were taken from their established lives and homes and incarcerated in internment camps, while their family members or friends fought proudly as Americans overseas.

, such as hurricanes, tornadoes, earthquakes, and massive wildfires, are a constant and often unpredictable threat, leaving deep and enduring emotional scars on the affected individuals. Mass shootings, drug-overdose deaths, motor-vehicle fatalities, homicides, and suicides leave a long trail of posttraumatic pain and suffering on too many people whose lives will never be the same. Cable TV works hard to show us traumatic events of every kind—virtually daily—which must leave an emotional imprint deep in our unconscious that sculpts our moment-to-moment experience. The COVID-19 pandemic has been an unwelcome addition to this list.

Finally, each of us is influenced by traumas of many types, experienced by our families from generations past—family narratives that shape us in many ways, some of which we are aware, and others hidden. I would like to share one of my family narratives as I end this editorial.

My father shared with me how his father suffered from panic attacks, agoraphobia, and anxiety after his wartime service. He worked close to home at the United Shoe Machine Corporation in Beverly, Massachusetts, designing machines to make shoes. When his anxiety intruded, his supervisors allowed him to leave work and walk home to find respite and relief. My grandmother referred to herself as a “cellar widow,” as my grandfather would arrive home from work, have his evening meal, and then go down to his workshop in the basement where he found relief working on an endless trove of projects. There is no doubt that my grandfather’s trauma from WWI has had an impact on me.

Many of the traumas described are out of our control, a result of random natural occurrences or unfortunate accidents. War and murder, however, result from choices made by an individual or a government. I often reflect on a talk given during a meditation retreat by my friend, colleague, and meditation teacher Joseph Goldstein, who lives and teaches at the Insight Meditation Society in Barre, Massachusetts.

He said: “Imagine what the world would be like if every person agreed to not kill any other person.”

is medical director, Brain Health, Exeter, New Hampshire; Editor in Chief, 

; staff psychiatrist, Seacoast Mental Health Center, Exeter; Consulting Psychiatrist, Exeter Hospital, Exeter; Consulting Psychiatrist, Insight Meditation Society, Barre, Massachusetts. 

The long trail of posttraumatic pain and suffering leaves behind too many people whose lives will never be the same...

Reflecting on Trauma

Prior to my decision to attend medical school, I was planning to become a basic science researcher. I studied biochemistry in college at a time when it was a relatively young field. My bachelor of science curriculum included 7 semesters of chemistry; 5 semesters of biochemistry, physics, microbiology, and zoology; and a senior honors thesis that entailed designing, completing, and defending a novel research project. I successfully defended my thesis, “An Analysis of the Fate of the Escherichia coli 4.5S RNA Gene in Yeast Using a Recombinant Plasmid,”

 and was planning to attend graduate school in genetics at the University of Washington in Seattle.

Between completing my senior thesis and my planned move to Seattle, I suddenly panicked and wondered: Is this truly the career path for me? Ultimately, I realized I did not have what it took to be a basic science researcher, so I worked for a year as a biochemical technician and applied to medical school—a decision I have never regretted.

Yet, I do not regret my background in biochemistry either. It is the foundation upon which all I have learned of medicine and psychiatry is built. The field of neuropsychopharmacology has evolved over the past 30 years, and I am filled with pride, awe, and excitement to have witnessed the clinical advancements that basic science researchers have made possible. However, in my opinion, there is 1 significant exception to all my accolades for how good science has advanced medicine: the research on cannabis.

The scientific method is used in medicine and has been the established paradigm for scientific inquiry since the 1600s. Thus, all clinical trials submitted to the US Food and Drug Administration (FDA) are meticulously designed to answer a primary outcome question about the drug under investigation. A necessary requirement of the study design is to ensure that the variables in the various arms of the study are identical except for one: drug A at dose X compared with placebo. If multiple doses of drug A or multiple drugs are being compared, each arm is precisely characterized so the conclusions drawn from the primary outcome will be highly accurate and reliable.

Over the past 10 years, I have read numerous articles in the psychiatric literature that draw conflicting conclusions about the effect of cannabis on cognition, its attendant risk of psychosis, its addictive potential, and its effect on suicidality, and about its impacts on depression, anxiety, pain relief, and apathy. (There appears to be only 1 consistent finding: Heavy cannabis use during brain development increases the risk of psychosis and cognitive impairment, especially when other risk factors are present.) A likely explanation for the wide-ranging discrepancies is that cannabis is the product of a plant that is not a single molecule or pure substance. Many articles with the word cannabis in the title can be discarded as meaningless unless the authors took the additional step of testing all of the cannabis used by their study subjects for the quantitative and qualitative molecules present.

