TL neuro

January 2, 2017

Current Topics in Behavioral Neurosciences on Novel Psychoactive Substances

Filed under: 4-MMC/Mephedrone, Cannabimimetics, Cathinones, IVSA, MDPV, Methylone — mtaffe @ 2:08 pm

There is a new Current Topics in Behavioral Neuroscience book on New and Emerging Psychoactive Substances that has been organized by Michael H. Baumann, Ph.D., of the Intramural Research Program of the National Institute on Drub Abuse. This editorial effort resulted in 18 chapters on various topics of interest which are now available online.

Chapter 1: Madras, B. The Growing Problem of New Psychoactive Substances (NPS) [link]

Chapter 2: Glennon, R.A. and Dukat, M. Structure-Activity Relationships of Synthetic Cathinones [link]

Chapter 3: Simmler, L.D. and Liechti, M.E. Interactions of Cathinone NPS with Human Transporters and Receptors in Transfected Cells [link]

Chapter 4: Solis, E. Electrophysiological Actions of Synthetic Cathinones on Monoamine Transporters [link]

Chapter 5: Baumann, M.H., Bukhari, M.O., Lehner, K.R., Anizan, S., Rice, K.C., Concheiro, M. and Huestis, M.A. Neuropharmacology of 3,4-Methylenedioxypyrovalerone (MDPV), its Metabolites, and Related Analogs [link]

Chapter 6: Negus, S.S. and Banks, M.L. Decoding the Structure of Abuse Potential for New Psychoactive Substances: Structure-Activity Relationships for Abuse-Related Effects of 4-Substituted Methcathinone Analogs [link]

Chapter 7: Watterson, L.R. and Olive, M.F. Reinforcing Effects of Cathinone NPS in the Intravenous Drug Self-Administration Paradigm [link]

Chapter 8: Aarde, S.M. and Taffe, M.A. Predicting the Abuse Liability of Entactogen-Class, New and Emerging Psychoactive Substances via Preclinical Models of Drug Self-administration.[link]

Chapter 9: King, H.E. and Riley, A.L. The Affective Properties of Synthetic Cathinones: Role of Reward and Aversion in Their Abuse [link]

Chapter 10: Kiyatkin, E.A. and Ren, S.E. MDMA, Methylone, and MDPV: Drug-induced Brain Hyperthermia and its Modulation by Activity State and Environment [link]

Chapter 11: Angoa-Pérez, M., Anneken, J.H., Kuhn, D.M. Neurotoxicology of Synthetic Cathinone Analogs [link]

Chapter 12: Wiley, J.L, Marusich, J.A. and Thomas, B.F. Combination Chemistry: Structure–Activity Relationships of Novel Psychoactive Cannabinoids [link]

Chapter 13: Tai, S. and Fantegrossi, W.E. Pharmacological and Toxicological Effects of Synthetic Cannabinoids and Their Metabolites [link]

Chapter 14: Järbe, T.U.C. and Raghav, J.G. Tripping with Synthetic Cannabinoids (‘Spice’): Anecdotal and Experimental Observations in Animals and Man [link]

Chapter 15:Halberstadt, A.L. Pharmacology and Toxicology of N-Benzylphenethylamine (“NBOMe”) Hallucinogens [link]

Chapter 16: Papaseit, E., Molto, J., Muga, R., Torrens, M., de la Torre, R. and Farre, M. Clinical Pharmacology of the Synthetic
Cathinone Mephedrone [link]

Chapter 17: Mayer, F.P., Luf, A., Nagy, C., Holy, M., Schmid, R., Freissmuth, M., Sitte, H.H. Application of a Combined Approach to Identify New Psychoactive Street Drugs and Decipher Their Mechanisms at Monoamine Transporters [link]

Chapter 18: Schifano, F., Orsolini, L., Papanti, D., Corkery, J. NPS: Medical Consequences Associated with Their Intake [link]

 

November 3, 2016

Thoughts on Proposition 64 to Legalize Recreational Marijuana in California

Filed under: Cannabis — mtaffe @ 10:41 am

I wrote a brief note on Facebook the other day to outline what I thought were several points that come up when people in the community ask me about the upcoming vote on recreational marijuana (link to ballotpedia summary of Prop 64). This was picked up in a post at Forbes by David Kroll (a handy summary video is here)

This piece was noticed by Sasha Foo at KUSI and she was kind enough to film a news segment which aired on 2 November, 2016. This links to the 6 pm broadcast version.

My Facebook remarks (with a few key links to data sources added):

I’m in California which will be voting on Proposition 64 which legalizes recreational marijuana. As many of my friends, neighbors and acquaintances are aware that I work in the substance-abuse fields of science, they have questions. So I thought I would put some of my usual responses/points down on a Fb post.

