Synthetic Cannabinoids: A Review

Synthetic Cannabinoids

A Review : Presented by Lauren Pace, DO

Transcript of Presentation:

Dr. Anish John: Good afternoon everyone, and welcome. I know some people here but for anyone I don’t know, my name is Anish John, I’m the Associate Medical Director here at Positive Sobriety Institute and I’m an addiction psychiatrist.

Dr. Angres is our Medical Director who actually founded this program but he is out of town this week so introductory responsibilities have fallen to me. I’m an adjunct associate professor at Northwestern University with the Department of Psychiatry and Behavioral Medicine, and they’re who we collaborate with to essentially organize this ongoing lunch and learn series. The idea being just furthering education in the field of addiction, exploring advances, in both the understanding, treatment of substance use and behavioral process addictions as well.

Coming to our presenter, Dr. Lauren Pace, she rotated with us here at PSI, and so I have the pleasure of getting to know her. Dr. Pace has quite an interesting background. Undergrad at Brown University, she majored in Visual Art and then later went on to receive a Master’s Degree in Fine Arts from the California College of the Arts in San Francisco. The pull of medicine, I think eventually did win out, and this just adds to the mood at this point.

So, yes, the pull to medicine prevailed. She essentially solidified her desire to work in Psychiatry in medical school in Colorado and retained her interests in engaging in the creative process in exploring the psyche. She completed her general psychiatry residency training at Baylor College of Medicine. Over the years, she’s had the opportunity to work with numerous individuals who struggle with addiction in a variety of settings. She’s currently an addiction psychiatry fellow at the University of Illinois at Chicago, which is how we came to know and work with her. She is a Board-Certified Psychiatrist and upon completion of her fellowship in July 2017 we’re very pleased to hear that she has accepted a position at the Meridian Psychiatric Partners. It’s a private practice here in downtown Chicago, and we wish her all the best.

Today she’ll be giving us an overview on Synthetic Cannabinoids. Without further ado, I will invite Dr. Pace to come on in.

Dr. Lauren Pace: Thanks so much, Dr. John for that introduction. So, as Dr. John mentioned, the talk today is going to be about synthetic cannabinoids and it’s going to be a basic overview. I apologize because I’m getting over a cold, so if there’s any coughing fits that go on during this talk, please excuse that.

Here’s the objectives for our talk today. I want to talk about the origin of synthetic cannabinoids, the legal restrictions that are in place, the prevalence of their use. I also want to explain their mechanism of action and how that differs from just natural marijuana. And then also, I want to demonstrate the effects of how the synthetic cannabinoid use through a couple of cases that I’m going to present where we see that people can really suffer unintended consequences when they’re using these substances heavily.

I have a few questions here.

• The first question: Synthetic cannabinoids are detected in urine drug screens. Who think it’s true? Who thinks false? You guys are right. Okay, they are not and we’ll get to that later as well.
• Synthetic cannabinoids are schedule 1 controlled substances. True? False? They are in fact schedule 1 controlled substances.

Synthetic cannabinoids may be more ly to cause psychotic symptoms as compared to marijuana due to their lack of one of these four – we don’t have to go through all of them, but this will come up later in the talk as well. And then, it has been proposed that synthetic cannabinoids may cause symptoms of psychosis including catatonia through a mechanism similar to one of these four items listed here. And again, this will come up later so just keep it in the back of your minds.

So, I want to start out with a couple of case descriptions and these are cases of patients that I encountered during my training in Houston. I think in Houston synthetic cannabinoids might have been a little bit more popular than they are in Chicago, at least from what I’ve seen thus far. And actually, I did not meet either of the patients that I’m going to talk about but because of my interest in addiction psychiatry I was asked to come on board and help write the paper.

