10/4/22

It Bites Like a Serpent

Because it gives such a vivid picture of compulsive drinking, Proverbs 23:29-35 is a favorite passage of mine.

image credit: iStock

29 Who has woe? Who has sorrow? Who has strife? Who has complaining? Who has wounds without cause? Who has redness of eyes?

30 Those who tarry long over wine; those who go to try mixed wine.

31 Do not look at wine when it is red, when it sparkles in the cup and goes down smoothly.

32 In the end it bites like a serpent and stings like an adder.

33 Your eyes will see strange things, and your heart utter perverse things.

34 You will be like one who lies down in the midst of the sea, like one who lies on the top of a mast.

35 “They struck me,” you will say, “but I was not hurt; they beat me, but I did not feel it. When shall I awake? I must have another drink.”

Not only does this passage truly capture the out-of-control drinking of an alcoholic, it also displays the rich imagery of biblical Hebrew in the process. The description of unmanageability and negative consequences would fit right in with the personal stories in the AA Big Book or on one of the modern recovery blogs.

The passage begins with a series of rhetorical questions that lays out the unmanageability suffered by alcoholics and problem drinkers throughout the ages: woe, sorrow, strife, complaining, wounds without cause and red eyes. Who has all things? “Those who tarry long over wine.” The litany of questions also suggests someone who is familiar with the negative consequences from “tarrying over wine.” It seems that the author knew of what he wrote from personal experience.

According to R. Laird Harris in the Theological Wordbook of the Old Testament, wine was the most intoxicating drink known in ancient times. The reference to mixed wine suggests a process of first evaporating wine with a high sugar content; then mixing it with more wine to get a higher alcoholic content in the “mixed wine.” Even in Old Testament times problem drinkers knew how to maximize their high with the “hard stuff.”

The imagery of verse 31 is wonderfully seductive: red, red wine that sparkles in your cup and goes down smoothly. But watch out! It bites like a serpent and stings like an adder. The message then and the message today is the same for an alcoholic. The seductive appeal of sparkling wine is just as dangerous as a biting serpent. And if you do not listen to the warning , you could end up dead.

Now we enter into the heart of a drunken stupor: your eyes see strange things; your heart utters perverse things. Watch this YouTube video of Robin Williams describing how alcoholics “see strange things and utter perverse things.” Nothing much had changed there.

The imagery in verse 34 is of being on a ship in the midst of a storm. Tossed about by the waves, one minute you are in the midst of the sea; the next at the top of the mast. In Psalm 107:27, sailors in a storm are said to be reeling like drunken men. Drunkenness is feeling like you are on a storm tossed ship. Can anyone relate? Like a storm, drunkenness must be “ridden out;” endured until the end. And you are powerless to calm the seas and end the storm.

The drinker says that he was struck, but not hurt (35a); beaten, but he did not feel it (35b). When you’re drunk, pain fails to register. Sometimes you don’t even remember what hit you. The terror of the strange things seen and perverse things uttered is like a dream: when will he awake? And if he does, more wine becomes the goal: “I must have another drink.”

Wine leads to negative consequences for those who pursue it; and the aftermath of a drunken storm leads right back to wine. A bleak, hopeless circle is depicted. The main point of the passage is then: Do not look at wine; it bites like a serpent and leads to an unending circle of sorrow.

So why do we do it? Why do humans turn to wine and other intoxicants? Ronald Siegel suggested in his book, Intoxication, that pursuing intoxicants is a “fourth drive,” following hunger, thirst and sex.

“History shows that we have always used drugs. In every age, in every part of this planet, people have pursued intoxication with plant drugs, alcohol, and other mind-altering substances. . . . This ‘fourth drive’ is a natural part of biology, creating the irrepressible demand for drugs.”

I think Leo Tolstoy is closer to the truth. In his essay “Why Do Men Stupefy Themselves?” he said:

“For man is a spiritual as well as an animal being. He may be moved by things that influence his spiritual nature, or by things that influence his animal nature. . . . People drink and smoke, not casually, not from dullness, not to cheer themselves up, not because it is pleasant, but in order to drown the voice of conscience in themselves.”

In the end, the apostle Paul had it spot on. In Romans 7:21-23 he said: “So I find it to be l law that when I want to do right, evil lies close at hand. For I delight in the law of God, in my inner being, but I see in my members another law waging war against the law of my mind and making me captive to the law of sin that dwells in my members.”

Originally posted on 8/1/2014.

08/2/22

The Future of Marijuana Legalization in Pennsylvania

The World Drug Report for 2021 reported that roughly 200 million people used cannabis in 2019, roughly 4% of the global population. North America has the highest number of cannabis users, with an estimated 14.5% of its population use in 2019. The percentage of THC (∆9-THC), the main psychoactive ingredient in cannabis, rose from around 4% in 1995 to 16% in 2019. Although THC is responsible for the development of mental health disorders in long-term, heavy cannabis users, the percentage of adolescents who view regular cannabis use as harmful has decreased by as much as 40% during the same time period. While the potency of cannabis has increased four-fold since 1995, fewer young people see it as harmful.

Such a mismatch between the perception and the reality of the risk posed by more potent cannabis could increase the negative impact of the drug on young generations. Scientific evidence has demonstrated the harm to health caused by regular use of cannabis, particularly in young people. Evidence from surveys suggests a link between a low perception of risk and higher rates of usage. This is the case not only in Europe and the United States, but also in other parts of the world.Aggressive marketing of cannabis products with a high Δ9-THC content by private firms and promotion through social-media channels can make the problem worse. Products now on sale include cannabis flower, pre-rolled joints, vaporizers, concentrates and edibles. The potency of those products varies and can be unpredictable – some jurisdictions where cannabis use is legalized set no limit on THC content – and may be a public health concern.

(See the following charts from the World Drug Report for 2021)

In 2020, 14.6% of high-school students reported past-month use of cannabis. There was a significant increase in the daily or near-daily use of cannabis in the past two years (20919 and 2020). The daily or near-daily use of marijuana was estimated at 4.1% among high-school students in 2020, compared with almost 1% in 1991. In the past few years, the debate about medical marijuana and measures allowing for the non-medical use of cannabis in the United States have led adolescents to perceive cannabis as less harmful than was true in the past.

In the United States, the decreasing perception of risk from occasional or regular use of cannabis is considered to be a spillover effect as debates over measures allowing the medical and non-medical use of cannabis in the states considering those measures extend to other states, and the result of an increase in regular cannabis use, which comes to be perceived as less risky among users, as well as media coverage of the medical use of various cannabis products in many states containing claims of the medical benefits of cannabis products, including those of CBD.

Not only are there concerns for increases in mental health disorders among youth, there are other concerns with how cannabis effects young adults. Cannabis use among adolescents was found to be related to impaired cognition; showing delayed effects on self-control, working memory and concurrent effects on delayed memory recall and perceptual reasoning (ability to think and reason using pictures or visual information). So, exactly what are the risks when individuals, particularly adolescents and young adults, use marijuana? A meta-analysis published in The Lancet Psychiatry suggested the equivalent of one joint can induce psychotic and other psychiatric symptoms in healthy adults with no history of a major mental illness.

In “Psychiatric symptoms caused by cannabis constituents: a systematic review and meta-analysis,” the researchers their findings highlighted the acute risks of cannabis use, as “medical, societal, and political interest in cannabinoids continues to grow.” Significantly, they concluded that CBD (the second most common cannabinoid in cannabis) did not induce psychiatric symptoms; and the evidence that it moderated the induction of psychiatric symptoms was inconclusive. These effects were larger with intravenous administration than with inhaled.

Commenting on the results for Medscape, senior investigator Oliver Howes said “As clinicians, we need to be aware that the medical use of marijuana comes with a risk of inducing psychiatric symptoms, even in people with no vulnerability, and this needs to be factored into decisions to prescribe and to monitor.” Even if the symptoms are short-lived, people need to be aware of them because not only van they be distressing, but they can also affect decision-making and behavior. With regard to the failure of the researchers to find evidence that CBD moderates the psychotic effects of THC, Howes said, “I think it’s fair to conclude there’s a lack of consistent evidence that CBD is protecting against THC’s effect.” The mean age of the subjects ranged from early to late 20s.

An editorial of the study by Carsten Hjorthøj and Christine Merrild Posselt said the finding that low doses of THC can induce psychotic symptoms was “extremely worrying,” because they were similar to those found in medical marijuana. They also said there was no clear evidence that concurrent administration of CBD reduces symptoms induced by THC. “The authors failed to find any clear evidence that concurrent administration of cannabidiol (CBD) reduced these symptoms. Indeed, such an ameliorating effect was observed in only one of four included studies.”

This growing scientific consensus is not reflected in the mainstream public discourses, which have a major effect on the political agenda to decriminalise or legalise cannabis. It also appears that, in many places (eg, several US states), the first thing to be legalised is medicinal cannabis followed by increasing decriminalisation and sometimes complete legalisation of cannabis. It is thus of utmost importance that the public and politicians are informed of the most up-to-date evidence on cannabis. Adding to the state of this evidence is the systematic review and meta-analysis by Guy Hindley and colleagues in The Lancet Psychiatry. The authors demonstrate that Δ⁹-tetrahydrocannabinol (THC) leads to an increase in total symptoms, which was assessed in nine studies, with ten independent samples, involving 196 participants: standardised mean change in scores (assessed with the Brief Psychiatric Rating Scale and the Positive or Negative Syndrome Scale) 1·10 (95% CI 0·92–1·28, p<0·0001). The effect sizes were also large for other symptoms (including general psychiatric symptoms), and were induced even with low doses of THC, somewhat similar to the doses often seen in medicinal cannabis, which we find extremely important and worrying.