It is well established that cannabis contains 

 These constituents include more than 100 cannabinoids, more than 200 terpenoids (terpenes), and numerous flavonoids. Two cannabinoids are most prevalent in cannabis: Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), both of which exist in an extremely wide range of ratios depending on the specific strain of cannabis assayed. Significantly, these 2 cannabinoids are oppositional in their clinical effects and have dramatically different pharmacodynamic effects. In reviewing the literature on cannabis, a consistent finding is that potency of cannabis is a proxy for the amount of THC. Although this is likely a result of the psychoactive effects of cannabis that have been noted for more than 6000 years,

 CBD has surfaced as an important cannabinoid with many positive medicinal properties. Notably, cannabis remains a Schedule 1 drug by the Drug Enforcement Administration (DEA), while CBD is unscheduled.

documents some of the significant differences between THC and CBD. Despite these differences, the vast majority of publications on cannabis draw conclusions based on participants’ self-reports of quantity and frequency of cannabis use. In these studies, the molecular components of the cannabis used are not known, nor is the important ratio of THC to CBD.

A fair analogy would be to evaluate a new drug; let us call it Sedalant. Sedalant contains a wide-ranging ratio of 2 molecules with different mechanisms of action: one a sedative, and one a stimulant. Without knowing the exact ratios and concentrations of each of these molecules in clinical studies of Sedalant, no evidence-based conclusions could be drawn from the drug studies.

Naturally occurring cannabis plants produce roughly an equal ratio of THC to CBD, containing approximately 2% of each. However, over the decades, with selective breeding in some strains, THC has been increased significantly while CBD has been virtually bred out. 

 analyzed the concentrations of THC and CBD from 38,681 samples of illegal cannabis seized by the DEA between 1995 and 2014. The authors found a clear trend of increased THC in cannabis over time, with an average concentration of 4% in 1995 that increased to 12% in 2014. Simultaneously, CBD concentration steadily declined, from 0.5% in 2004 to less than 0.2% in 2014. The investigators concluded that the ratio of THC to CBD increased from 14-fold in 1995 to 80-fold in 2014.5 Some strains of cannabis today may contain up to 30% THC with virtually no CBD, while other strains have high concentrations of CBD with minimal THC.

To further complicate the cannabis story, very few of the other cannabinoids in cannabis plants have been characterized pharmacodynamically or pharmacokinetically. The characterization of 3 of these more than 100 cannabinoids—Δ-9-tetrahydrocannabivarin, cannabichromene, and cannabigerol—tells us that they are 

Interestingly, the odors (skunk is a common description) often associated with cannabis are largely due to the complex combination of terpenes, another compound that complicates the study of cannabis. (Cannabinoids are odorless.) An extensive literature documents the essential role terpenes play in the biology of the cannabis plant, the plant’s production of cannabinoids, and the properties of a specific strain of cannabis that help determine its market value. Terpenes likely also contribute pharmacodynamic and pharmacokinetic effects that impact the neuropsychopharmacology resulting from ingestion of each different strain of 

Several publications since 2018 have appropriately concluded that we know very little about the range of pharmacological effects from cannabis due to the large variability of cannabinoids, terpenes, and flavonoids that are present in 

For this very reason, it would be contrary to the scientific method of research to attempt to gain FDA approval of cannabis.

Only 1 of the more than 100 cannabinoid components in cannabis has been sufficiently studied to receive FDA approval: CBD. Following a comprehensive analysis as well as clinical trials of pure CBD, it received 

 for the treatment of seizures in Dravet syndrome and in Lennox-Gastaut syndrome in children and adults.

 We may see additional approvals in the future for this well-studied compound, as a growing and consistent body of evidence shows that pure CBD in defined dosages has antipsychotic effects in patients with schizophrenia.

The practice of medicine is built upon evidence-based treatments that have been appropriately vetted by well-established protocols. CBD traveled this path to become an FDA approved drug, and so should any other component of the 500-plus molecules in cannabis. Accordingly, clinical publications should be held to a higher standard of identifying and defining what components of cannabis are relevant in any article being submitted for publication.