So, the first case is a 21-year-old African-American male. He had a reported history of untreated ADHD. He was brought to Harris County Hospital in Houston by his mother due to gradually worsening psychiatric symptoms over about a year’s duration. His family was reporting that he was isolating, he was not taking care of his grooming and hygiene, he was eating less, and eventually couldn’t feed himself at all. He also had a positive history of occasional cannabis use but then it came out that he had been using Cush or synthetic cannabinoids really heavily over the past year and a half. So, as you noted, he didn’t have any previous mood or psychotic symptoms. In an interview, he had this catatonic picture where he was largely mute, he couldn’t really interact with staff members trying to ask him questions. He could nod yes or no, or just utter his first name. He was described as being kind of lost in the chart in the ER. He was positive for self-talk, and then also inappropriate laughter. His urine drug screen was positive for cannabis and his medical work up in the emergency room was negative.

While in emergency department, the patient was given Ativan, a benzodiazepine, in order to address the catatonic symptoms. And so, there was some improvement. He was able to converse a little bit better, he was following simple commands, and he was also able to eat. He was then admitted to the in-patient psychiatric unit within the county hospital. Risperdal, an antipsychotic was started along with Ativan. Ativan was also titrated to a little bit higher dose twice a day. However, poverty of thought remained as well as delayed responses, inappropriate smiling, and then he had this multiple paraphasic errors in communication. That would be adding extra syllables to words, or adding words where they don’t belong. So, at that point in time, Risperdal was switched to Abilify and that was titrated to up 25 milligrams a day.

The patient’s catatonia did resolve completely during the admission but he did have these cognitive deficits that sort of persisted. This was the incongruent affect and then the paraphasic errors as well, which would be more consistent with the picture of dementia. You might see something that. He was not psychotic at the time of discharge. When he was discharged, he was given a long-acting injection of Abilify and there was concern that he lacks insight into what was going on and that he probably might not come back for a follow up so we want to sort of cover the basis there a little bit. He was taught that his symptoms were pretty much substance induced and hope that after some time he’d be a candidate for being able to come off the anti-psychotic completely.

The second case is a 17-year-old Caucasian male also with no psychiatric history, and he presented to local emergency department with psychosis after a two week Spice binge. He also had history of smoking cannabis periodically for about a year. He was brought with his parents and they described his initial symptoms as being sort of more manic where he has euphoria, he had grandiosity, a little bit of paranoia, he didn’t really need to sleep very much, and he was pretty disorganized. He had been admitted to another hospital in Houston and started on Risperdal as well and failed to improve and worsened over time actually.

He then presented to Menninger Hospital in Houston which is a private hospital. On that admission, his picture had changed a little bit. So again, he was coming in with a more catatonic type of picture. So not really speaking, just sort of blank affect, blank stare, couldn’t really complete any sentences. He did try to make attempts but it just wasn’t really happening. His urine drug screen was also negative and the medical work up was negative as well.

So, in this case, he was cross treated from Risperdal to Abilify and still no critical response. Ativan again was started and titrated again up to two milligrams twice a day and so this did result in some improvement in speech and a little bit more coherent thought processes as well. However, it was noted that he did have sort of excessive sematic delusions and ideas of reference. So, because of those features, Olanzapine was added, also with partial benefit. Later Valproic Acid or Depakote was added and that was titrated up while Abilify was tapered off. With that, regimen improvement was evident because his speech became more spontaneous, he was more organized, he was no longer rigid, his movements were a little bit more fluid. But he did also have cognitive deficits that persisted including difficulty reading and concentrating. And this was someone who previously had been a straight A student, doing really well in his final year in high school and now he can’t read a book. He was discharged on Depakote, Ativan and Zyprexa and also with plans to follow up in outpatient clinic.

I just want to go into a little bit of background and history about synthetic cannabinoids, and I’ll refer to them as SCs to shorten down that word. They are now included in a group called new psycho active substances or NPS. These are unregulated psycho active substances. They’re mind altering substances. They’re newly available, and their intention is to mimic illegal substances. A lot of them probably have been around for some time but come back in vogue when there was a resurgence in popularity which is what’s happened with synthetic cannabinoids.

In terms of natural marijuana there’s about 60 cannabinoids found including Delta-19 tetrahydrocannabinol (THC) and that is most psychoactive cannabinoid. Cannabidiol and cannabinol are also found in natural marijuana. Synthetic cannabinoids are analogs of natural cannabinoids and are chemically synthesized in laboratories. They were initially developed to get a better understanding of how these compounds affect signaling pathways in the body, and also there was a demand for research to see if there could be any sort of therapy that benefits with compound that are found in natural marijuana. So that was what got that research going.