The significance of the above research findings should not be lost on Pennsylvania citizens and politicians. As the availability of cannabis increases in the state, as the potency of THC in that marijuana increases, we will see a corresponding increase of psychosis and other mental health-related problems among regular users. This is the future of marijuana legalization in Pennsylvania.

Medical marijuana has been legal in Pennsylvania since April 6, 2016. The first dispensary opened in the Pittsburgh area in Butler PA, on February 1, 2018. But medical marijuana dispensaries continue to spring up like “weeds.” The Weedmaps website indicated there were 39 dispensaries in the Pittsburgh area. Nineteen advertised they provided Curbside pickup.

John Fetterman, the current lieutenant governor of Pennsylvania, is running for the office of U.S. Senator and wants to see Pennsylvania “go full Colorado.” Its governor, Tom Wolf, has publicly supported the legalization of recreational marijuana. There has been legislation proposed by two state senators, the Adult-Use Cannabis Act, to legalize recreational marijuana in the state. See “Should Pennsylvania Go ‘Full Colorado’ With Marijuana?” Part 1 and Part 2.

07/12/22

Tranq Dope and Its Consequences

A church friend of mine was lamenting his recent visit to Philadelphia. He said that for a city with so many different historic sites, he thought the officials there should have done a better job keeping the sites cleaned up. One of the noticeable parts of the debris were used needles and syringes. This led to us exchanging comments on the opioid epidemic, and how fentanyl had made the situation even worse. What neither of us realized at the time was that our assessment wasn’t quite accurate. We had never heard of “tranq dope.”

Although fentanyl has been replacing the heroin in the Philadelphia drug market, increasingly a substance known as xylazine has been found combined with fentanyl. It is a non-opioid veterinary tranquilizer that is not approved for human use. A brief report by Johnson et al, published in the journal Injury Prevention, reported that xylazine was detected in merely 2% of the unintentional overdose deaths in Philadelphia between 2010 and 2015. That rose to 11% in 2016; 18% in 2018 and 31% in 2019. See the chart below taken from the brief report.

NIDA (National Institute on Drug Abuse) said most overdose deaths linked to xylazine and fentanyl also involved other substances, including cocaine, heroin, benzodiazepines, alcohol, gabapentin, methadone and prescription opioids. When xylazine is taken in combination with other central nervous system depressants, it increases the risk of overdose.

Focus groups in Philadelphia said xylazine added to fentanyl gives the ‘nod’ that heroin provided before fentanyl took over the drug market. It “makes you feel like you’re doing dope (heroin) in the old days.” STAT News reported on paper published in the journal Drug and Alcohol Dependence that said while fentanyl produces a powerful high, its euphoria is short-lived when compared to other opioids like heroin. Adding xylazine gives fentanyl “legs,” meaning it extends the high.

The newer study by Friedman et al noted xylazine use is spreading beyond the Philadelphia area. It was found increasingly present in overdose deaths in all four US Census Regions. The highest prevalence data was still in the North East, in Philadelphia (25.8% of deaths), followed by Maryland (19.3%), and Connecticut (10.2%). Disturbingly, xylazine-involved overdoses may resist naloxone since it isn’t an opioid. That’s not all. “People who used drugs with xylazine seem to be more susceptible to wounds and infections on their skin and other tissues.”

The arrival of xylazine is “when we started to see way more people coming in with necrotizing skin and soft tissue issues. The amount of medical complaints related to xylazine was pretty astounding and terrifying. Xylazine wounds are a whole other kind of … just horror.”

The term “opioid crisis” doesn’t really capture what is developing with overdoses in the U.S. over the past two years. It’s an overdose crisis of polysubstance use—opioids, stimulants, and benzodiazepines; often used in combination. Friedman was quoted by STAT News as saying xylazine was an “especially noxious contaminant that is spreading through the drug supply.” A CDC MMWR Report said during January-December of 2019, xylazine was found in the overdoses reported in 23 states. It was listed as the cause of death in 64.3% of deaths in which it was reported.

Xylazine, or “tranq dope” as it’s known on the streets in Philadelphia, is an analogue of clonidine, and is used for sedation, anesthesia, muscle relaxation and analgesia in animals. It seems to reduce sensitivity to insulin and glucose levels in humans. It can lead to diabetes mellitus and hyperglycemia. Its side effects include bradycardia (a slow, resting heart rate), respiratory depression, blurred vision, disorientation, drowsiness, fainting, slurred speech, staggering, and shallow breathing. Chronic use is associated with physical deterioration, abscesses and skin ulceration.

Since xylazine is FDA approved for veterinary use only, it is not a controlled substance by the DEA. It is available in liquid form and is structurally similar to phenothiazines (first generation antipsychotics).

Its human use in Puerto Rico was reported by Rafael Torruella in a short report for Substance Abuse Treatment, Prevention, and Policy in 2011. He said Puerto Rican injecting users had been using it since the early 2000s. There, it is called Anestesia de Caballo (Horse Anesthetic). The report contained descriptions of how xylazine was viewed from a drug user’s perspective. One individual said the following about the first time he used xylazine and his later physical dependence on both heroin and xylazine:

I shot the anestesia […] and I felt asleep face first and when I opened my eyes five hours had gone by and I was laying on the floor. […] I don’t remember anything. I don’t remember anything! I fell down and I was gone. And I said: What the hell is this?! Oh, and I woke up sick [withdrawing]!I get there and don’t cop just heroin. I cop anestesia. Because that it what is going to get me high and what is going to get me straight [and reverse withdrawal symptoms]. I am not going to waste my money in just heroin because I’m going to stay the same. Do you understand? I’m going to stay the same.

Torruella said abscesses or ulcers were a serious health concern for several reasons. First, they are very painful. This encourages further injections in the abscess site with xylazine functioning as a sedative/anesthetic. This creates a need for medical attention and treatment.

Second, these open skin ulcers ooze and emit a strong odor. In severe cases, the mobility of the extremities where they appear is limited. Sometimes, amputations have been performed on the affected limbs. Third, when xylazine users asked for help in Puerto Rico, they were denied services because of their ulcers. The drug user quoted above said he was lucky because by the time his abscesses developed, he had relocated to the states and could access medical services:

[T]he times when the abscesses […] started to appear, I would come here, to the United States. […] [When the abscesses began to appear] I already knew. […] I had seen them [before]. […] [T]here are people that take a longer time in blowing up [with abscesses] than others. […] I am one in which it took a while. But when I saw that people were rotting I would get scared because I always have said that I am a junky with style.

Without basic healthcare needs, like medical/wound care, syringe exchanges and education, these open sores look terrible to both the medically trained and the untrained-eye. When a colleague saw the ulcers and their effects on non-users, she said: “Injecting drug users are being treated as if they were lepers.”

According to NIDA, the full scope of overdose deaths involving xylazine is unknown. But research shows they have spread westward across the U.S. NIDA-supported research is underway to illuminate emerging drug use patterns and changes to the illicit drug supply across the U.S. with xylazine, opioids and the evolving pattern of polydrug use, abuse and overdose. Stay tuned for the next sea change.

06/21/22

Gambling with Cannabis and Psychosis

Biological evidence supports a causal link between marijuana and psychosis. Additionally, this seems to be dose-dependent—with higher potency marijuana, there is an increased likelihood of a psychotic disorder. What is not clear, however, is whether at a population level patterns of cannabis use influence the levels of psychotic disorder. A new study published in The Lancet Psychiatry reported there is a strong link between high-potency marijuana and psychosis. “The odds of psychotic disorder among daily cannabis users were 3·2 times higher than for never users, whereas the odds among users of high potency cannabis were 1·6 times higher than for never users.”

If an individual began using marijuana before the age of fifteen, the odds were slightly increased, but not independent of the frequency of use or the potency of cannabis used. Compared with individuals who never used marijuana, those who used high-potency marijuana daily had four-times higher odds of psychosis. People who were using high-potency marijuana doubled their risk of psychotic disorder. “Our results show that in areas where daily use and use of high potency cannabis are more prevalent in the general population, there is an excess of cases of psychotic disorder.” The researchers estimated that 20% of the new cases of psychotic disorder could have been prevented if the daily use of cannabis had been arrested.

The study drew its data on first-episode psychosis cases from 17 areas in England, France, the Netherlands, Italy, Spain and Brazil. The novelty of this study was its multicenter structure and the availability of incidence rates for all the sites. The use of high-potency cannabis was a strong predictor of psychotic disorder in Amsterdam, London, and Paris where it was widely available. In the Netherlands the THC content can reach as high as 67%. See the chart below.

In conclusion, our findings confirm previous evidence of the harmful effect on mental health of daily use of cannabis, especially of highpotency types. Importantly, they indicate for the first time how cannabis use affects the incidence of psychotic disorder. Therefore, it is of public health importance to acknowledge alongside the potential medicinal properties of some cannabis constituents the potential adverse effects that are associated with daily cannabis use, especially of highpotency varieties.