With each passing year, more US states legalize cannabis for medical use, recreational use, or both. It is likely that federal laws will eventually make cannabis use legal on a national level. That will create an opportunity to require a comprehensive analysis and disclosure of all the components of the numerous strains of cannabis currently being sold in state dispensaries or on the streets. Concurrently, the individual molecular components of the cannabis plant should be identified and pharmacologically characterized. This would create a treasure trove of possible drug candidates for specific clinical indications, and it would allow for a more informed choice when choosing a cannabis product.

In this scenario, cannabis should be regulated federally similar to tobacco products and alcohol. Both of these have significant risks, and both are tightly controlled. Ideally, the taxes imposed on federally regulated cannabis could help fund the extensive research needed to allow a more competent understanding of the complex combination of molecules that different strains of cannabis contain.

1. The word cannabis should not be used casually in medical literature, as it is nonspecific and includes varying molecular combinations of diverse cannabinoids, terpenes, and flavonoids.

2. Future research involving cannabis should use a single strain in each study; each strain used should be analyzed quantitatively and qualitatively for biologically active components.

3. If multiple strains are used in a clinical trial, they should be analyzed (as noted in #2), and each strain should be studied as a separate arm compared with placebo.

4. Increased funding is needed to accurately characterize the 500-plus molecular components of the cannabis plant, including the pharmacokinetics and pharmacodynamics of each component.

5. A public education campaign should aggressively disseminate the molecular facts about cannabis, especially the oppositional effects of THC and CBD. Similarly, the risks of increased psychosis and cognitive impairment with heavy regular use of THC in the developing brain should be explained, much like disclaimers on alcohol about drinking during pregnancy.

6. Cannabis should be federally legalized and regulated similarly to alcohol and tobacco products.

7. Cannabis should not be regulated by the FDA due to its extreme heterogeneity of components and the associated unpredictable pharmacological properties.

8. Cannabis should not be prescribed by medical practitioners. However, as molecular components of cannabis are developed and garnish FDA approval, those components should be prescribed appropriately.

9. Pharmacological exploration and development of cannabis components that demonstrate medical benefits should be continued. CBD is a successful model of such.

10. Medical practitioners should discuss cannabis with their patients only after they have attained competence in understanding the science and factual risks/benefits/adverse effects of cannabis, similar to how a practitioner would discuss alcohol or tobacco use.

With this structure in place, we have the ability to inform and support our patients appropriately. And, with more information, we can help end the cannabis confusion.

 is medical director, Brain Health, Exeter, New Hampshire; Editor in Chief,

1. Miller J. An Analysis of the Fate of the Escherichia coli 4.5S RNA Gene in Yeast Using a Recombinant Plasmid. Senior undergraduate honors thesis. University of Washington, Amherst; 1981.

2. Lafaye G, Karila L, Blecha L, Benyamina A. Cannabis, cannabinoids, and health. 

4. Atakan Z. Cannabis, a complex plant: different compounds and different effects on individuals. 

5. ElSohly MA, Mehmedic Z, Foster S, et al. Changes in cannabis potency over the last 2 decades (1995-2014): analysis of current data in the United States. 

6. ElSohly MA, Radwan MM, Gul W, et al. Phytochemistry of Cannabis sativa L. 

7. Nachnani R, Raup-Konsavage WM, Vrana KE. The pharmacological case for cannabigerol. 

8. Sommano SR, Chittasupho C, Ruksiriwanich W, Jantrawut P. The cannabis terpenes. 

9. Booth JK, Bohlmann J. Terpenes in cannabis sativa – from plant genome to humans. 

10. Baron EP. Medicinal properties of cannabinoids, terpenes, and glavonoids in cannabis, and benefits in migraine, headache, and pain: an update on current evidence and cannabis science. 

11. Jett J, Stone E, Warren G, Cummings KM. Cannabis use, lung cancer, and related issues. 

12. Epidiolex. Greenwich Biosciences; 2020. Updated April 2020. Accessed July 7, 2021. 

13. McGuire P, Robson P, Cubala WJ, et al. Cannabidiol (CBD) as an adjunctive therapy in schizophrenia: a multicenter randomized controlled trial. 

14. Elsaid S, Le Foll B. The complexity of pharmacology of cannabidiol (CBD) and its implications in the treatment of brain disorders. 

15. National Academies on Sciences, Engineering, and Medicine. 

The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research

16. Rong C, Carmona NE, Lee YL, et al. Drug-drug interactions as a result of co-administering Δ9-THC and CBD with other psychotropic agents. 