John W. Huffman, a PhD at Clemson, started research on these class of chemicals that are found in natural marijuana, the cannabinoids in the 1980s. His work continued over the course of 20 years and he was funded by NIDA. Over that time, he and his team developed over 450 different SCs that could mimic the effects of natural marijuana. A lot of these compounds has the initials JWH which are his initials with numbers after them. So JWH 018 is one of the most common chemical found in SCs.

It was found that these SCs were becoming drugs of abuse in Europe in about 2004. Then they made their way over to the US in about 2008. In March of 2011, SCs were classified as Class 1 controlled substances by the US DEA so now they are illegal to possess, sell or use. In July 2012, the synthetic drug abuse prevention act was also signed into law. So formerly you could get these things anywhere. You can get them out in gas stations, drug paraphernalia shops head shops. Obviously, you could get them from on the internet pretty easily. Now they can still be purchased online as well but you know it’s harder to find out on the streets. A synthetic compound is usually added to herbs or plants. A lot of times it’s just spray it on dead leaves. And so. they try to make it look a natural product and then they’ll market it as herbal incense or herbal remedies. The clinical effects can really be similar to natural marijuana but synthetic cannabinoids also can result to much more life-threatening consequences.

Just one thing to note as well that the chemical analogs of THC that are used in SCs are constantly changing, so they can avoid these regulatory oversights and this continues to happen. And then these constant changes can also introduce more toxic effects overtime. So, this is just some names of SCs. The most common ones you might encounter would be K2, Kush, spice, maybe kaonic, and they are sold in these really colorful foil packages, usually labeled not for human consumption. In terms of epidemiology, as noted these have emerged as significant drugs of abuse in Europe and in the US. One study reported that about 7,000 cases were reported annually of people using single agent and having adverse effects more in the emergency department care. There also have been fatalities reported as well. The users are typically young males in their 20s, may be late teens, early 30s. However, about 11% of high school seniors have reported using and that was back in 2012. That’s a big number for that age group. And I think that also points to the fact that they are probably pretty easy to obtain, people thought that they were more safe.

This bar graph compares synthetic cannabinoids to marijuana in terms of percent of emergency department visits. This is by age in the bottom, and you can see that the age from 12 to 20, synthetic cannabinoids account for much higher percentage of ED visits than natural marijuana. Whereas, natural marijuana is pretty consistent over time and age. There have been recent reports also that synthetic cannabinoids are just behind natural marijuana in terms of elicit substances being used in that population that we just described. There has been another study that reported that adolescents account for about a quarter of the patients presenting to hospitals and clinics for acute synthetic cannabinoid poisoning. This is also increasing in Europe. SCs are representing about two-thirds of all new substances reported to European drug monitoring and early warning system.

As noted, the easy access to this products in the belief that they’re natural and they’re not harmful probably contributed to their use among young people. A 3-gram bag cost between $20 and $50. Three grams is a pretty food amount. So, I think you can get them pretty cheap. And then as noted, standard drug test is not going to pick up synthetic cannabinoids. And for that reason, SCs have become popular with people who have to undergo random drug screens. Sometimes military personnel. I saw a lot of patients coming in to the Houston VA who have been using and became acutely paranoid. Also, people who are on probation, parole, who you know have to get drug screened. And then an interesting one, it just made me think of even professionals on this program who have to undergo random urine drug screens. (This is not going to show up.)

Let’s move on to talking about toxicity, pharmacology, and mechanism of action of these substances. So that’s just a picture of what this stuff looks . As you can see, it does a little bit a regular marijuana. In terms of how it’s used, it’s used in a much similar fashion so you can smoke it. Some people mix it with marijuana and smoke it. You can bake it in brownies and cookies, other types of food. Some people to vaporize it in e-cigarettes. It’s metabolized via the liver aside from oxidase enzymes. It’s really excreted. Again, it’s difficult to report a specific toxic dose because the compounds are continuously changing. And then the degree of toxicity would depend on the amount that has been used or the specific compound that was used.