First, some background on my opinions. I work for you, the taxpayer of the US. This is because my work is funded by grants from the National Institutes of Health. Because these are primarily from the National Institute on Drug Abuse, my role is to investigate the effects of recreational drugs on the brain (and the rest of the body) with some attention paid to how this might affect the health of humans.

This is most emphatically not a policy role. I have no special expertise on public policy and my comments are not meant in that way. I do hope that science can be used to inform policy and, frankly, I wish that public policy across the board paid a lot more attention to facts and data. This is not to say, however, that I believe that the facts necessarily lead all interested people to the same *policy* decision. Because policy requires the weighing of factors and pitting positives and negatives of various kinds against each other.

As far as legalizing recreational marijuana goes, I do think that the epidemiological, human laboratory and animal laboratory data has some relevance to the Prop 64 issues. So, I’m going to list a few facts.

1) Marijuana is addictive. Full stop. The conditional probability of dependence is about 9% where like-to-like comparisons put cocaine and methamphetamine at 15%, heroin at 25-45% (data are terrible) and alcohol at 4%. Alcohol is a huge problem because 85%+ of people consume it at least annually. In contrast, less than 1% of people have ever tried heroin, 0.4% in the past year. Marijuana comes in at about 32% annual prevalence for ages 19-28. The scope of the addiction issue depends on how many people are using it, obviously. This will go up with legalization- but we don’t have any idea how much.

2) 5-6% of high-school seniors use Marijuana daily. Daily. That’s the US average. I don’t have numbers for California. http://www.monitoringthefuture.org/data/15data/15drfig4.pdf

3) Marijuana addiction is as “real” as any other. Frequency of withdrawal symptoms and severity of those symptoms were compared between marijuana and tobacco smokers and the data were nearly indistinguishable. Most people are much more familiar with nicotine dependency (which is a higher rate, btw, probably 33%+) since it is more common, not embarrassing to discuss in public and is conventionally recognized. A lack of personal familiarity with the scope of withdrawal in the people who are marijuana dependent doesn’t mean that it doesn’t exist.

4) There is no such thing as “psychological” versus “physical” dependence since the brain is part of the body and the mind is the functioning of the brain. Keep in mind that people can be months to years out from their last use of any drug and still relapse severely. This is not being driven by the withdrawal symptoms that most everyone recognizes when they talk about “physical” dependence.

5) Marijuana acutely impairs cognitive and other behavioral functions.

6) Behavioral tolerance with chronic exposure is substantial. Blood levels of THC in animals or humans are a poorer proxy for impairment (versus other drugs) if you do not know anything about the prior exposure history.

7) THC is detectable in the body for a very long time compared with many other drugs of abuse. One study found detectable THC, or one of the main metabolites, for 30 days of in patient study (chronic users).

8) Trying to make specific predictions about an individual who uses marijuana from general findings (there is always a central tendency or average around which the distribution of data points or individual outcomes varies) is a fools’ errand. We can only predict general trends. Conversely, and this is important for your personal introspection, the evidence from one given data point or individual doesn’t tell us much that is informative about the average trend. The fact that it is your personal experience does not make it more valid.

Finally, there is much we simply don’t know. Any given scientific study or data set is limited by how it was generated. This doesn’t mean we throw up our hands and say it is all bunk or uninterpretable but it means one does have to think about it a bit.

I would invite you to read over the Prop 64 provisions. Personally, I see a fair bit of investment of the tax revenue in state sponsored activities to answer some of these issues better, to address some of the obvious concerns, etc. To me this is a positive. The extent to which this will happen, the extent to which actionable information will result, the extent to which activities intended to head off or ameliorate obvious negatives is, however, an unknown.

May 31, 2016

Inhalation model for evaluation of e-cigarette based delivery of THC

Filed under: Cannabis, E-cigarettes, Vape inhalation — mtaffe @ 11:13 am

Our interest in developing inhalation techniques for delivering cannabinoids, most especially the primary active constituent Δ9-tetrahydrocannabinol (THC), to rats arose from the realization that increasing numbers of people were using non-combusted methods for inhalation. When we started this project there were no studies using a Volcano type or e-cigarette type of system to deliver THC to rodents. Of course the majority of cannabis consumption has always been via smoke inhalation and there have been a few prior studies in laboratory models, primarily from the Lichtman laboratory. Our focus was therefore on the non-combustible techniques stemming from the evidence of personal acquaintance reports, a plethora of Web sites advertising methods, an emerging literature showing human practices (Giroud et al, 2015, Morean et al, 2015) and from suggestions that e-cigarette delivery may offer a safer alternative for medical cannabis consumers (Varlet et al, 2016).