10 keys to understanding the science of cannabinoids. 

Cannabis Confusion

Imagine practicing medicine in the early 1900s before the advent of antibiotics, anesthesia, laboratory data, radiology, and intensive care units. Clinicians did not need to know as much as we do today. Of course, that also meant there was less we could do for our patients. I can recall as a child during the 1960s my grandmother was hospitalized for a week for a headache—and the prescribed treatment was to rest.

Fortunately, we continue to expand our understanding in all medical specialties at an exponential rate. Add to that the extraordinary demands of clinical practice, and at the end of our workday, we simply do not have the energy to read an

in a medical journal. Not surprisingly, this void has been filled by 

, where the goal is to focus on learning all that is new and important in our chosen field of medicine. These conferences are often enriched by reunions with our longtime friends and colleagues as well as by spending a few extra days vacationing away from our usual routines. This combination of events likely enhances retention of the material learned and provides a well-needed respite from our daily medical practices.

John J. Miller, MD, is medical director, Brain Health, Exeter, New Hampshire; Editor in Chief, 

In the attempt to keep mental health professionals up-to-date, the mission of 

 since 1985 has been to provide evidence-based, peer-reviewed, clinically relevant information for psychiatric clinicians in an engaging format. We appreciate your feedback that Psychiatric Times

 is your go-to source for timely, diverse, and digestible monthly publication. Similarly, over the past several years, the 

 website has blossomed into a highly regarded resource with daily updates and a large archive to explore.

The information trifecta has been completed with our annual CME conference, which is modeled after our well-respected monthly publication. Through numerous brief lectures—most 15 to 30 minutes long—presented by leading topic experts, the conference provides a rich, diverse curriculum that is designed to reward attendees with a meaningful and broad educational experience. Plus, the CME credits earned are a pleasant value-added perk.

will be held September 30 through October 2. Building on last year’s successful virtual conference, we are excited to offer a hybrid conference model that allows attendees to participate in person—in 

—or virtually, with both formats providing access to the same great information and same outstanding faculty. In addition to updates on the usual topics like 

, presenters will share their experiences and insights on numerous specialty topics.

This year’s conference will begin with a mini-symposium on “Psychiatry in the Age of 

,” exploring how our lives changed during this once-in-a-century pandemic, and how this experience has changed the way we practice psychiatry, grieve from a global disaster, and heal from the physical and mental scars left behind.

Needless to say, the past 18 months have been extraordinary in many ways: The United States and our world community came to a screeching halt as the 

 pandemic ramped up. So many aspects of life that we took for granted were off-limits, and we had to reimagine how to move forward safely. For instance, before the pandemic, I had never engaged in 

. Yet, like so many of you, starting in mid-March 2020, I began meeting with all of my patients either through doxy.me or over a telephone line.

I never fully adjusted to this new way of practicing psychiatry, and beginning a few months ago, I started seeing patients again in my small but comfortable office. It has been fascinating to hear the many different opinions about telemedicine. One thing seems clear: A hybrid model will likely become the “new normal” in health care delivery.

Many other lessons have been learned—like the importance of 

and caregivers—and hopes for improvement abound as we venture forth. As many have said, returning to normal should not be the goal: We should aim to better incorporate the successful innovations gleaned from the pandemic into our routines.

In addition, the COVID-19 pandemic remains unleashed in many countries, and although vaccination rates in the United States continue to rise, most of us still feel off-balance because of the raw experiences of the past 18 months. There is much to feel, discuss, share, and process about this viral pandemic, and this symposium’s sessions will explore all of that, as well as the psychiatric implications of COVID-19.

In another vein, the conference will feature a series of presentations examining what we know about 

, tetrahydrocannabinol, and cannabidiol, a timely focus with cannabis legalized—both medically and recreationally—in a rapidly growing number of states. In the not-so-distant future, it could be legalized throughout the United States. Similarly, psychedelics, which had been marginalized since the 1960s, have resurfaced with possible benefits for some psychiatric disorders. For instance, more than 50 clinical trials are currently registered with the US Food and Drug Administration researching the putative benefits of psilocybin for various indications. How might psychedelics become a novel psychiatric treatment in our toolbox? The conference will explore new research and what you need to know.

So many more equally fascinating talks are scheduled. In partnership with 

 (PER®), we are continuing our conference model of presenting many diverse topics in briefer time intervals to allow for a broad curriculum, providing you with key take-home points in a clear and focused manner. I invite you to review our 

 to attend either in person or virtually.