Susan Gage, a psychologist and epidemiologist at the University of Liverpool, wrote a commentary on the study. Commenting for NPR, she said: “What this paper has done that’s really nice is they look at rates of psychosis and cannabis use in lots of different places where underlying rates of psychosis are different.” With regard to the finding that cities with more easily available high-THC marijuana have a higher rate of new diagnoses of psychosis, she said: “That’s a really interesting finding, and that’s not something anyone has done before.”

However, there are some who seek to minimize the findings. In “Psychosis is the last marijuana side effect you should be worried about,” on the Popular Science website, Kat Eschner not-so-subtly dismissed the findings as “an ableist morality fable,” comparing it to the film, Reefer Madness. For more on the film Reefer Madness, see “Remembering Reefer Madness.” She acknowledged that for a specific population of marijuana users, there was a link, but “overemphasizing the connection poses its own problems.” She quoted a University of York mental health and addiction researcher, Ian Hamilton, who pointed out the connection between cannabis and psychosis has been known for a long time and said: “I think we have to be careful we don’t exaggerate the risk.” But that was not all Hamilton had to say on the matter.

Hamilton published his own research into the association of cannabis and psychosis, in the journal Addiction. The University of York press release on his study indicated that while the population level risk of developing psychosis was low, and those vulnerable to developing serious mental health problems is relatively rare. But for individuals who already have schizophrenia, marijuana can make their symptoms worse. He said: “The research was clear that the more high potency cannabis used, the higher the risk of developing mental health problems, even if they are relatively low in number. For those who already had schizophrenia cannabis exacerbated the symptoms.”

Professor Robin Murray, a Scottish psychiatrist and Professor of Psychiatric Research at King’s College, London, “cautioned that cannabis is not as safe as was once thought.” In an editorial for the British Journal of Psychiatry, he said 10 of 13 longitudinal studies showed cannabis users are “at significant increased risk of subsequently developing psychotic symptoms or schizophrenia-like psychotic illness.” The remaining three studies showed a trend in the same direction. “A recent meta-analysis reported that the odds ratio for developing psychotic symptoms or a psychotic disorder in individuals who had used cannabis over non-users reached 3.9 (95% CI 2.84–5.34) among the heaviest users.”

He noted where most forms of cannabis in the 1960s and 1970s contained less than 4% of THC and an equal proportion of CBD (which ameliorates the psychoactive properties of THC). But these have been displaced by stronger varieties, which range in THC potency from 16% up to 90% as wax “dabs.” Then there is the rise of synthetic cannabinoids. “In contrast to THC which is a partial agonist at the cannabinoid CB1 receptor, most synthetic cannabinoids are full agonists and consequently more powerful.” He noted how “the USA and Canada have embarked on a major pharmaceutical experiment with the brains of their youth.” He suggested that the UK “wait and see the outcome of the experiment.”

Researchers at Radbound University published the results of a large-scale genetic study in Nature Neuroscience. “The researchers found that people with schizophrenia are also more likely to use cannabis.” There were 35 different genes associated with cannabis use, particularly with the gene CADM2. This gene was already associated with risky behavior, personality and alcohol use. They found a genetic overlap between cannabis and the risk of schizophrenia, which was no big surprise as other studies have shown the association of cannabis use and schizophrenia. However, they also showed a causal connection.

The researchers used an analysis technique called “Mendelian randomisation” to show a causal relationship between schizophrenia and an increased risk of cannabis use. This may indicate that people with schizophrenia use cannabis as a form of self-medication. However, the researchers cannot exclude a reverse cause-and-effect relationship, meaning that cannabis use could contribute to the risk of schizophrenia.

It seems that adolescents are at a greater risk of experiencing symptoms like hallucinations, paranoia and anxiety with marijuana use. Levy and Weitzman published a research letter in JAMA Pediatrics. They found that of 146 teen marijuana users, 40 (27%) reported hallucinations and 49 (34%) said they experience paranoia or anxiety. “Compared to youth who said they had only tried marijuana once or twice, adolescents who used it every month were more than three times more likely to experience hallucinations, paranoia or anxiety.” One in four reported symptoms of depression.

Adolescents with symptoms of depression were more than three times more likely to experience paranoia and anxiety. And they were 51% more likely to report hallucinations than teens without depression. Sharon Levy, one of the researchers said:

We don’t know if the greater exposure to marijuana over time made the brain more susceptible to psychotic symptoms, whether kids who experienced psychotic symptoms became more likely to continue to use marijuana or if some third factor, such as depression, made kids both more likely to use marijuana heavily and also more susceptible to psychotic symptoms triggered by marijuana. . . . Regardless of which of these explanations is most accurate, there is clearly an interaction between marijuana use and brain function.

A study published in The Journal of Child Psychology and Psychiatry found that increased use of cannabis between 13 and 16 was associated with a higher likelihood of having psychotic-like experiences (PLEs). The lead author of the study said: “Our findings confirm that becoming a more regular marijuana user during adolescence is, indeed, associated with a risk of psychotic symptoms.” Going from occasional use to weekly or daily use increased an adolescent’s risk of PLEs by 159%. Also see: “Psychosis and Adolescent Marijuana Use.”

It seems clear that as a society we are moving towards increased use and availability of marijuana. And where recreational marijuana has been legalized, there appears to be more potent forms of marijuana and an increasing incidence of psychosis. While a 1:20,000 risk of developing symptoms of psychosis is negligible, it won’t remain that rare as people play the odds with marijuana and psychosis.

This article was originally posted on 5/21/2019.

06/7/22

A Coming Opioid Storm?

When Rahul Gupta was sworn in as the Director of the Office of National Drug Policy (ONDCP) on November 18, 2021, he said on Twitter that the overdose epidemic would be his top priority. He is the first physician to lead the ONDCP. President Biden made it clear to him that addressing the overdose epidemic was an urgent priority. “As director, I will diligently work to advance high-quality, data-driven strategies to make our communities healthier and safer.” Tellingly, the day before Gupta was sworn in, the CDC reported on November 17^th that there were an estimated 100,306 drug overdose deaths in the U.S. during the 12-month period ending in April of 2021, an increase of 28.5% from the same time period the year before.

Overdose deaths from opioids increased to 75,673 in the year prior to April 2021, an increase of 35% from the same time period the year before. Nearly 500,000 people died from overdoses involving any opioid from 1999-2019. The CDC said this took place in three distinct waves, with commonly prescription opioids (1990s), heroin (2010) and synthetic opioids (2013). See the graph below, which shows the three categories as well as opioids overall.

The Stanford-Lancet Commission was formed in response to the rising opioid-related morbidity and mortality rates in the USA and Canada over the past 25 years. An article by Humphreys et al in The Lancet in February of 2022, “Responding to the opioid crisis in North America,” noted that in the past 25 years, more people died of overdoses in the USA and Canada than World War 1 and World War 2 combined. Following the above-noted waves, the article made the following observations.

Humphreys et al said the approval of Purdue Pharma’s opioid medication OxyContin in 1995 marked the beginning of the first wave. Purdue fraudulently marketed it as less addictive than other opioids and thus more acceptable for a broad range of indications at high doses. See “Giving an Opioid Devil Its Due,” “The Tale of the OxyContin Lie,” and “Doublespeak in the Opioid Crisis, Part 2” for more on Purdue Pharma and OxyContin.

Backed by the most aggressive marketing campaign in the history of the pharmaceutical industry, OxyContin became the best known of a number of opioid medications (both extended-release and immediate-release formulations) whose prescription rate exploded in the USA and Canada.

There was a departure from decades of medical practice where opioids were used mainly for cancer, surgery and palliative care (people living with a serious illness like cancer). US and Canadian medical practitioners expanded opioid prescribing to include a broad range of non-cancer pain conditions that included lower back pain, headaches and sprained ankles. Per-person opioid prescribing roughly quadrupled between 1999 and 2011. There were 275 million opioid prescriptions written—approximately equal to the population of the two nations. The following graph shows UN data on international per-person consumption of opioids in 2010-12.

The political and cultural environment at the time the crisis emerged was not conducive to an early response; indeed, complacency allowed it to worsen. To attain respectability, trust, and influence throughout the world, opioid manufacturers strategically donated a small share of their profits to prominent institutions, including hospitals, medical and dental schools, universities, museums, art galleries, and sporting events. These donations secured goodwill and increased the credibility of the industry’s message that it was a selfless healer, pushing back against cruel anti-opioid prejudices.

The second wave began around 2010, as drug traffickers realized individuals addicted to prescription opioids were an untapped potential market for heroin. People were drawn in by the comparatively lower price of heroin. Before controls on prescribing were introduced, an analysis of national data suggested that 79.5% of Americans using heroin started with prescription opioids. When efforts began to stop the increase in prescriptions and reduce diversion of prescription opioids, addicted people began turning to heroin more rapidly than they otherwise might have.

The third wave of the opioid crisis began around 2014, as illicit drug producers began adding extraordinarily powerful synthetic opioids, such as fentanyl, to counterfeit pharmaceutical pills, heroin, and stimulants. This wave brought unprecedented lethality in addition to—rather than instead of—the previous waves, both of which continue today. Large numbers of US and Canadian people are still becoming addicted to prescription opioids each year, and most of those who die from heroin and fentanyl overdoses are previous or current users of prescription opioids.