The following has been recently accepted for publication in Neuropharmacology.
Inhaled delivery of Δ9-tetrahydrocannabinol (THC) to rats by e-cigarette vapor technology. Jacques D. Nguyen1, Shawn M. Aarde1, Sophia A. Vandewater1, Yanabel Grant1, David G. Stouffer1, Loren H. Parsons1, Maury Cole2 and Michael A. Taffe1
1Committee on the Neurobiology of Addictive Disorders; The Scripps Research Institute; La Jolla, CA, USA
2La Jolla Alcohol Research, Inc; La Jolla CA, USA

Schematic of the inhalation chamber

Schematic of the inhalation chamber


Our exposure model for this study involved a standard sized rat housing chamber with a sealed lid- these are commercially available for a variety of purposes. The chamber was plumbed for regulated airflow and incorporated the ability to deliver and exhaust the vapor from an e-cigarette type device. We tried a number of commercial tanks in this study, one specific example is the Protank 3 Atomizer by Kanger Tech. The overall approach for delivery to rodents is under patent to La Jolla Alcohol Research, Inc which has been instrumental in developing the equipment for our studies. This collaboration has resulted in a number of studies so far, this one is the first to be published. The company has also recently been awarded an SBIR Phase II Grant (R44 DA041967) to further develop and enhance commercialization of the device.

Dosing control was managed in this system with the manipulation of a number of variables. One of the major goals of this study was to determine how the dose delivered to the animal might be regulated by altering these vaping parameters. The concentration off the drug (in this case Δ9-tetrahydrocannabinol (THC) may be altered in the propylene glycol (PG) vehicle (aka “e-juice”)- our standard condition for this study was 200 mg/mL but effects from 25-100 mg/mL were also explored and showed a concentration-dependent effect when the puffing and inhalation duration was held constant. The puffing regimen and duration of inhalation exposure can be altered as well. In most of our studies we delivered 10-s vapor puffs with 2-s intervals between them every 5 minutes for durations of 10-40 min (approximately 0.125 ml was used in a 40 min exposure session). This study established that for a given THC concentration in the vehicle, the duration over which animals were exposed could produce graded effects consistent with a dose-dependent pattern.

Mean (N=8; ±SEM) temperature response to THC inhalation for 10, 20 or 30 min in 5 min intervals. A significant difference from both the baseline and the other exposure conditions is indicated by the open symbols and from the 10 min condition by the shaded symbols.

Mean (N=8; ±SEM) temperature response to THC vapor inhalation for 10, 20 or 30 min in 5 min intervals. A significant difference from both the baseline and the other exposure conditions is indicated by the open symbols and from the 10 min condition by shaded symbols.


This first figure depicts THC-induced reductions in body temperature produced by THC inhalation for 10-30 minutes in male rats, using a radiotelemetry system for reporting temperature every 5 minutes. The figure depicting this experiment in the paper depicts 30 min averages but I really like this version so I’m including it here. [For those concerned with statistics, see below.] The points to the left indicate a pre-inhalation baseline interval in the telemetry recording chambers. There is a break in the series because we didn’t record them during vapor inhalation (see our SFN 2014 poster presentation for a pilot study recording during inhalation). The main point here is that 10 min of inhalation doesn’t change body temperature, 30 min has a major hypothermic effect and 20 min produces an intermediate effect. Thus, this system is able to produce dose-dependent effects that are so helpful for interpretation of behavioral pharmacology studies. We show in the paper that i.p. injection of 10-20 mg/kg THC produces a temperature nadir similar to that produced by 20-30 min of inhalation (see a blog post on our 2015 paper on temperature responses to injected THC for comparison). Our telemetry measure of locomotion did not show any suppression in this experiment but we do show a suppression of activity in both males and females in Figure 2 of the paper. There was some evidence that female rats are more sensitive to the hypothermia induced by, e.g., THC 50 mg/mL for 30 min in this study, likely because of their lower bodyweight compared with the male rats.

Mean tail-flick latency measured following 20 min of exposure with pre-treatment with SR141716 (SR; 4 mg/kg, i.p.) or Vehicle (N=8). Significant differences compared with respective vehicle condition are indicated by *, differences from SR+THC vapor by #.

Mean tail-flick latency measured following 20 min of exposure with pre-treatment with SR141716 (SR; 4 mg/kg, i.p.) or Vehicle (N=8). Significant differences compared with respective vehicle condition are indicated by *, differences from SR+THC vapor by #.


One of the major tests of cannabinoid activity in a rodent is a decrease in nociception. The ability to sense a noxious stimulus was tested by placing the tail in a 52°C water bath and timing the latency for it to flick it out. The experiment in the figure depicts a study in which the animals were exposed to PG or 200 mg/mL THC for 20 min with and without prior treatment with the cannabinoid 1 receptor antagonist SR141716 (Rimonabant; 4 mg/kg, i.p.). This shows that THC inhalation extends the time for the animal to flick its tail out of the warm water and that this effect is blocked with the antagonist pre-treatment. Although not shown here, the magnitude of the latency change caused by vapor inhalation of THC was the same as that produced by a 10 mg/kg THC i.p. injection. This comparability of the effect of inhaled versus injected THC was also highly consistent with data we generated showing that blood concentrations of THC were very similar when observed 30 min after THC (200 mg/mL) inhalation or 30 min after 10 mg/kg, i.p. injection.