My favorite part of our annual conference is the ample time for faculty interaction with attendees to discuss cases or delve deeper into topics of interest. For participants attending in person, please join us for a networking reception on the evening of Friday, October 1. If you have previously visited San Diego, you already know why it is such a special city. If you haven’t, it is time to find out.

I look forward to seeing you there—and learning together! ❒

Recognizing the need to stay up-to-date with psychopharmacology and issues affecting psychiatric practice, Psychiatric Times' Editor in Chief invites readers to join him and leaders in psychiatry for a fascinating educational conference.

Perfecting the Trifecta

, a research team at Icahn School of Medicine at Mount Sinai Health System in New York City made a fascinating discovery: Early life stress in mice resulted in an epigenetic modification of methyl groups on histone-3 in neurons in the nucleus accumbens, which in turn led to a lifelong increase in the mice’s vulnerability to stress. The team then demonstrated that treating the mice during exposure to early life stress with pinometostat, a drug currently in clinical trials to treat acute myeloid leukemia in humans, inhibited the enzyme responsible for this epigenetic methylation modification and decreased the effect of early-life stress exposure on 

This study is but one of a growing number of publications demonstrating the essential role of epigenetics in animal development, health, and disease. Without much fanfare, our understanding of epigenetics has been a significant paradigm shifter. Before we explore epigenetics, we need to review the foundational field of genetics.

The 3 billion base pairs that constitute the human genome is the sequence of covalently bonded nucleic acids—adenine (A), thymine (T), cytosine (C), and guanine (G)—that form the double helix of DNA. This sequence forms the basis of the field of genetics and is created when the sperm joins the egg to form a zygote, which will contain this unique DNA sequence that remains constant throughout our life. In the case of identical twins, 100% of this DNA sequence is exactly the same, as both twins derive from the same zygote. With fraternal twins, 2 different sperm fertilize 2 different eggs to create 2 unique zygotes that have DNA sequences as different as 2 siblings with the same parents.

Let’s look at the genetic risk of schizophrenia, for example. In the general population, the risk of developing schizophrenia is about 1%, but if your identical twin develops schizophrenia, your risk increases to 50% due to the identical shared genome. In fraternal twins, the risk drops to roughly 16%, and in siblings it further drops to 9%. This demonstrates the role genetics plays on increasing or decreasing a person’s risk for various medical conditions. Significantly, the identical twin also has a 50% likelihood of not developing schizophrenia, which is attributed to numerous nongenetic factors. One of these factors is the individual’s epigenome, which can be different than 

In 2001, the Human Genome Project (an international consortium of research labs spearheaded by the US National Institutes of Health) and Celera Genomics (a private research company) announced they had independently completed a first draft of the sequencing of the human genome’s 3 billion base pairs. By 2003, the final draft was complete. Speculation by scientists, world leaders, and the media projected that, over the next decade, science and medicine would discover the genetic basis to many human diseases and disorders, with associated novel treatments. The complete sequencing of the human genome was an incredible achievement that continues to advance our understanding of the role of genes on health and disease. However, 20 years later it is disappointing to see how few actionable treatments have been developed. So, what’s next?

The foundation of the epigenome involves covalent changes on certain areas of our chromosomes that will either increase or decrease the amount of activity at genes, hence impacting which gene products will be made in each particular cell. Think of the epigenetic processes like the software that determines which programs on a computer’s hard drive (the DNA genome) will be opened in RAM (in our analogy the genes that are ultimately expressed, creating our phenotype). The zygote has access to 100% of the genome. As embryological development occurs, cells begin to specialize and only require a small subset of the 20,000 or so protein coding genes that are available. One line of cells will begin to only produce proteins necessary for skin, while another set of cells will produce proteins for muscle, and yet another for neurons. This is an energy efficient process.

 that the chromosomal DNA/histone complex can be covalently modified to decrease or increase gene expression: methylation of the gene, or adding chemical tags to histones (the proteins around which the DNA is wrapped).

 In humans, the part of the gene that is methylated is the “promoter sequence,” a specific sequence of nucleotides, including a large density of CpG sites, which serve as a beacon and landing pad for the proteins that will then transcribe the messenger RNA (mRNA). mRNA will ultimately code for the gene’s protein. The more methyl groups attached to the promoter sequence, the less gene product will be synthesized. In specialized cells, the unneeded genes are heavily methylated and buried deep in the histones, likely never to be transcribed again.