An anonymous editorial in The Lancet accompanied the report of the Stanford-Lancet Commission, Managing the opioid crisis in North America and beyond.” It said the COVID-19 pandemic may have contributed to the number of overdose deaths by disrupting treatment programs and access to medications like naloxone, as well as disrupting support networks. The Commission called for characterizing opioid use disorder (OUD) as a chronic condition, requiring “innovation in treatment of OUD and in the treatment of pain. However, this innovation “must be met with reinforced regulation.”

A Mental Elf article commenting on the Stanford-Lancet Report, said it was an important and authoritative summary of the development of the opioid crisis in North America. It was called an invaluable resource for anyone interested in the problems associated with opioids. But the author, Ron Poole, thought it has a number of weaknesses. He said in his opinion, “at the heart of the international opioid problem is a false belief that pain can be eliminated pharmaceutically.” If we are to move forward, we need to embrace a rehabilitation approach to chronic pain “where opioids play a small and specific role,” rather than continuing to search for an “analgesic magic bullet.”

The pain-elimination myth is not soley the creation of the pharmaceutical industry; it has deep-seated roots in medical socio-cultural beliefs.”In the UK, gabapentinoids are frequently used alongside heroin, and the combination is a potent cause of respiratory depression and death. Gabapentinoids have a limited role in pain management, but they are widely prescribed. They are dependency forming in much the same way as benzodiazepines. Gabapentinoids are not mentioned in the Report.

Poole is right to point to these weaknesses with the Stanford-Lancet Report, especially the failure to mention that gabapentin, which is the sixth-most prescribed medication in the U.S. It has an addictive potential, but is not yet a scheduled substance by the DEA. Other researchers have referred to concomitant use of gabapentinoids and heroin as an emerging public health problem. See “The Truth About Gabapentin.”

Hopefully, we will have time to implement the recommendations in the Stanford-Lancet Report. Humphreys et al said it took more than a generation of mistakes to create the opioid crisis in North America and might take a generation of wiser policies to resolve it. Let’s hope the three “waves” of the opioid crisis, illustrated in the above CDC graph, aren’t signaling a coming storm surge of the opioid epidemic before that time.

05/17/22

Shamanistic Healing with Ayahuasca

Shaman in Ecuadorian Amazonia during a real ayahuasca ceremony, as seen in April 2015; © ammit | 123rf.com

Ayahuasca had (has?) a Hollywood connection. Celebrities like Jim Carrey, Lindsay Lohan, Chelsea Handler and others took the ayahuasca train for reasons as varied as personal enlightenment and telepathic experience. Celebrity interest in ayahuasca dates back to William Burroughs, who said the effects of yage (ayahuasca) were indescribable. “It is the most powerful drug I have ever experienced. That is, it produces the most complete derangement of the senses.”

The above quote is found in “The Yagé Aesthetic of William Burroughs,” the PhD Thesis of Joanna Harrop. She noted how The Yage Letters, published ten years after his own search for ayahuasca, did not include these comments. Perhaps Burroughs telepathically anticipated the actions that would later classify ayahuasca’s psychedelic ingredient, DMT (dimethyltryptamine), as a Schedule I controlled substance and intentionally left out those comments. Harrop noted that in his correspondence Burroughs seems to think of yage was a secret Cold War weapon. He said, “I know the Russians are working on it, and I think U.S. also. Russians are trying to produce ‘automatic obedience,’ have imported vast quantities of Yage for experiments on slave labor.”

While some follow Burroughs in his journey to the South American rainforests in search of their ayahuasca ritual, others simply fly a shaman in to L.A. from the Amazon River region to perform an ayahuasca ceremony. Because DMT is illegal in the U.S. these ceremonies are “invite-only.” You have to be vetted beforehand and show you’re serious about having the experience. In 2015, it was said: “On any given L.A. night, there are 50 to 100 circles being conducted.”

Scientific Studies of Ayahuasca for Healing

Yet there are also scientific studies being done to determine if ayahuasca can treat or heal depression, anxiety, PTSD and alcohol abuse. Scientists are also exploring how DMT alters the user’s waking brain-wave patterns, producing an experience that has been described as “dreaming while awake.” A study published in Scientific Reports by Timmermann et al found that immersion in the DMT state led to marked decreases in the user’s brain-wave patterns. Ars Technica said the subjects were fitted with EEG caps and electrodes to monitor their brain activity while being given an infusion of DMT. “The team found that the DMT caused a marked drop in alpha waves, a mark of wakefulness, along with a corresponding brief increase in theta brain wives, indicative of a dream state.”

These researchers also found there was more chaotic brain activity in subjects who were under the influence of DMT. They speculated this may explain why ayahuasca users report more vivid visual effects and a greater sense of immersion in the psychedelic experience. The lead author of the study, Christopher Timmermann, said: “From the altered brainwaves and participants’ reports, it’s clear these people are completely immersed in their experience—it’s like daydreaming only far more vivid and immersive, it’s like dreaming but with your eyes open.”

Co-author Robin Carhart-Harris said it was hard to capture and communicate what it is like for people experiencing DMT, comparing it to dreaming while awake or near-death experiences. “Our sense is that research with DMT may yield important insights into the relationship between brain activity and consciousness, and this small study is a first step along that road.”

A Brazilian study sought to assess the impact of ceremonial use of ayahuasca on alcohol and tobacco use disorder. Barbosa et al recruited 1,947 members of UDV—Uniã do Vegetal— from 10 states from all the major regions of Brazil. “Current use disorders for alcohol and tobacco were significantly lower in the UDV sample than the Brazilian norms.” This difference was even greater when UDV membership was more than 3 years.

We also found that ayahuasca use variables—ceremonial attendance during the previous 12 months and years of UDV membership—were much stronger predictors of reduced alcohol and tobacco use disorders and use during the previous 12 months than were the SES variables age, gender and level of education.

An another mostly Brazilian study by Palhano-Fontes et al of the therapeutic potential of ayahuasca on depression found evidence of rapid antidepressant effect after a single dose of ayahuasca when compared to placebo. The researchers noted that the severity of depression changed significantly, but differently for the ayahuasca and placebo groups. A review of the study in Mad in America by Hanna Emerson commented how the researchers noted a high placebo rate in their study—46% on day 1 and 26% on day 7. Their hypothesis was that the high placebo response was potentially associated with the ‘care effect,’ the comfortable and supportive environment experienced by participants in the study who were from low socioeconomic populations.

While all of the 29 participants reported feeling safe in the study, some participants reported it was not necessarily a pleasant experience. Some reported the experience was accompanied by a good bit of psychological stress. Most reported experiencing nausea and about 57% vomited. “Although vomiting is traditionally not considered a side effect of ayahuasca, but rather part of the purging process.” All participants were naïve to ayahuasca, with no previous experience with any other psychedelic substance.

The researchers touted their study as the first randomized placebo-controlled trial to investigate the antidepressant potential of a psychedelic with treatment-resistant depression. Because of the unique effects of psychedelics, a major challenge of the research was maintaining double blindness. They thought the additional measures taken in the study, including the use of an active placebo that increased anxiety and induced nausea, adequately preserved blindness in their study. But I wonder if that judgement was just wishful thinking on the part of the researchers. How do you truly double blind something with unique effects?

Uthaug et el concluded the drug was no better than a placebo. In order to understand the role of set and setting on psychological effects observed after participating in an ayahuasca ceremony, a naturalistic, placebo-controlled observational study was done. The researchers hypothesized that set and setting would impact both groups, but the pharmacological effects would only be seen in the ayahuasca group. Set referred to the intentions, mood state and expectations of the individual taking part in an ayahuasca ritual, and setting referred to the context in which the ceremony takes place.

A review of the study on Mad in America by Peter Simons observed that there was no difference between the ayahuasca group and the placebo group on outcome measures of anxiety, depression or stress. This suggested an important role for the set and setting of the ayahuasca ceremony itself. The researchers in Uthaug et al said:

Together, ratings of the psychedelic experience in the present study indicate that participants in both groups experienced altered states of consciousness during the ceremony and that the strength of the mean experience was low, with individual experiences ranging from absent to strong.

Participants in the study had extensive previous experiences with ayahuasca and may have developed personal sets of expectations and intentions. They speculated that repeated participation in ayahuasca ceremonies might stimulate learned associations with enhanced well-being, “which are memorized and experienced even when assigned to a placebo group.”

The present study primarily focused on the general impact of set and setting per se. In this context, it should also be noted that for many indigenous traditions, it is not necessary for the participants to consume ayahuasca. The belief held is that the shamans perform their work to aid those in the ceremony, even if they have not consumed the brew. [emphasis added]

The Shamanic Origins of Ayahuasca

Evidence of ayahuasca use can be dated back 1,000 years. In the 16^th century, missionaries from Spain first encountered indigenous people using ayahuasca in the western Amazonian basin. Their earliest reports described it as “the work of the devil.” Its transition from an indigenous South American healing ritual, to fashionable Hollywood “circles” and a potential treatment for various mental health conditions was facilitated by William Burroughs, his book The Yage Letters, a Chilean psychiatrist and the Esalen Institute.

When he was travelling through South America, Burroughs read a paper by an American ethnobiologist, Richard Evan Schultes, who is known for his studies of the use of plants, especially hallucinogenic plants, found in Mexico and the Amazon. Burroughs then sought ayahuasca in hopes that it could cure or relieve his opiate addiction. It did not cure his addiction to opiates, but it did lead to the publication of The Yage Letters.