Compared with natural marijuana, SCs have a much greater potential for severe neuropsychiatric toxicity so this will include hallucinations, delirium, paranoia, psychosis. And also, there can be life threatening toxicity caused by severe agitation, seizures. This is much more characteristic of SCs than natural cannabis. SCs, they’re chemically hydrogenic group of compounds. Similar to natural marijuana, they act as agonists at cannabinoid CB1 and CB2 receptors. CB1 receptors are found more on the central nervous system. CB2 more on the peripheral nervous system. CB1 receptors, they play a very important role in inhibitory and excitatory neurotransmissions. Other receptors might be involved as well NMDA receptors and serotonin receptors. It’s important to note that various SCs have a diversity of potency in clinical effects due to their affinity for the binding site on CB1 and CB2 receptors. However, due to the CB1 receptor antagonism many of the physiological effects of SCs are comparable to that of natural marijuana. As you’d see the same symptoms of intoxication conjunctival injection, increased appetite, staginess, ataxia, slurred speech, maybe a little bit of paranoia. However, it’s also important to note that SCs are much more potent agonists at these receptor sites. So, potencies can range from anywhere 2 to 800 times greater than Delta-9 THC.

Also, the herbal plant or the product that’s carrying this compound can have its own hallucinogenic properties or can contain contaminants, or sometimes they put caffeine, nicotine, tramadol, things that in there that could also really enhance the toxic effects. Also, important to note SCs have been found to lack cannabidiol. So, this is the flavonoid found in THC that actually has anxiolytic and antipsychotic properties. So, when people say that natural marijuana helps with their anxiety it’s ly because of cannabidiol, this compound. In synthetic cannabinoid, they don’t have that. You are sort of having all of these other effects without the anxiolytic effects. That might explain the severe psychosis that we see with synthetic cannabinoids. As the use is expanding, people are using more and more, more serious effects are being reported psychosis, impaired cognition and catatonia as we discussed earlier on with the two gentlemen I presented.

In 2016, at that time, there were about a hundred and seventy known SCs that were being manufactured by illicit drug labs. And then just definitely potential for novel compounds to appear in the future. They’ve fallen to a few structural groups, so classical cannabinoids which are analogs of Delta 9 THC, the non-classical cannabinoids and then a bunch of others that I didn’t want to bore you with on this slide.

So, let’s talk about clinical manifestations and what happens when someone uses. When someone is using, smoking synthetic cannabinoids there is a wide spectrum of effects that occurs soon after inhalation. They’ll usually lasts hours maybe days depending upon the potency and the compound. And then the signs of intoxication are getting buried by whatever compound they had been using. So again, thinking that a lot of the effects are going to be similar to that of marijuana as what we’ve talked about but there can also be more adverse clinical effects. There was this one report where 2000 reports of single agent exposure. The most adverse effects include tachycardia, agitation, and vomiting and this is what brought people into the emergency department at that time. From mild to moderate symptoms duration is usually going to be less than eight hours so kind of similar to natural cannabis.

They do have the potential to cause much more serious toxicity. Another study reported the frequency of adverse symptoms after just single agent exposure. Agitation, psychosis, paranoia, I’d include in there as well, in about two-thirds of people; bradycardia, tachycardia, other cardio vascular findings in about 17%. Rhabdomyolysis is 6%, respiratory depression is 5%, and then acute kidney injury is 4%. So pretty serious repercussions. Neurological findings severe psychomotor agitation, psychosis, seizures, hallucinations, delirium, dystonia, paranoia.

They have been highlighted in several case reports and case series and also similar to what we were talking about earlier on. If someone is very agitated or having seizures that mark motor activity could result in hyperthermia or rhabdomyolysis. Death has also been reported as noted so there was this one death of a 17-year-old adolescent after just first-time use of inhaled synthetic cannabinoids. This is sort of interesting. This one report of mass exposure of 33 adults to burning SCs as they’re called AK47 24 karat gold. The intoxication was marked by lethargy, blank staring, zombie groaning, slow mechanical movement of the arms and legs. Sounds pretty frightening. If you encounter the group of 33 people undergoing something that. But symptoms did resolve after about 12 hours.