The 3-dimensional shape of a histone can vary depending on chemical groups that can be covalently added depending on the degree of access needed to the gene associated with a particular histone. There are many chemical tags for histones, but the 2 best understood are methyl groups, which generally help the histone fold to hide the gene; and acetyl groups, which generally help the histone open up and make the gene more accessible.

There are enzymes that exist with job descriptions to either add or remove these methyl groups or acetyl groups to gene promoter sequences or histones, which in turn will be induced or repressed depending on the organism’s environment. At any given moment in time, an individual’s epigenome is unique and reflects the infinite number of events that determine what genes are turned on, or off, or somewhere in the middle.

Remember those identical twins that share 100% of the same DNA sequence? Epigenetic processes are already at work creating different expressions of this identical genome as soon as the shared zygote splits in 2 to create the twins.

, baby rats respond to stress differently (throughout their lives) depending on how much grooming and licking they receive from their mother in the first week of their life.

 Some mother rats provide abundant grooming and licking to their babies, while other mother rats are less interactive with their babies, paying less attention with significantly less grooming and licking. Research found that the baby rats that received plenty of grooming and licking during that first week of life remained notably calm when exposed to stressful situations as adults. Meanwhile, the baby rats deprived of their mother’s attention during the first week of life responded with distress when exposed to the same stressful situations as adults.

The researchers then swapped the baby rats at birth: Babies of low grooming/licking mothers were switched to mothers that were high groomers/lickers, and vice versa. Remarkably, the first week of life for the baby rats was the determining factor for stress response as adults, rather than any inheritance from their biological mother. In addition, the stress-tolerant adult rats had lower levels of cortisol, adrenocorticotrophic hormone, and corticotrophin-releasing hormone than the adult rats that were neglected during that first week of life. Further research demonstrated that the stress-tolerant adult rats had decreased methylation of their cortisol receptor gene, in contrast to the neglected rats. Hence, that initial increased grooming created an epigenetic change that resulted in a lifelong increased expression of the cortisol receptor, creating greater resilience to stress.

Can epigenetic modifications that occur during a person’s life be passed on to their offspring and future generations? From November 1944 through the spring of 1945 of World War II, the Germans, who controlled the Western Netherlands, set up a blockade that created a scarcity of food and severe starvation. From the detailed historical health care records, we have been able to study the long-term effects of the famine. Babies born to women who experienced starvation for the first 3 months of pregnancy and then resumed a normal diet when the blockade ended and food was available were likely to have a normal body weight at birth. However, babies born to women who were 6 months pregnant when the famine began were more likely to be underweight at birth.

These babies were followed by the health care system for decades. Remarkably, researchers discovered that the low-birth-weight babies continued to have body weights below average throughout their lives, including decreased rates of obesity as compared to the general population. The babies whose mothers experienced starvation during the first trimester of their pregnancy and had normal body weights at birth, had higher rates of obesity as compared to the general population decades later. Moreover, the grandchildren of the women who were starved during their first trimester also demonstrated some similar effects, suggesting a transgenerational inheritance.

One current hypothesis is that epigenetic changes to genes associated with nutrition and metabolism in the fetus would occur during a state of starvation to maximize the utilization of each calorie available. Significant epigenetic processes are in play during the first 3 months of fetal development, and these epigenetic modifications can then persist throughout life. Subsequent studies have shown that DNA methylation patterns in survivors of the Dutch Hunger Winter have demonstrated epigenetic modifications at genes involved in metabolism. The tragic circumstances of the Dutch Hunger Winter have provided a rare opportunity to study the potential effects of epigenetic changes early in life being passed on to future offspring. This is just one study; there is a growing literature in support of transgenerational epigenetic inheritance.

 for epigenetics in the National Library of Medicine generated 107,287 results, and 105,343 of these were published since the year 2000, demonstrating the explosion in this field over the past 2 decades.

Epigenetic modifications sculpt an individual’s phenotype 

 Epigenetic processes are most active, ubiquitous, and consequential throughout fetal development, as well as during the first 2 decades of life.

Returning to our identical twins, epigenetic differences are evident at birth, and these differences increasingly diverge throughout the twins’ lives. Research abounds comparing epigenetic profiles of individuals with and without a specific disease state to better understand the role of epigenetics in contributing to disease processes.