A Chilean psychiatrist and self-proclaimed shaman named Claudio Naranjo convinced Schultes to permit him to travel up the Amazon with him in order to study ayahuasca with indigenous tribes. Naranjo brought back samples and eventually published the first scientific description of the effects of ayahuasca in 1967. In the U.S., he became a close friend of Carlos Castaneda (author of The Teachings of Don Juan), and worked with Fritz Perls, the originator of Gestalt therapy, as part of the early Esalen Institute community. He returned to Chile and began research into psychopharmacology. Afterwards he wrote The Healing Journey, originally published in 1973. Naranjo dedicated this book was to Franz Hoffman, “who sponsored my career as research psychiatrist in psychopharmacology and shamanism.”

Stanislav Grof, a well-known name in the psychedelic community, wrote the Foreword to The Healing Journey. In 1970 he presciently said that with the increasing knowledge of the nature and emotional dynamics of psychosomatic disorders, it became obvious there would be no overnight cure in the form of a new miraculous antidepressant agent. But he thought two independent streams seemed to have promise—the use of chemical agents with psychotherapy and the development of “new experimental psychotherapeutic techniques.”

Claudio Naranjo is an outstanding representative of both of these streams, and his synthesis of drug-assisted psychotherapy and the new experimental techniques seems to offer an interesting approach to the problem of brief therapy. . . [His] experience with psychoactive substances is even more impressive than his work with new psychotherapeutic techniques. Over the years, he has experiments with more than thirty compounds—mostly psychedelics and amphetamine derivatives—as adjuncts to psychotherapy. He made a special canoe journey up the Amazon River to connect with South American Indians and study their use of ayahuasca or yage.

Naranjo is the embodiment of the shaman-psychiatrist, combining psychedelics with psychotherapy to promote his sense of healing. His last talk, given six weeks before his death in 2019 was titled “The relevance of ayahuasca in the problems of the world.” After an extended discussion of civilized culture, original sin, and the patriarchal order, he turned to ayahuasca. He then described some of his experiments in Chile.

There was group of people who were naïve to the culture of indigenous peoples, who didn’t know what they were taking. They would start seeing birds and snakes and other “typical indigenous images of ayahuasca, which are depicted in the ceramics of the South American peoples.” He convinced himself this was something like what Carl Jung called the archetypical world. He thought the most striking phenomenon in ayahuasca was not the appearance of the animal aspect, the personification of the primitive. “What’s striking about ayahuasca is a change of attitude toward the animal.”

We have transformed some animals into terrible animals, but clearly the terrible is a part within ourselves. But there is the potential of recognizing another type of animality that is sometimes called a power animal or a sacred animal. I don’t think that this is a strange phenomenon of ayahuasca, because one of the pillars of psychotherapy was the Freudian ambition of decriminalized instincts. It’s not usually achieved. Other things are much more easily achieved. The depth of the original sin leaves a really deep imprint in us. So we feel bad because we carry a life of instincts. So it’s quite rare to have this phenomenon, which we sometimes easily see in ayahuasca. One of my first voluntary subjects, a woman, came across a Siberian tiger, a white tiger, and the tiger then became her guide. She’s now older, she’s my age, and she still feels that the tiger is her spiritual guide.

We are at a time when mental health professionals are being challenged to seriously investigate the supposed scientific potential of various psychedelics like ayahuasca, MDMA and psilocybin for conjoint use with psychotherapy. We should also become aware of the long association of psychedelics with shamanistic healing rituals and the clearly unscientific explanations of their power. Is the discussion of dramatic healings with ayahuasca and other psychedelics just a description of a shamanistic healing ritual couched in scientific rhetoric? While further study is needed, it seems to me that the placebo effect of the ceremony, not the psychedelic compound itself, is the significant factor in reported therapeutic changes with ayahuasca.

For more information on Claudio Naranjo, see “Is the Enneagram Spiritually Neutral? Part 2 and Part 3.

04/26/22

It’s Strictly Business

While news on the fighting in Ukraine was dominating the headlines at the beginning of March in 2022, a struggle of a different kind came closer to an end. The legal battle between the Sackler family and Purdue Pharma on the one side, and a group of states who refused to sign off on the settlement last summer seems to have ended when both sides agreed to a mediated settlement. The New York Times reported it was the first time in three years of negotiations that all states accepted a settlement agreement with Purdue Pharma and the Sacklers. “While the deal is a breakthrough, it is likely to leave many people disappointed that members of the Sackler family did not acknowledge wrongdoing or any personal responsibility for the public health crisis.”

If the judge presiding over Purdue’s bankruptcy proceedings approves the agreement, the Sackler family would pay up to $6 billion to help communities provide assistance for the damage from the ongoing opioid crisis. This was an increase of more than $1 billion from an earlier offer. The Sacklers would have 18 years to make payments of the additional $1 billion. In return, Sackler family members would be protected from all current and future civil claims against them over their company’s prescription opioid business. However, the deal does not protect them from potential criminal cases, which are difficult to prove.

The Sacklers’ position on prohibiting future civil lawsuits was a major obstacle for states that opposed the plan. The latest deal included an agreement by the Sacklers to create a public repository of confidential documents that detail lobbying, public relations and marketing activities with OxyContin. The attorney general of Connecticut, one of the states that rejected the earlier offer, said the settlement was both significant and insufficient, “constrained by the inadequacies of our bankruptcy code.” This settlement resolves their claims against Purdue and the Sacklers, but the fight continues against the wider addiction industry.

The new mediated agreement has several additional terms. Family members from the Sackler family were to attend a hearing that would allow people who suffered from OxyContin addiction to describe what they endured. Any medical centers, art or educational institutions that bear the Sackler name can remove it without their action being contested by the family. Also, there was a statement attached to the settlement that was characterized as an “apology.” Widely described as an apology, this statement doesn’t seem to qualify as one. The Sackler family said:

The Sackler families are pleased to have reached a settlement with additional states that will allow very substantial additional resources to reach people and communities in need. The families have consistently affirmed that settlement is by far the best way to help solve a serious and complex public health crisis. While the families have acted lawfully in all respects, they sincerely regret that OxyContin, a prescription medicine that continues to help people suffering from chronic pain, unexpectedly became part of an opioid crisis that has brought grief and loss to far too many families and communities.

The new settlement still faces a difficulty. The U.S. Trustee program, which oversees the bankruptcy system within the Department of Justice, has argued vigorously against the proposed immunity shield for the Sacklers. Before the tentative agreement, there was a conflict building in the U.S. Court of Appeals for the Second Circuit. So far, the Justice Department has not commented on whether it would continue to challenge that condition of the tentative settlement.

The above-noted hearing was conducted on March 10^th by the judge overseeing Purdue’s bankruptcy and featured 26 people from 19 states. The NYT said it was the first time individuals were able to directly address members of the Sackler family. The three members of the Sackler family who attended the hearing were: Dr. Richard Sackler, a former president and chairman of the board; David Sackler, a former board member; and Dame Theresa Sackler, a former board member and widow of Dr. Mortimer Sackler, one of the company’s founders.

Dame Theresa sat quietly; her expression unchanging. David Sackler sometimes shifted his position. Dr. Richard Sackler, who was the family member seen as most involved in the company’s aggressive marketing of OxyContin, remained off camera the whole session. This infuriated some of the participants. One of the individuals referred to the Sacklers as “killers,” saying that to this day, they deny any wrongdoing; that the family acted lawfully in all respects. “Richard, can you honestly say that with a straight face? If so, why don’t you turn on your camera and let’s see?”

Dr. Sackler was permitted to remain off camera by prior agreement. Also by prior arrangement, the Sacklers did not speak during the session and did not issue a statement afterwards. An individual testifying at the hearing, who was himself in recovery from an opioid addiction, quoted a statement made by Dr. Sackler in 2001, which said: “We have to hammer on the abusers in every way possible. They are the culprits and the problem. They are reckless criminals.” He then accused Richard Sackler, “You are the abuser. You are the criminal and you are the culprit . . . I hope that every single victim’s face haunts your every waking moment.”

A man from Indiana, who was a criminal court judge, lost his son to an overdose. The man and his wife began their testimony time by playing a recording of the 911 call made when they found their son dead from an overdose. He was “a straight-A student in college, studying law.” The judge said to Dr. Sackler, “I have put away drug dealers with a single rap of a gavel without blinking an eye. Oh, how I wish I could do the same to you, Richard Sackler.”

Foundations, art galleries and museums around the world have requested they become distanced from the Sackler name, including: The Metropolitan Museum of Art and the Dia Art Foundation in New York, the Serpentine Gallery and the four Tate galleries in the U.K., and the Louvre in Paris. Others, including the Guggenheim and the American Museum of Natural History in New York, and the British Museum in London have not announced plans to remove the Sackler name from their institutions.

Members of the Sackler family have persistently denied that the billions of dollars removed from Purdue Pharma over the course of a decade was done to shield assets from potential litigation over their role in the opioid crisis. But a review of emails, memos and other documents showed that Sackler family members discussed exposure to potential litigation as early as 2007, “a full decade before they faced a new wide-ranging legal attack and significant financial transfers stopped.”