In summary, we’ve created a new model for evaluating inhaled delivery of THC to rats via an e-cigarette type of method. We’ve found significant effects on three of the four traditional measures (Tetrad Test) of cannabinoid activity in a rodent- hypothermia, hypolocomotion and antinociception (the fourth, catalepsy, was not assessed). Effects were of comparable magnitude to those produced by intraperitoneal injection, allowing these data to be placed in context with prior studies using injection delivery of THC. There are several advantages of this model, most pertinently the more rapid timecourse of effects compared to what is produced with an i.p. injection.
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Jacques D. Nguyen, Shawn M. Aarde, Sophia A. Vandewater, Yanabel Grant, David G. Stouffer, Loren H. Parsons, Maury Cole and Michael A. Taffe. Inhaled delivery of Δ9-tetrahydrocannabinol (THC) to rats by e-cigarette vapor technology, 2016, Neuropharmacology, in press. DOI: 10.1016/j.neuropharm.2016.05.021 [PubMed]

Funding and Disclosures for this paper: This work was funded by support from the United States Public Health Service National Institutes of Health (R01 DA024105, R01 DA035281 and R44 DA041967) which had no direct input on the design, conduct, analysis or publication of the findings. Development of the apparatus was supported by La Jolla Alcohol Research, Inc and MC is inventor on a patent for this device. SAV consults for La Jolla Alcohol Research, Inc.

[Stats for body temperature figure: The ANOVA of the five minute temperature intervals (including three baseline samples, -15 to -5, and 40-180 min following initiation of vapor) confirmed main effects of Time post-initiation [F (32, 224) = 38.36; P < 0.0001], Duration of vapor exposure [F (2, 14) = 38.66; P < 0.0001] and the interaction of factors [F (64, 448) = 16.64; P < 0.0001].
The Tukey post-hoc test confirmed significant temperature reductions after 20 (40-70 min post-vapor initiation) or 30 min (40-155 min post-vapor initiation) of vapor exposure to THC compared with each of three baseline samples. Furthermore, the post-hoc test confirmed that temperature after all three exposure durations differed significantly from each other from 40-150 and 160-165 min following vapor initiation. Significant differences in temperature between 10 and 30 min vapor exposures were confirmed for the entire post-vapor duration.]

December 17, 2015

Daily Marijuana Use In Adolescents

Filed under: Cannabis — mtaffe @ 9:38 am

The Monitoring the Future Study of longitudinal drug trends releases the latest updates in December each year. The website has links to the updated tables and a few selected Figures.
2015-DailyPot-MtFThis graph depicts the percentage of 8th, 10th and 12th grade students in the US who indicate that they have used marijuana at least 25 days out of the past 30 (their definition of “Daily” in the survey). For those who want precision, the 2015 numbers are 1.1% for 8th graders, 3.0% for 10th graders and 6% for 12th graders. You may be inclined to view single digit percentages as no big deal. It seems like a small number. One percent? Hardly worth talking about, right?

Except if, as I do, you have children in one or more of these age ranges. And you go so far as to become acquainted with some of your children’s friends and schoolmates. And acquainted with some of their parents. What you quickly realize is that you know at least 50 kids within your child’s circle at least a little bit. Enough to know their name and something about them. Maybe 100. And your kid probably knows at least 200 fairly well.

So look around? Which 1 of these kids is already smoking pot every day in 8th grade? Which 6 are at the end of high school?

EVERY day. Smoking pot. And the odds are very good that this kid is smoking multiple times a day. Staying high for extended periods.

Remember this when you think dismissively to yourself that “that 7th grader looks stoned, hahaha” as I once did before catching myself. I should know better. And even I don’t really think specific kids are the ones smoking pot every day. Until I think about it.

But the stats say they are. Some of them.

 

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It is also the case that 6.5% of 8th graders, 15% of 10th graders and 21% of 12th graders have used marijuana at least once in the past month. 35% of 12th graders in the past year. This means the daily use rate is 17% of 12th graders who have tried marijuana at least once in the past year.

June 30, 2015

Smokers have to adapt to e-cigarettes to maximize nicotine yield

Filed under: Cannabis, Public Health, Tobacco/Nicotine — mtaffe @ 1:20 pm

One of the reasons that smoked/inhaled drug delivery is highly associated with addiction is that this route allows humans to exquisitely titrate their dosing. Thus for drugs like nicotine that become aversive at higher doses, smoking tobacco in several punctate inhalations over a short interval of time permits the user to avoid unpleasant dose levels.

This contrasts, for example, with buccal administration. If anyone recalls sampling chewing tobacco as a youth, you will understand what I mean. The relatively slowed onset and the larger available dose of the wad of tobacco or snuff packed up against the gums is frequently associated with severe nausea in the naive user.