One significant consequence of the epigenetic contribution to phenotype is our growing understanding that genes that code for cytochrome P450 (CYP450) metabolic enzymes can be silenced or amplified, rendering the genotype of an individual’s CYP450 pharmacogenomic profile incomplete and unreliable. A recent study of CYP450 2E1 has demonstrated this 

 This growing understanding of the epigenetic effects on CYP450 gene expression calls into question the reliability of pharmacogenomic testing that reports a genotype, but does not factor in the epigenetic phenotype that ultimately will determine CYP450 metabolic enzyme activity.

Epigenetics has provided fertile ground to understand how early life experience can directly increase or decrease the risk and severity of psychiatric disorders such as schizophrenia, bipolar disorder, and 

The epigenetic paradigm shift has received relatively little attention compared to the human genome sequencing, despite the broad and significant impact it has had on our understanding of how environmental factors during a single lifetime can covalently regulate which genes are expressed, and to what degree, from the fixed human genotype. In fact, it is the epigenome that ultimately determines the individual’s phenotype for increasing or decreasing the risk of various diseases and the functioning of 

In the field of oncology, drugs that treat some cancers by epigenetic mechanisms are already FDA approved and in clinical use. Azacitidine and decitabine are both inhibitors of DNA Methyltransferase-1 and are approved for myelodysplastic syndrome—a disease of the bone marrow. Vorinostat and romidepsin both inhibit a histone deacetylase and are approved for the treatment of refractory cutaneous T-cell lymphoma. Time will tell if epigenetic modifying drugs will become part of our treatment arsenal in psychiatry.

In this issue we are delighted to present 2 important articles by Bursztajn et al expanding on the field of epigenetics. Their first article, “Harnessing Epigenetic Knowledge to Promote Resilience while Avoiding the Historical Pitfalls of Genetic and Social Reductionism,” provides a historical overview of the field of epigenetics, as well as offering some philosophical reflections. Their second article, “Transgenerational Transmission of Resilience After Catastrophic Trauma,” our featured CME article, explores the rapidly evolving understanding of the potential epigenetic role on resilience after severe trauma, and how this resilience may be passed along to the traumatized individual’s offspring.

is Medical Director, Brain Health, Exeter, NH; Editor in Chief, 

Staff Psychiatrist, Seacoast Mental Health Center, Exeter, NH; Consulting Psychiatrist, Exeter Hospital, Exeter, NH; Consulting Psychiatrist, Insight Meditation Society, Barre, MA.

1. Kronman H, Torres-Berrio A, Sidoli S, et al. Long-term behavioral and cell-type-specific molecular effects of early life stress are mediated by H3K79me2 dynamics in medium spiny neurons. 

2. Dempster EL, Pidsley R, Schalkwyk LC, et al. Disease-associated epigenetic changes in monozygotic twins discordant for schizophrenia and bipolar disorder. 

3. Kular L, Kular S. Epigenetics applied to psychiatry: Clinical opportunities and future challenges. 

6. Kanherkar RR, Bhatia-Dey N, Csoka AB. Epigenetics across the human lifespan. 

7. Kronfol MM, Jahr FM, Dozmorov MG, et al. DNA methylation and histone acetylation changes to cytochrome P450 2E1 regulation in normal aging and impact on rates of drug metabolism in the liver. 

8. Blacker CJ, Frye MA, Morava E, et al. A review of epigenetics of PTSD in comorbid psychiatric conditions. 

9. Mazzone R, Zwergel C, Artico M, et al. The emerging role of epigenetics in human autoimmune disorders. 

10. Ling C, Ronn T. Epigenetics in human obesity and type 2 diabetes. 

Early-life stress can modify an individual's genetic code, leading to mental health problems later in life. But by understanding the science of epigenetics, psychiatrists can treat these conditions, and prevent intergenerational trauma. 

Exploring the Epigenetic Paradigm Shift

John J. Miller, MD, talks about treatment options for delirium. 

staff psychiatrist, Seacoast Mental Health Center, Exeter; Consulting Psychiatrist, Exeter Hospital, Exeter; Consulting Psychiatrist, Insight Meditation Society, Barre, Massachusetts.

Videos

What treatment options are available when dealing with delirium?

John J. Miller, MD

Articles

Epigenetics Collide With Pharmacogenomics

Reflecting on Trauma

Cannabis Confusion

Perfecting the Trifecta

Exploring the Epigenetic Paradigm Shift

Pharmacological and Nonpharmacological Approaches to Delirium