Blomberg Businessweek published an article noting “How the Sacklers Shifted $10.8 Billion of Their Opioid Fortune.” Initially, Purdue and its subsidiaries moved billions to companies registered in Luxembourg, the British Virgin Islands and Delaware. “From 2008 through 2017, $10.8 billion flowed out of Purdue in hundreds of transactions through numerous subsidiaries.” The money eventually landed in two Delaware companies, Rosebay Medical Co. and Beason Co., which are trusts for the benefit of the Sackler family. See the Bloomberg article for particulars of the monetary shell game with Purdue funds.

Blomberg said a spokesperson for the family said in a statement: “All of the Sackler family members, including those who served on Purdue’s board, have always conducted themselves properly.” From 2007 to 2019, 10 Sacklers were Purdue directors. The following graphic appeared in the Blomberg article.

NPR reported last year that “Purdue Pharma conducted Massive Probe of the Sacklers, But The Findings Are Secret.” The company acknowledged hiring attorneys, forensic accountants and other financial experts to probe members of the Sackler family. The team searched for evidence of wrongdoing by the family and reported their findings to a special committee of Purdue’s board between April 2019 and March of 2021. But Purdue chose to reveal essentially nothing of what investigators uncovered. “Purdue’s disclosure filing says it paid its lawyers for a 22,000-hour investigation of the Sacklers, but it doesn’t disclose any of their findings.”

Writing for NPR, Brain Mann said the Purdue Pharma document suggests the primary goal of the investigation “was to inform and shape bankruptcy talks” that were underway at the time. Speaking on behalf of the Sacklers, spokespersons downplayed the significance of the investigation and maintained members of the family did nothing wrong. An attorney for the Raymond Sackler family said: “As we have said before, we support the release of documents and they will continue to show Sackler family members who served on Purdue’s board acted ethically and legally.”

A few clues about what investigators found were evident in the filing. The filing stated that “certain dealings between Purdue Pharma and the Sackler families and various Sackler entities were not conducted on arm’s-length terms.” There is a link to the “Alix Report on Distributions to Sacklers,” noting compensation, pension benefits, travel and expense reimbursements, legal expenses incurred on behalf of Sackler family members, and fringe benefits provided to members of the Sackler family such as cell phones, fleet vehicles and personal service employees up until April 30, 2019.

It seems the Sacklers were playing the long game from the time of Purdue’s first admission of illegal actions in “misbranding” OxyContin in 2007. See “Giving an Opioid Devil Its Due.” From 2008 until 2017 there was a transfer of over $10 billion out of the company. From 2007 to 2019, 10 different members of the Sackler family served on Purdue board. An extensive investigation by Purdue was done of members of the Sackler family looking for evidence of wrongdoing.

The investigative team reported to a special committee of the board between April of 2019 and March of 2021, but failed to publicly disclose any of its findings. The Sacklers consistently denied any wrong doing and repeatedly warned that a failure to protect family members from all current and future civil claims against them over their company’s prescription opioid business would scuttle the bankruptcy negotiations and perhaps end “The ability of creditors, communities, and individuals to receive billions in value to abate the opioid crisis,” according to Steve Miller, Purdue’s chairman.

The Sacklers will not face any civil charges; criminal filings are very difficult to prove and will likely not be filed. Despite the transfer of billions of dollars from Purdue, ultimately to family trusts, members of the family deny having done anything ethically or legally wrong. Their so-called apology was formed in non-apologetic rhetoric that took no responsibility for Purdue Pharma’s or the family’s role in birthing the opioid crisis. There is no apparent remorse by members of the Sackler family involved in the day-to-day operations and decisions of Purdue Pharma that led to the eventual addiction and deaths of hundreds, if not thousands of people. There seems to have been one unverbalized, but clearly communicated statement by the Sacklers in their so-called apology quoted above: “It’s not personal; it’s strictly business.”

For further information on the Sacklers and Purdue Pharma, see: “It Doesn’t Seem Right,” “Carrot-and-Stick Tactics of Purdue and the Sacklers” and “What Purdue and the Sackler Family Treasure.”

04/5/22

The Psychedelic Pendulum and Psychiatry, Part 1

In November of 2020, Oregon became the first state to legalize the use of psilocybin in therapeutic settings. Measure 109 created a two-year time period during which regulatory details were to be worked out by the Oregon Psilocybin Advisory Board (OPAB). These details would include issues like what qualifications would be required of therapists overseeing those who chose to use psilocybin. Significantly, psilocybin treatment will not be limited to individuals struggling with mental health issues. Anyone 21 or older who passes a screening will be able to access these psychedelic services for “personal development.”

The first draft of rules recommended by the OPAB were made public in February of 2022. Manufacturers will only be permitted to cultivate one of about 200 different types of mushrooms containing psilocybin, Psilocybin cubensis. Some people were concerned with this recommendation, believing the board was also limiting potential benefits. “It is believed that different species promote different types of experiences.”

Psilocybe cubensis was chosen because it’s one of the most popular mushrooms consumed and one of the most studied. Advisory board members also thought that it would be best to start simple, with one mushroom. Other species might be introduced later.

The OPAB also recommended a ban on growing Psilocybe cubensis in wood chips. This is to prevent a rare condition known as wood lover’s paralysis that produces muscle weakness a few hours after hallucinogenic mushrooms grown in wood chips are consumed. Scientists don’t know why this condition occurs. “But it isn’t believed to happen with Psilocybe cubensis.”

The rules also prohibit the chemical synthesis of psilocybin. Measure 109 also requires the state to only license people to set up grow operations who have been Oregon residents for at least two years. Well, at least until 2025. These recommendations are attempting to allow small farmers to set up grow operations and limit the ability of large pharmaceutical companies to move in and potentially dominate the market.

There are other reasons for banning synthesized psilocybin. The synthesis requires using toxic chemicals that have to be extracted before sale so there’s no residue in the final product. Mason Marks, a member of the OPAB, said synthesizing psilocybin is a huge undertaking. “There was some sentiment that that might be maybe unrealistic or overly burdensome, at least initially to expect people to have that level of expertise or equipment in order to do that.”

Manufacturers will have to use clean, food-grade equipment in an area that can be locked. They won’t be permitted to make psilocybin products that may appeal to minors, like in the shape of cartoon characters. Psilocybin is only permitted to be used orally—not with an inhaler, a suppository or an injection. Students will have the opportunity to observe “non-ordinary states of consciousness.”

Facilitators (not therapists?) will have to take at least 120 hours of instruction, covering everything from the history of psilocybin use to safety concerns. They will have to have sufficient experience to teach classes for individuals interested in trying psilocybin. But what about ethical expectations and boundaries with clients under the influence?

Therapeutic facilitators of individuals doing psychedelic therapy from the time of its origins in the 1950s recommended two therapists, one male and one female. This was to minimize the possibility of sexual exploitation of the clients when they are under the influence of psychedelics. More about this in part 2 of the article.

These draft rules need to be discussed and adopted by the Oregon Health Authority. Other rules are still pending, such as how research with psilocybin should be conducted, and the conditions (i.e., schizophrenia) that would prohibit people from trying psilocybin treatment. There are more complicated issues that need to be decided as well. There’s a desire to permit microdosing psilocybin (taking one-tenth or one-twentieth of a normal dose), over a few days. This practice is thought to boost creativity and focus, as well as alleviate depression.

Oregon’s psilocybin system is scheduled to begin in 2023. The Oregon Health Authority will begin taking applications for licenses to manufacture, transport, deliver, sell and purchase psilocybin products on January 2, 2023.

Psychology Today has a page that introduces the reader to “Psychedelic-Assisted Therapy,” giving information on the most common psychedelic substances, their general effects and properties, as well as potential harms and proposed therapeutic uses. It also has a section on “Understanding Microdosing.” The most common psychedelic substances listed on the page were: psilocybin, LSD, ayahuasca, mescaline and MDMA. All but MDMA listed psychosis as a potential harm. Therapeutic uses being investigated include: PTSD, addiction to alcohol, tobacco and cocaine; anxiety associated with terminal illness; depression and general anxiety.

Dependence or substance misuse is not listed as a potential harm for any of the psychedelics, which do have a low risk for addiction. But the repeated therapeutic use of psychedelics increases the ritualized, long-term use of these drugs, and raises the possibility of misuse or dependence problems developing in users over time.

Information on microdosing said there was some evidence of positive effects performance and creativity, but it was mostly anecdotal. One 2018 study published in the journal Psychopharmacology, “Exploring the effect of microdosing psychedelics on creativity,” found support for its cognitive enhancing properties, but fluid intelligence was unaffected. The researchers concluded that while large doses of psychedelics can introduce several undesirable side effects, microdoses might be an alternative that could eliminate the risks of these side effects, while maintaining the benefits on emotion and thinking.

A 2016 study by Roland Griffiths et al, also published in the journal Psychopharmacology, found that when a high dose of psilocybin was administered to patients with a life-threatening cancer diagnosis under supportive conditions, there were “substantial and enduring” decreases in depressed mood and anxiety. It also resulted in increases in measures of quality of life, life meaning, the acceptance of death, and optimism. The effects were sustained for six months.