More seriously, synthetic cannabinoids have also been associated with stroke, subarachnoid hemorrhage, chest pain, heart attack, ischemia in adults and adolescents who have no risk factors for these events. Also, because they are inhaled in a manner similar to a natural cannabis, they can cause exacerbation, lung problems such as asthma and pneumothorax. There haven’t been any reports of synthetic cannabinoid use in young children. But based on what we’ve seen about cannabis exposure in young children, and central nervous system excitation in older patients, you could expect a wide range of toxicity including agitation, seizures, and potentially even coma.

So, let’s move on and talk about diagnosis. Just first, I’m just wondering has anyone have experience with patients or people using synthetic cannabinoids here? Oh, okay. Alright. There’s a couple of you. Furthermore, does anyone ask routinely about synthetic cannabinoids when doing a full screen for substances of abuse? Alright. I mean I forget to do it all the time but I think it’s something that’s really important to think about. So, acute intoxication is going to be a clinical diagnosis for the most part. You can make the diagnosis if someone reports that they are using spice or fake weed. Sometimes they might even have the product on them. Usually though you’re going to need collateral from family or friends. And then as I’ve said a few times now, rapid urine drug screens are not going to detect synthetic cannabinoids because the chemical compounds and metabolites don’t cross react with THC. So that’s what these screens are designed to detect. So, you can do confirmatory testing via liquid chromatography and mass spectrometry but these are not going to return in a timely manner, so it’s not potentially helpful if you’re in an emergency room setting. If the original product is available, you could send that off to a lab for an examination, but again that’s going to take time. And also, because these chemical compounds are changing so much, they can really evade any sort of identification from reference laboratories. So, it can be sometimes difficult to differentiate synthetic cannabinoids use from other drugs of abuse.

As noted, mild SC use can look very much like natural marijuana use. The difference would be that the drug screen would be negative. If the drug screens are positive for cocaine or amphetamine or anything else, that doesn’t necessarily mean that they’ve not been using synthetic cannabinoids as well. In terms of more serious intoxication, the presentation might look more similar to someone who’s been using sympathomimetic or hallucinogens such as cocaine, amphetamine, LSD, PCP, and even bath salts.

In terms of treatment, what do we do? A lot of times the management is just going to be supportive and this is going to be determined by how severe the case is, and how severe the manifestations are. So, if someone is coming into the ER or in to an urgent care, the symptoms of intoxication usually will resolve in a couple of hours. It’s probably best just keep someone in a dim room with low stimulation, more of a calming supportive environment. Reassurance is also really important, benzodiazepines can be helpful in controlling the agitation if that’s present. When someone has sobered up you definitely want to do a thorough drug screening for any other substance usage use and then underlying mental illness as well.

Severe intoxication can be life threatening and you definitely want to treat in a manner that is directed at the most significant findings. Some of the patients will require large amounts of sedation, you might have to treat seizures, manage complications, intoxication that we talked about like hypothermia, rhabdom, MI, pneumothorax, or AKI, so hospital admission might be warranted. And then also in the two cases that I noted, admission to in-patient psychiatry is warranted as well. On that note, just want to go back to the cases quickly.

I just want to talk a little bit about catatonia, and give a little bit of overview here. So, this is the state of behavior abnormally in neurogenic immobility as first described in 1800, late 1800s by Karl Kahlbaum. It’s characterized as a motor disorder representing a phase in an illness that progresses to final end stage of dementia. Symptoms can include catalepsy, waxy flexibility, stupor, mutism, posturing, mannerisms, stereotypy, echolalia, echopraxia. So typically, people you can position them in all sorts of different positions and they’ll hold that position or they might just have this manner of holding this position for an hour or two. They might repeat what you say, they repeat what you do. They might just be completely mute. That’s something to look out for. It is estimated that catatonia does occur in about 10% of all patients with psychiatric illness so that’s a lot. And now it’s considered as a specifier for other psychiatric conditions. So, either mutes, psychosis, anxiety not just a sub type of schizophrenia as it was before. So, in terms of catatonia the pathophysiology and mechanism still remain poorly understood. Neuro imaging has suggested that it might be due to disruption of basal ganglia over the frontal and limbic circuits so this results in a dopamine and GABA depletion, and glutamate excess.