A similar situation obtains with cannabis for which smoking has been the preferred route of administration. There is, however, relatively familiar use of cannabis via the oral route- think pot brownies. Increasingly, the medical marijuana entities are also selling a variety of edibles for oral administration of marijuana. Again, it is relatively common for naive consumers of edible products to overdose because the subjective effects hit long after a ballistic, irreversible drug administration has been accomplished.

A recent paper on the use of e-cigarettes for cannabis delivery (Etter, 2015) piqued my interest because it suggested that experienced cannabis smokers did not really like the e-cigarette delivery all that much.

Presentations at the recent CPDD meeting referred to the fact that nicotine seekers who use e-cigarette devices have to learn to adjust their inhalation behavior relative to their tobacco smoking. This is described in a paper that I located:

Farsalinos KE, Spyrou A, Stefopoulos C, Tsimopoulou K, Kourkoveli P, Tsiapras D, Kyrzopoulos S, Poulas K, Voudris V. Nicotine absorption from electronic cigarette use: comparison between experienced consumers (vapers) and naïve users (smokers). Sci Rep. 2015 Jun 17;5:11269. doi: 10.1038/srep11269.

Farsalinos15-nicotine-experiencedvapersThe authors examined e-cigarette (EC) use in groups of ex-smokers who had quit and had been using ECs for at least a month and another group of smokers who were not EC users (available for free at PMC here). Subjects were asked to take 10 puffs from a standardized EC device in the first five minutes and then use it at their own discretion for another hour. The study sampled their blood for nicotine levels that were achieved across the study and the key figure from this paper is depicted here. As you can see, the experienced EC users (vapers) reached higher plasma nicotine levels than did the EC-inexperienced smokers. Each group averaged the same number of puffs, around 85-90, but the experience vapers took longer puffs (3.5 vs 2.3 seconds).

The simple interpretation is that if nicotine amount is a function of vapor cloud volume, and delivery across the lungs depends on retention time within the lungs, then longer puffs would result in greater nicotine delivery. The slightly more complex issue, mentioned at the CPDD annual meeting but not addressed in this paper, is that the rate at which a user inhales can be important. The idea is that if you pull too much of the EC vehicle across the heating element it can cool the element, resulting in lower nicotine yield.

Bottom line, EC inhalation for maximum nicotine yield and tobacco smoke inhalation for maximum nicotine yield may require a different inhalation approach.

This then reminds us that when ECs are adapted for crude cannabis extracts or even other drugs, it will require users to learn to adapt their behavior for idealized drug yield before we truly understand the risks. An initial report like Etter (2015) showing cannabis users don’t like to use ECs to deliver THC as well as they like to smoke cannabis need to be viewed in that light

March 13, 2015

Review/commentary on likely lasting impacts of increasing marijuana use

Filed under: Cannabis — mtaffe @ 10:30 am

From Jerry Wright, published as a commentary in Drug and Alcohol Dependence.

Wright, MJ, Jr. Legalizing marijuana for medical purposes will increase risk of long-term, deleterious consequences for adolescents. Drug Alcohol Depend, Volume 149, 1 April 2015, Pages 298–303

This is actually a fairly good review article, not merely a commentary. Lots of citation to relevant research articles.

The main purpose from the Introduction:

Marijuana use for medical purposes is currently legal in 23 states in the U.S.and Washington,DC.This commentary reviews evidence linking frequent marijuana use in adolescence with risk for mental illness and cognitive impairment,the impact of medical marijuana legalization on increasing rates of adolescent marijuana use, changes in the potency of marijuana overtime,and research on marijuana-based medications to make the case that legalizing medical marijuana will increase health-related risks, particularly among adolescents

and the key points from the Conclusion.

Too many adolescents have access to marijuana currently and there is very little evidence that adolescent access to recreational marijuana can be reduced while simultaneously increasing the availability of medical marijuana for adults.Public health interests would be better served by streamlining the bureaucracy that impedes research on marijuana-based medications and focusing our efforts on identifying compounds in marijuana that confer unique therapeutic benefit.

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Jerry was a postdoctoral fellow in the Taffe Lab from 2009-2012.