There has been a veritable flood of articles and research on the supposed benefits of psychedelics, particularly psilocybin and MDMA, over the last several years besides these two Psychopharmacology studies. In 2019, the FDA designated psilocybin therapy as a breakthrough therapy for Usona Institute, the second pharmaceutical company to gain such an approval in that year. The first company, Compass Pathways, is looking at how psilocybin may help with treatment-resistant depression, that is patients who have not improved after trying two different antidepressants. The significance of the second FDA breakthrough approval is related to how it expands the potential market from the relatively small population of individuals struggling with treatment resistant depression to the estimated 17 million with major depressive disorder, according to a statement by Usona:

This is a significant milestone for the over 17 million people in the US who suffer from MDD. Although there are several existing MDD treatments, Breakthrough Therapy Designation recognizes that psilocybin may offer a clinically significant improvement over these therapies. Psilocybin potentially offers a novel paradigm in which a short-acting compound imparts profound alterations in consciousness and could enable long-term remission of depressive symptoms.

Dr. Samoon Ahmad provided a helpful description of how psilocybin affects the brain in a Psychology Today article, “Understanding the Buzz About Magic Mushrooms.” He said psilocin, not psilocybin, seems to be the substance responsible for the psychoactive effects of “magic mushrooms.” Psilocybin and other psychedelics like LSD and mescaline activate the 5-HT1A and 5-HT2A receptors in the prefrontal cortex, which in turn has downstream effects on serotonin and dopamine. “The increase in dopamine is believed to be part of the reason for some of the psilocybin’s effects on mood, such as euphoria, and the commonly reported phenomenon of depersonalization.”

He said the probability of serious adverse events and abuse of psilocybin was low when compared to other classes of abused drugs. The association of the lifetime use of psychedelics and an increased likelihood of mental illness or suicidality “simply does not exist,” according to Ahmad. By associating “lifetime use of psychedelics” and an “increased likelihood of mental illness or suicidality,” Ahmad’s sidesteps how psychedelics can be destabilizing for some individuals who have a past history of psychotic disorders like schizophrenia. See Part 2 for more information on concerns with psychedelic psychotherapy.

Psilocybin can also produce side effects like hypertension, nausea, vomiting, anxiety, confusion and more. Ahmad also pointed out the importance of “set and setting,” the individual’s mindset and their environment.

A positive experience may inspire life-changing epiphanies and grant individuals a greater perspective on life. A negative experience may result in disturbing thoughts or hallucinations, which may lead to anxiety, disorientation, delirium, and, in extreme circumstances, temporary psychosis. Researchers have found that they can significantly diminish the likelihood of negative experiences by providing patients with more preparation and interpersonal support during the period of drug action.

There is still a risk if the interpersonal support is inadequate or inappropriate—not respecting clear, therapeutic boundaries between the support person and the client. And the preparation may not get the person ready for the actual psychedelic experience. Careful attention to the “set and setting,” the inner and outer environments of the drug event, is crucial for a positive experience.

Ahmad said research has shown that psychedelics hold a great deal of promise, “as long as they are administered in a controlled and clinical environment or under the guidance of individuals who are experienced in the use of psychedelics.” But stigma surrounds the use and research into these drugs. His hope is that there will be a loosening of restrictions and regulations in the U.S. as there is more research published, “and the case for the use of psychedelics becomes stronger.”

Dr. Ahmad and researchers like Roland Griffiths (see this Google scholar link for “Roland Griffths psilocybin”) are representative of those who see the potential for psychedelic therapy, particularly with psilocybin. Rick Doblin and his organization MAPS (Multidisciplinary Association for Psychedelic Studies) are attempting to bring MDMA to market as a treatment for PTSD see this Google scholar link for “Rick Doblin MDMA”). British researchers including Robin Carhart-Harris and David Nutt want to treat depression with psilocybin. Michael Pollan, author of a best-selling book on psychedelics, How to Change Your Mind, thought there has been a sea change in attitudes towards psychedelics. In “The Psychedelic Revolution Is Coming,” he said, “Given the mental health crisis in this country, there’s great curiosity and hope about psychedelics and a recognition that we need new therapeutic tools.”

But what are the risks in turning to psychedelics like psilocybin and MDMA as the next great hope in psychiatric drug treatment? As Andrew Jacobs noted in his NYT article, “The Psychedelic Revolution Is Coming,”

The question for many is how far — and how fast — the pendulum should swing. Even researchers who champion psychedelic-assisted therapy say the drive to commercialize the drugs, combined with a growing movement to liberalize existing prohibitions, could prove risky, especially for those with severe psychiatric disorders, and derail the field’s slow, methodical return to mainstream acceptance.

We’ll look at some of the concerns others see with the growing move towards psychedelics as the newest fad in the pursuit of therapeutic tools in Part 2 of this article. For more information on psychedelics as therapy, see the following articles on this website: “Psychedelics Are Not a Magic Bullet,” “The Long, Strange Trip of Psychedelic Psychiatry,” “Give MDMA a Chance?,” and “Psychedelic Renaissance?”

03/15/22

Trends in Substance Use and Abuse

The National Survey on Drug Use and Health (NSDUH) provides information on tobacco, alcohol, and drug use, mental health and other health-related concerns in the US. NSDUH began in 1971 and is conducted yearly in all 50 states and the District of Columbia. The National Survey on Drug Use and Health (NSDUH) for 2020, published in October of 2021, interviewed almost 70,000 people. It is directed by the Substance Abuse and Mental Health Services Administration (SAMHSA), an agency in the U.S. Department of Health and Human Services. NSDUH has been conducted by RTI International, a nonprofit research organization in North Carolina.

Criteria from the DSM-5 were used in order to categorize the substance use disorders (SUD) of the respondents. SUDs are classified by impairment caused by the recurrent use of alcohol or other drugs, including health problems, disability, and the failure to meet major responsibilities at work, school, or home. Respondents were said to have an SUD if they had two or more of the eleven criteria noted on page 27 of the 2020 NSDUH survey. The following figure provided an overview of the number of people aged 12 and older who initially used the noted substances in the past 12 months.

A surprising finding was that there are more people trying hallucinogens for the first time in the past year than cigarettes. This is likely a result of popular and research interest into using hallucinogens such as ketamine and MDMA, to treat mental health issues. See “Psychedelics Are Not a Magic Bullet”, “Give MDMA a Chance?”, “In Search of a Disorder for Ketamine” and other articles on this website.

But it should come as no surprise that the top two substances used for the first time in the past year were alcohol and marijuana. Alcohol is legal in all states and although marijuana is illegal under federal law, recreational marijuana is legal in 18 states and 37 states have legalized medical marijuana. Only in four states, South Carolina, Kansas, Idaho and Wyoming is marijuana still fully illegal. See “Map of Marijuana Legality by State.”

The above figure shows that in the past 12 months, 4.1 million people began using alcohol and 1.3 million people tried a cigarette for the first time. There also were 2.8 million new marijuana users, 1.4 million new hallucinogen users, 1.2 million people who first misused prescription pain relievers, 950,000 new misusers of prescription tranquilizers, and 734,000 new misusers of prescription stimulants. There were also 489,000 new cocaine users and 153,000 new methamphetamine users.

Despite the opioid epidemic, estimates of initial heroin use in the past year were the lowest category of new users at 103,000. Nearly 90 percent of individuals using heroin for the first time did so after the age of 25. Among adults aged 26 or older, 91,000 people initiated heroin use in 2020.

Substance use disorders are with alcohol or drugs; or a mixture of both. There were 40.3 million people 12 or older estimated as meeting the criteria for a SUD in the past year. This included 28.3 million who had an alcohol use disorder (AUD) and 18.4 million who had an illicit drug use disorder (IDUD). Among those individuals with an AUD, 21.9 million had AUD but not an illicit drug use disorder. Among the 18.4 million people with a past year IDUD, 11.9 million has an IDUD but not AUD. This meant there were 6.5 million who met the criteria for both AUD and IDUD. See the figure below.

Age is again seen as a factor with the presence of SUDs in the past year. When the figures for substance use disorder were looked at by age, the percentage of people with a past year SUD was highest among young adults aged 18 to 25 (24.4% or 8.2 million people). This was followed by adults 26 or older (14.0% or 30.5 million people).

Among people aged 12 or older, 10.2% (28.3 million people) has a past year AUD. The percentage of people who had past year AUD was highest among young adults aged 18 to 25 (15.6% or 5.2 million people). Again, this was followed by adults 26 or older (10.3% or 22.4 million people).

Among people aged 12 or older, 6.6% (18.4 million people) had an IDUD in the past year. The percentage of young adults aged 18 to 25 (14.6% or 4.9 million people) was higher than the percentages of adults aged 26 or older (5.6% or 12.3 million people) and adolescents aged 12 to 17 (4.9% or 1.2 million people). See the following figure.

However, the vast majority of the population did not have a SUD of any kind in the past year. The 40.3 million people with a past year SUD represent 14.5% of the population aged 12 or older. The remaining 236.6 million people, 85.5% of the population aged 12 or older, had no past year SUD. But when substances are distinguished as marijuana, methamphetamine, cocaine, stimulants, pain relievers and heroin, the number of people with the respective substance use disorder was as follows. Notice that a significant majority of people with an illicit drug use disorder had a marijuana use disorder.

Among people aged 12 or older, 5.1% (or 14.2 million people) has a marijuana use disorder in the past year. With people aged 12 or older, .8% (or 2.3 million people) had a prescription pain reliever use disorder; and 6% (or 1.5 million people) had a methamphetamine use disorder. Among people aged 12 or older .5% (or 1.3 million people) had a cocaine use disorder; .6% (or 1.5 million people) had a methamphetamine use disorder; .3% (or 758,000 people) had a prescription stimulant use disorder; and .2% (or 691,000 people) had a heroin use disorder.