Catatonia caused by excessive glutamate may respond well to NMDA antagonists Ketamine or Memantine. And then in cases of drug induced catatonia, there’s just sort of scattered case reports so not really any specific guidelines to go from there. So, in the cases that we presented we believe that the catatonic states were brought on by synthetic cannabinoids. This was in light of the fact that there was no pre-existing psychosis, mood, or medical disorders. They developed this prolonged catatonia and also with these cognitive deficits that persisted after using SCs. There haven’t been any studies linking catatonia to natural marijuana use, so it’s interesting that these two cases presented so closely together after synthetic cannabinoid use. It was thought that the catatonic state was brought on by persistent high use of SCs.

Clinically a diagnosis can often be made of catatonia in terms of response to benzodiazepines or ECT. Benzodiazepines are the first line treatment. It’s important to remember that symptoms of catatonia the motor slowing, immobility, mutism, lack of appropriate responses, these can sometimes be confused with illicit drug withdrawal states as well. Sustained cognitive impairment have not been reported previously at least at the time that we wrote this paper associated with SCs but we found it in both of these patients. Definitive treatment for catatonia does remain elusive. If the patient is not psychotic you should really use dopamine antagonists with caution because neuroleptics can worsen the clinical picture of catatonia. And then medically induced catatonia of course you want to treat the underlying medical condition. We did propose that catatonia might share a path of mechanism similar to neuroleptic malignant syndrome. This is because of the decrease in dopamine and GABA as well as the excessive glutamate that’s present. This made the Abilify more possible treatment option because it’s a partial agonist of dopamine DP receptors and serotonin type 1 receptors and antagonist of serotonin type 2 receptors.

The first patient did do well on Abilify. The second patient did not. It might have been because of a low dose, or it might’ve have been because of something else. And then valproic acid was proposed as a treatment because of its action on GABA as well. Both patients were started on Ativan, a benzodiazepine. One of them experienced remarkable but transient improvement and the second had just more modest effects. When thinking beyond catatonia treatment, as mentioned benzodiazepine can be very helpful in terms of treating the agitation that might be present as well as tachycardia. So ECT is also successfully use in the treatment of catatonia. There were a couple of case reports that came off before we published this where ECT was used in the case of SC induced catatonia. Both patients did fail to improve with Risperdal and one failed the Abilify trial. We are thinking that this was because it might have been that high potency antipsychotics are not very effective for catatonia. The second patient was given Depakote and he did have some clinical improvement after failure of anti-psychotic trials.

Neither patient that we knew of had an underlying psychotic disorder but both did exhibit these kinds of sustained cognitive impairments that lasted after their symptoms improved, their other symptoms improved. The second patient was reporting these ideas of reference and somatic delusional concerns. So, this was suggested that perhaps an underlying psychosis might’ve been masked by the catatonia. Also, the fact that these two gentlemen were in the prime age range when one might expect the first break psychosis. That could’ve muddied the clinical picture a little bit as well. So, we did use an expanded panel of medications with different mechanism of actions to treat these patients because they failed to respond to traditional recommendations.

One last time, routine drug screens do not detect synthetic cannabinoids, and they can be detected by gas chromatography or mass spectrometry. You won’t get rapid results and it can be limited when you’re in an acute setting. Also, additives within SC mixture is a concern and this might also worsen the clinical picture for some. Until GC, MS or other testing is more available, personal and collateral history are going to remain the most important avenues in terms of gathering clinical data. This was illustrated in the two patients above who were brought in by their family members. Just last point is that when confronted with a similar case or circumstance you need to keep an open mind regarding treatment options as well as the diagnostic complexities. And that is all I have. Thank you so much for your attention. Questions? Comments?

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