November 23, 2014

Cannabidiol fails to attenuate THC-induced hypothermia

Filed under: Cannabidiol, Cannabis — mtaffe @ 11:24 am

The following has been accepted for publication:

M A Taffe, K M Creehan, S A Vandewater Cannabidiol fails to reverse hypothermia or locomotor suppression induced by ∆9-tetrahydrocannabinol in Sprague-Dawley rats. (2015) British Journal of Pharmacology, in press. [Publisher Site; PubMed]

Cannabidiol (CBD) is a constituent of some strains of recreational cannabis plant material but the content of CBD-enriched strains is highly variable in the market (Morgan et al., 2010; Burgdorf et al., 2011). Cannabidiol has traditionally been viewed as an inactive constituent of cannabis, for example it produces minimal disruption of behavioral tasks in humans, monkeys or rodents (Belgrave et al., 1979; Lichtman et al., 1995; Winsauer et al., 1999). There has been a lot of recent interest in CBD for anti-seizure properties (see this blog post for example)

Morgan and colleagues have shown (blog writeup) that smoking cannabidiol-enriched marijuana does not cause the deficits of immediate and delayed prose recall that were caused by CBD-poor cannabis (Morgan et al., 2010) and users habitually exposed to CBD-containing cannabis may have relatively preserved recognition memory versus CBD-poor cannabis users (Morgan et al., 2011). The limits of human field studies (varying CBD/THC dose, no control of individuals who select CBD-rich vs. CBD-poor cannabis) and human lab studies (limited dosing ranges of CBD vs THC) motivate animal studies to investigate how CBD modulates the effects of THC.

Unfortunately, the available evidence on interactive effects of CBD and THC in rodent models present a more complicated picture. While CBD can reverse a conditioned place aversion produced by 10 mg/kg THC in rats (Vann et al., 2008), it may be the case that CBD potentiates the anxiogenic and locomotor suppressant effects of THC in rats treated chronically (Klein et al., 2011). In addition CBD / THC interactions may depend on the pre-treatment offset, as briefly reviewed (Zuardi et al., 2012). When CBD is administered 30 min (or up to 24 hrs) prior to THC in rats or mice, a potentiation can be observed whereas co-administration results in blockade or amelioration of THC effects. The picture may be complicated even further by a suggestion that CBD/THC ratios on the order of 8 are necessary for antagonistic properties and only 1.8 for potentiation of THC-related effects in rodents (Zuardi et al., 1984).

Our study was designed to determine if CBD attenuates, potentiates or extends the duration of hypothermia and hypomotility produced by acute THC in rats, using radiotelemetric monitoring.

The investigation found no evidence that cannabidiol can ameliorate the thermoregulatory or hypolocomotor effects of THC when administered either simultaneously (as in Figure 1, below) or prior to THC. Increasing the ratio of CBD:THC from 1:1 to 3:1 had no differential effect. Thus we find no protective effect of CBD against these particular endpoints in the rat. This contrasts with our recent finding that CBD can be protective against memory-impairing effects of THC in the monkey (PubMed, blogpost).

Taffe2015CBD-THCFig1Figure 1: Mean (N=5; ±SEM) telemetered body temperature (left panels) and activity rate (right panels) after treatment with 30 mg/kg THC with 30 mg/kg cannabidiol or the vehicle, i.p., administered simultaneously. A Vehicle-only control condition (Veh) is also depicted. Upper panels display the data as collected (5 min intervals) and the lower panels depict the hourly averages used for analysis. A significant difference from Veh (only) is indicated by * and from both other conditions by #. Significant differences from the first hour (within treatment condition) are indicated by §.

November 13, 2014

SfN 2014 Presentation: Vape drug delivery

We will present a poster describing our efforts to develop technologies for the intrapulmonary (inhaled) delivery of psychoactive drugs at the 2004 meeting of the Society for Neuroscience.

Abstract 810.04 on Board AA05: Development and validation of a device for the intrapulmonary delivery of cannabinoids and stimulants to rats .
Authors: M. A. TAFFE, S. M. AARDE, M. COLE;
Cmte Neurobio. of Addictive Disorders, The Scripps Res. Inst., LA JOLLA, CA;

The presentation time is Wednesday, Nov 19, 2014, 1:00 PM – 5:00 PM.

Abstract Text:

The recent popularization of non-combustible methods for intrapulmonary delivery of psychoactive drugs to humans (Vape, Volcano, e-cigarette, etc) has stimulated interest in the intrapulmonary administration models for rodent studies. We have designed a sealed rodent chamber, with a well regulated air flow, that is suitable for the controlled exposure of rats to psychoactive substances. Use of e-cigarette type delivery systems was found to afford excellent dosing control for this purpose. Studies were conducted in male rats to verify the in vivo efficacy of drug delivery. Implantable radiotelemetry methods were used to demonstrate that a 20 min exposure to [[unable to display character: ∆]]9-tetrahydrocannabinol (THC), or the CB1 receptor full agonist JWH-018, produces a robust hypothermia. The temperature nadir was reached within 40 min of exposure, was of comparable magnitude to that found after 30 mg/kg THC or 1.1 mg/kg JWH-018, i.p. and had resolved within 3 hours compared with a 6 hour time course following injection. Studies also demonstrated that 30 min of intrapulmonary exposure to methamphetamine (MA) significantly increased home cage locomotor behavior for up to 2 hrs. A final study showed that a 30 min intrapulmonary exposure to MA reduced drug intake during the loading phase of intravenous self-administration of MA. Finally, it is shown that rats will nosepoke for the delivery of MA vapor. These studies show that an electronic cigarette type delivery system can be successfully used to model intrapulmonary drug delivery in rats. These techniques will be of increasing utility as recreational users continue to adopt “vaping” for the administration of psychtropic drugs.