When the use of marijuana, pain relievers and methamphetamines were looked at by age, the percentage of young adults aged 18 to 25 with marijuana use disorder (13.5% or 4.5 million people) was significantly higher than the percentages for adolescents aged 12 to 17 (4.1% or 1.0 million people) or adults 26 or older (4.0% or 8.7 million people). Prescription pain reliever use disorder and methamphetamine use disorder for all three age groups were only nominally different from each other. See the following figure.

There seems to be a clear pattern, particularly among young adults, that beginning marijuana use leads to an increased chance of developing a marijuana use disorder. Data on the perceived risk of harm with the above substances may be one factor explaining where this trend may be headed. Respondents of the 2020 NSDUH survey were asked how much they thought people risk harming themselves physically and in other ways when they used various substances in certain amounts or frequencies.

Among people 12 and older, 70.7% of people thought there was a great risk of harm from smoking one or more packs of cigarettes daily, and 68.7% saw great risk from having four or five alcoholic drinks nearly every day. The percentages of people who thought there was a great risk from cocaine or heroin use once or twice a week were 84.7% and 93.2%, respectively. “In contrast, about one fourth of people (27.4%) perceived great risk from smoking marijuana once or twice a week.” See the following figure.

Young adults aged 18 to 25 in 2020 were less likely than adolescents aged 12 to 17 or adults aged 26 or older to perceive great risk of harm from smoking marijuana weekly. Research has identified associations among adults between decreases in perceptions of great risk of harm from smoking marijuana weekly and increases in marijuana use. Nevertheless, people can experience adverse effects from marijuana use, such as marijuana use disorder or injury resulting from operating a motor vehicle while impaired by marijuana. Therefore, it is necessary to educate young adults about adverse effects of marijuana use.

The growth of the marijuana legalization movement will likely lead to increased marijuana use and disorder over all age groups. The 2.8 million first time users of marijuana in 2020, along with the 14.2 million marijuana users who meet the criteria for marijuana use disorder, and the significantly lower perception of there being a risk of harm from smoking marijuana once or twice a week suggest as much. But that isn’t the only concern the NSDUH 2020 hints at. In the near future, I’ll look at other issues present in the data, so return and search for “NSDUH 2020.”

The NSDUH provides information that can be used to support prevention and treatment programs, monitor substance use trends, estimate the need for treatment and inform public health policy. Let’s hope its information on marijuana and other substances is helping to inform public health policy and is used to develop future prevention and treatment programs.

02/22/22

Risks of Ketamine for Suicide Prevention

As 2021 drew to a close, there was another study published online that evaluated ketamine’s value in mental health therapy. As other research has shown, this metanalysis found that ketamine could quickly relieve depression and thoughts of suicide. But the rapid response was usually short-lived. While there was some evidence it helped with other disorders, the evidence base was of a small number of primarily non randomized trials with short follow-up periods, which require confirmation and extension.

The study, “Ketamine for the treatment of mental health and substance use disorders,” was published in the British Journal of Psychiatry Open. The write up of the study in Medical News Today, “What 83 studies say about ketamine and mental health,” was generally positive. However, one of the study’s co-authors thought it was best administered in a clinical environment. In such a setting, people can be provided with “preparation and psychological support during and after the ketamine infusions” which can reduce the risk of adverse events. This is a methodology that follows similar attention to the “set and setting” in psychedelic drug research.

Commenting on the study, Alan Schatzberg, a professor of psychiatry and behavioral sciences at Stanford, thought the research to date was not enough to determine whether ketamine was effective enough to be worth it. He said, “I haven’t seen enough real data to say that we [have] got a huge winner here.” One of his concerns was that he thought ketamine worked through an opioid mechanism, acting significantly with mu opioid receptors. In certain forms and situations “it’s highly addictive.” Opioid drugs had been used to treat depression until the mid-1950s, but were largely abandoned because of concern about abuse.

Schatzberg was the senior author of a 2018 study in The American Journal of Psychiatry that showed how ketamine activates the opioid system. The study was created after the authors saw research that suggested drugs that only worked on the brain’s glutamate system weren’t very effective antidepressants.

Speaking to NPR about the study, Schatzberg said: “We think ketamine is acting as an opioid. . . That is why you’re getting these rapid effects.” The researchers commented their findings challenged the current understanding of ketamine’s mechanisms of action and its antidepressant properties.

They designed their study to investigate whether ketamine activates mu opioid receptors. This meant they treated patients with depression in two ways. First, depressed patients were given an infusion of ketamine alone. Second, depressed patients were given naltrexone, which blocks the effects of opioid drugs, before they received their infusion of ketamine. This was not a blinded study for ketamine; it is essentially impossible to design a double-blinded study with drugs like ketamine that have dissociative side effects.

An analysis of a dozen patients who got both treatments showed a dramatic difference. Seven of the 12 saw their depression symptoms decrease by at least 50 percent a day after they got ketamine alone. But when they got naltrexone first, there was “virtually no effect.”

Dr. Schatzberg gave a talk on “Clinical Use of Ketamine in Suicide Prevention” for McLean Hospital and discussed the above research. In the slide below, taken from his talk, you see a clear antidepressant effect with the ketamine plus placebo group (K+P). When the same patients get naltrexone first (K+N), there is no evidence of a ketamine effect. The “B” graph shows the dissociative effect of ketamine was not blocked in the ketamine and naltrexone group, while the antidepressant effect was.

The anti-suicide effects of ketamine were also blocked by naltrexone, as shown in the graph below, taken again from Dr. Schatzberg’s McLean talk. This led the researchers to conclude, “the antidepressant effect of the ketamine is being mediated in some way through mu opioid receptors.”

Schatzberg noted how there have been five reports since 2018, three of which have been published, all of which show that mu opioid antagonists block ketamine’s behavioral effects. “We can show that ketamine works through an opioid effect.” He then asked, if this effect could be harnessed. In further research, Schatzberg and others looked at buprenorphine, which is a partial mu opioid agonist. At high doses (16-24 mg per day) it has an antagonist effect, blocking typical opioid effects. But very low doses, under 2 mg, have been used to treat refractory depression.

There was a 1995 study by Bodkin and Cole that investigated the potential for low doses (less than 2.0 mg per day) of buprenorphine to treat refractory depression. Its findings suggested a potential role for buprenorphine in treating depression. There was also a 2016 Israeli study by Yovell et al that looked at whether ultra-low doses of buprenorphine (.2 mg-.8 mg) could treat severe suicidal ideation.

At two weeks, Yovell et al had a dramatic reduction in suicidal ideation as assessed by the Beck Suicide Ideation Scale. This was true at the end of two weeks and at the end of four weeks. At the end of week 4, the buprenorphine was discontinued, reportedly without withdrawal symptoms at a one-week follow-up appointment. “It is possible that in this opioid-naïve population, the short duration and low dosages protected against dependence.” See the graph below taken from the Yovell et al study.

Notice that the dramatic reduction in suicidal ideation was not evident until after one week of ultra-low dose buprenorphine. Contrasting this to the rapid, within one day, antidepressant response noted above, raised a research question Schatzberg and other are currently investigating. Can you get a more immediate anti-suicide effect if you first pre-treat buprenorphine patients with ketamine?

Schatzberg and a team of researchers are looking at 60 patients with major depression and active suicidal behavior. They are repeating the Israeli experiment, but adding it after a ketamine infusion. All patients receive an open label, intravenous infusion of ketamine. Two days later, patients are randomized to receive ultra-low dose buprenorphine or placebo for 4 weeks. This research is ongoing; no results were discussed or presented in Schatzberg’s talk.

Given the previous research, it seems likely these researchers will demonstrate a rapid antidepressive reduction in active suicidal behavior. Combining ketamine and buprenorphine as Schatzberg does in this experiment will simultaneously engage two systems that seem to mediate depression and suicidal ideation—the endogenous opioid system and the glutamatergic system. However, we need to keep in mind that both of the drugs in Schatzberg’s experiment, ketamine and buprenorphine, are classified as Schedule III Controlled Substances.

The Yovell et al study suggested that ultra-low doses of buprenorphine were successfully discontinued without withdrawal. But wasn’t that after a single treatment? Studies of ketamine’s rapid antidepressant effects indicate the changes are temporary and require repeated therapeutic interventions in order to maintain an improvement in mood. In time, could tolerance and withdrawal become evident with ultra-low dose buprenorphine as it has already been shown with ketamine?

Considering the ultimate risk of suicidal ideation leading to completed suicide, it would seem to be an acceptable risk-benefit ratio as a therapeutic intervention for suicidality. But as an ongoing, repeated cycle to treat major depression, the ketamine-buprenorphine combination does not appear to be an acceptable risk to me. In time, the patient could add physical dependency concerns with ketamine and buprenorphine to his ongoing struggle against depression.

I look forward to the completion of Schatberg’s study and hope the publication of the results will address this concern. For more information on ketamine, see this review of research by The Mental Elf and other articles on this website: “Ketamine to the Rescue?”, “In Search of a Disorder for Ketamine,” and “Is Ketamine Really Safe & Non-Toxic?”

Faith Seeking Understanding

Charles Sigler, D.Phil.

Category Archives: Addiction & Recovery