SrN2014-teaserFigureDisclosures: M.A. Taffe: None. S.M. Aarde: None. M. Cole: E. Ownership Interest (stock, stock options, royalty, receipt of intellectual property rights/patent holder, excluding diversified mutual funds); La Jolla Alcohol Research, Inc..

This work was supported by NIH grants DA035281 and DA024105.

This figure is small preview of the data that we will be presenting. The figure depicts body temperature responses to 20 minutes of Vape-exposure to THC and the synthetic cannabinoid JWH-018 (upper panel) and locomotor activity responses to 30 minutes of Vape-exposure to methamphetamine (lower panel) in a group (N=7) male rats. In both panels there are comparison data for a session in which animals were just in normal cages with no drug intervention (No Chamber) and another session in the inhalation chamber in which animals were exposed to the Vape delivery vehicle without any drug in it (Vehicle). As you can see, we were successful in delivering active doses of the drugs, each of which had class-specific effects, i.e. cannabinoid hypothermia and stimulant hyperlocomotion.

July 9, 2014

Medical marijuana, skepticism and the content of that marijuana

Filed under: Cannabidiol, Cannabis — mtaffe @ 1:08 pm

Physician Peter Lipson has posted an opinion on Forbes that expresses his skepticism about the benefits of medical marijuana.

Why I’m Skeptical About Marijuana’s Medical Benefits

In this article he criticizes a CNN bit by Sanjay Gupta on medical marijuana called “Weed2: Meet Vivian“.

From Lipson:

It followed the sad case of a young girl with a horrible seizure disorder and her parents’ struggle to get her help. According to Sanjay Gupta, they finally found some help with cannabis, and the piece documents their struggle to get their daughter the medicine that they believe is helping her.

He then goes on to make an assertion that I think is really flawed:

It makes for a great story, but it gives us no help in deciding if marijuana has any legitimate medical uses. A thorough search of the medical literature finds no good studies that support the use of cannabis or any of its constituents in seizure disorders.

I think there are certainly good studies that support the use of cannabis constituents and, pertinent to the “Vivian” story a compound called cannabidiol*.

The CNN story, and much other popular media coverage of the antiepileptic effects of cannabidiol is doing a serious, perhaps intentional, disservice by referring to “marijuana” only.

There is a published case report on “Vivian” (she’s “Charlotte” in the Case) by Maa and Figi. This specifies that the strain of cannabis being used to generate the crude extract that they are dosing with contains “a high concentration cannabidiol/Δ(9)-tetrahydrocannabinol (CBD:THC)“. I didn’t find a content analysis in the Case Report but an article in the Huffington Post contains aclaim from the grower/breeder developing what is now called the “Charlotte’s Web” strain of cannabis: “This particular plant has 0.5 percent THC and 17 percent CBD — or cannabidiol“. I’ll assume that is a valid statement, although of course we have no independent verification at this time.

We can see from Morgan et al 2010 [see Figure, left, and my blogpost] and from Burgdorf et al 2011 that 0.5% THC is really low for recreational grade cannabis. The North American Industrial Hemp Council, Inc claimsIndustrial hemp has a THC content of between 0.05 and 1%. Marijuana has a THC content of 3% to 20%“. A white paper from El Sohly, who grows the marijuana supplied by NIDA for research purposes attests to about a 1.6-1.8% THC content in the “low potency” research marijuana.

These analyses also verify that 17% cannabidiol is really high for a recreational marijuana strain. CBD appears to come in around 0.5% of the vast majority of street marijuana with a range of about 2-6% in the low proportion of high CBD strains identified in Morgan et al 2010.

In short, this “marijuana” which so bothers Dr. Lipson is not really “marijuana” in terms of what people tend to assume. Most particularly, it is not “marijuana” in the sense that we infer harms associated with substantial THC content. It would be better for understanding if media reports were very clear on this because cannabidiol (CBD) has never been found to be psychoactive in the sense of producing a high or any sort of dependence profile. In fact, it seems to counter* some of the effects of THC.

This brings us to whether any marijuana constituents have evidence for utility in seizure disorders.

Here are a few papers I pulled up on PubMed which attest to the fact that CBD can block seizure in rodent models.

Hill et al 2013 : Cannabidivarin-rich cannabis extracts are anticonvulsant in mouse and rat via a CB1 receptor-independent mechanism.

Jones et al 2012: Cannabidiol exerts anti-convulsant effects in animal models of temporal lobe and partial seizures

Jones et al 2010: Cannabidiol displays antiepileptiform and antiseizure properties in vitro and in vivo.

Martin et al, 1987: Structure-anticonvulsant activity relationships of cannabidiol analogs. [I had to go pull this NIDA Research Monograph off the departmental bookshelf, but it indeed reports that CBD is anticonvulsant]

Finally, there is a parent survey of people like the parents of Vivian/Charlotte. Porter and Jacobson (2013) surveyed a Facebook group dedicated to parents using cannabis (allegedly CBD enriched, but this was in no way verified). Of the nineteen surveys suitable for inclusion 10 reported greater than 80% reduction in seizure frequency and 6 reported 25-60% reduction.

The paper also references a mixed bag of prior clinical trials in adult populations. The authors cite Mechoulam and Carlini (1978) and Cunha et al. (1980) as reporting some beneficial effect of CBD. Ames and Cridland (1986) found no effect.

Not overwhelming evidence, certainly. The translation from animal models to humans may be overconfident at this point. And perhaps we may find that there are other cannabinoids in “Charlotte’s Web” strains (even the remaining THC) that may be driving any anticonvulsant effect.

But there is definitely some evidence. In my view it is sufficient evidence not to dismiss the notion that CBD might have use as an anticonvulsant medication.

___
*In full disclosure, I have a grant which is funding research in the lab to determine the degree to which cannabidiol can oppose the effects of Δ9Tetrahydrocannabinol.

Maa E, Figi P. The case for medical marijuana in epilepsy. Epilepsia. 2014 Jun;55(6):783-6. doi: 10.1111/epi.12610. Epub 2014 May 22.

June 30, 2014

Behavioral/physiological tolerance and making regulations based on THC blood levels

Filed under: Cannabis — mtaffe @ 12:05 pm

Drug “tolerance” is a fairly simple concept (Wikipedia). It means that with successive exposure to a given drug, in many cases the same dose produces a reduced effect. This can be for any number of mechanistic reasons including a change in the metabolism and/or excretion of that drug, a change in the number or sensitivity of the receptor sites through which the drug interacts with the body or a change in the neuronal circuitry, or physiological processes, that are affected. Of course, things are complicated since tolerance may or may not be produced depending on the behavioral or physiological measure in question, on the drug in question, on the circumstances (dose, freqency, etc) of drug exposure and a whole host of other factors. Drugs can even produce sensitization, which is a progressive increase in the effect with successive exposure.

Legalization of marijuana for medical use purposes in many US states and the recent decriminalization of purely recreational marijuana use in Colorado and Washington states has been associated with an effort to determine legal impairment. This is most typically in the context of the limit for operating an automobile. In WA, the decriminalization initiative set 5 ng THC per mL of blood is the “per se” limit for presumed impairment of the ability to operate an automobile. In Colorado, the State Senate passed a similar limit.

Leaving aside the question of what the limit should be, today I want to discuss a paper that makes some of the issues involved clearer and shows why there are not any straightforward answers.

Ginsburg BC, Hruba L, Zaki A, Javors MA, McMahon LR. Blood levels do not predict behavioral or physiological effects of Δ⁹-tetrahydrocannabinol in rhesus monkeys with different patterns of exposure.Drug Alcohol Depend. 2014 Jun 1;139:1-8.
[PubMed, Journal Site]

Ginsburg and colleagues report the relationship between blood levels of THC and effects on behavior and thermoregulation in rhesus monkeys. The key part of the paper is the comparison between a group of animals who had received twice-daily THC (1 mg/kg, s.c.) or animals who had received lower doses of THC (0.1 mg/kg, i.v.) only every 3 o4 4 days. These are referred to as the Intermittent and Chronic exposure regimens/groups.

Ginsburg14-Fig1The study examined the effect of a 3.2 mg/kg, s.c. dose of THC in each group. The primary outcome measures were rectal temperature (hypothermia is a classical effect of cannabinoids in laboratory models), response rate on stimulus-termination operant procedure and blood levels of THC. Response rate may not be the most complex behavior going but it does tend to be sensitive to general intoxication level. As you can see in Figure 1, reproduced here, the groups differ in the effect of an identical THC dose on both temperature and behavior. The Chronic treatment group had minimal to no response to THC whereas the Intermittent group had a significant drop in body temperature and a slowing of response rate. The key consideration was that there was no difference in the blood levels of THC between the groups. Thus, the tolerance that was observed cannot be due to metabolic tolerance, i.e., a change in the rate of drug metabolism and excretion. Importantly, this means that chronic and occasional users of marijuana being tested for possible DUI will not differ due to metabolism of the drug.

As I noted, this study does not really speak to what blood level would be associated with impaired human driving after THC. The behavioral measure is simply too distantly related for good inference-particularly since driving crashes are more about failures of attention and judgment then about physical control over the car. What it does show, however, is that a given THC blood level is fairly meaningless as a predictor of the impairment of a given individual without any knowledge of that person’s history of exposure to THC.

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