TL neuro

October 16, 2017

High ambient temperature facilitates MDMA self-administration

Filed under: IVSA, MDMA, Thermoregulation — mtaffe @ 1:02 pm

The following has recently been accepted for publication:

Aarde, S.M., Huang, P-K  and Taffe, M.A. High Ambient Temperature Facilitates The Acquisition Of 3,4-Methylenedioxymethamphetamine (MDMA) Self-Administration. Pharmacol Biochem Behav, 2017, in press. 

This study was motivated by a finding from Cornish and colleagues in 2003 where they showed that rats trained to self-administer MDMA at 21 °C ambient temperature will significantly increase their drug intake when placed in a 30 °C ambient temperature. This finding was of interest to our lab because of our longstanding interest in the role of the body temperature response to MDMA. In brief, the effect of a given dose of MDMA at ~21-24 °C is generally to lower a rat’s body temperature whereas the same dose given at ~27-30 °C elevates body temperature. The typical laboratory ambient temperature of about 21-24 °C is actually somewhat cold for a rat since their point of thermoneutrality is up around 30 °C.  This led us to think that perhaps one of the reasons why MDMA is a poor reinforcer in the intravenous self-administration (IVSA) paradigm is because it lowers body temperature. If this effect is aversive to the rat, this may oppose the rewarding properties of the drug. Consequently, the Cornish finding may have illustrated increased IVSA due to a blunted hypothermia (but that study didn’t measure it). This rationale formed the basis for an entire Aim of a grant proposal which was submitted in original form in 2007 and eventually funded in 2011 (R01 DA024105-01A2).

In this figure from the paper we present the number of MDMA infusions (1.0 mg/kg/infusion) obtained by the groups of rats trained to self-administer under Cold (20 °C; N=12) or Hot (30 °C; N=11) ambient conditions in two-hour sessions. The schedule of reinforcement was FR5 for these studies meaning that each infusion required that the rat make five lever presses. As is obvious from the figure, the Hot group obtained more infusions of MDMA than did the Cold group. On session 16 only the drug-free vehicle was available and the increased responding (“saline bursting”) can be interpreted as a sign of drug-seeking behavior. This is particularly important for the Cold group given their very low (but consistent) numbers of infusions obtained. So to this point of the study, the behavior replicates and extends the work of Cornish and colleagues in 2003. They trained their rats in a lower ambient condition and then did post-acquisition tests at a higher ambient temperature and so the effect of ongoing experience in cold versus hot conditions could not be assessed. Interestingly, however, Feduccia and colleagues (2010) did a study much more like ours in design and failed to find any difference in the acquisition of IVSA in cold versus hot ambient conditions. There are a few procedural differences which may explain the difference in outcome but additional experiments would be required for firm conclusions. One potential difference is the selection of FR1 reward contingency which led to similar behavior in the MDMA groups and the groups allowed to self-administer saline only in that study. Although we did not have saline-only controls, our lever discrimination remained over 80% in both groups. In Aarde et al (2013) we ran a saline-only control group, pretrained to lever press for food at FR5, at normal laboratory ambient temperature (24 °C) and showed that lever discrimination breaks down significantly within the first 10 sessions of saline IVSA.

As outlined above, we were interested in the nature of the body temperature response during self-administration and how this might be changed by different ambient temperature conditions. Feduccia and colleagues had found no change in body temperature induced by MDMA IVSA at all, but their monitoring was via pre- and post-session rectal sampling. The temperature response to MDMA in rats is transient and it was likely that the sampling at 2 hours after the start of the session missed the dynamic response. This technique also requires handling the rats which can cause a stress response which may increase the body temperature. Our study used implanted radiotelemetry to observe the temperature response during the session. This adaptation of a figure from the paper presents 30 min averages (data collected every 5 minutes) of body temperature across the self-administration session and for one hour after the drug was no longer available. The daily responses are collapsed across blocks of 5-6 sequential training days. The takeaway here is that body temperature decreased in both Hot and Cold groups during the initial hour of the self-administration session and this response was gradually blunted in the Hot group across the self-administration training. The similar degree of hypothermia early in the acquisition phase and the course of tolerance versus drug intake in the Hot group was not consistent with our original hypothesis. It looked much more as though MDMA caused hypothermia under all training conditions and any attenuation of that response followed, rather than caused, increased drug intake over time.

To further probe the role of ambient temperature we next switched the temperature conditions and found that MDMA IVSA was unchanged within the groups. As if they’d been set on a preference trajectory. The failure to increase drug intake in the Cold group when placed in higher ambient temperature conditions was discordant with the original Cornish finding and we do not know why this might be the case. Most importantly, the Hot-trained group self-administered more drug in Cold ambient then did the Cold-trained group in Hot ambient and developed a more pronounced drop in body temperature. This showed that the ongoing self-administration training did not categorically alter the temperature response to MDMA in these animals.

The last study in the self-administering groups examined the effect of non-contingent administration of a range of MDMA doses (1-5 mg/kg, i.v.) on the body temperature response under Hot and Cold ambient temperature conditions. Up to this point, the animals self-selected their doses and so the interaction of dose with the temperature responses could not be easily disentangled. This last study found that hypothermia depended on dose, ambient temperature and the prior MDMA intake of the rat. Those individuals who self-administered very low amounts across the study (regardless of ambient temperature condition) were most sensitive to MDMA-induced hypothermia. Hypothermia was produced in both subgroups under Cold ambient, albeit to a greater degree in the animals with less cumulative MDMA intake. The takeaway from this part of the study is less clear cut. Clearly the hypothermic response to  MDMA under low ambient temperature conditions was only quantitatively, not categorically, altered in rats that self-administered more MDMA. Temperature responses under higher ambient temperature conditions were blunted- to the point that 3-5 mg/kg MDMA, i.v., did not change body temperature from baseline in the higher preference subgroup and while 2-3 mg/kg lowered body temperature in the lower-preference subgroup, 4-5 mg/kg did not.  [In general, the dose-effect relationship for MDMA-induced hypothermia does not reflect across Cold and Hot ambient temperatures. A high MDMA dose produces both less hypothermia under Cold conditions and increased hyperthermia under Hot conditions. Likewise, a moderate dose produces less hyperthermia in Hot conditions and more hypothermia in Cold ambient temperature conditions.] Thus, these data allow for the possibility that incremental blunting of the hypothermic response to MDMA may have some effect on sustaining IVSA behavior. Still, the overall thrust of this study suggests that the body temperature response is not a primary driver of self-administration of MDMA.

An additional study examined the effect of MDMA on intracranial self-stimulation (ICSS) reward in a different group of animals with no MDMA self-administration history. In ICSS the animal makes behavioral responses in response to small amounts of electrical current delivered to a specific region of the brain. We used a thresholding procedure in which the amount of current required for the animal to feel a rewarding effect can be determined from day to day. This procedure has been used by many laboratories over decades to show that treatments that make the animal feel good (such as an injection of methamphetamine) lower reward thresholds whereas conditions that make the animal feel bad (such as drug withdrawal in a dependent rat) lead to increased reward thresholds. Our study found that thresholds were increased merely by being placed in a hot environment (these data are all relative to individual thresholds from a 24 °C uninjected test session). Under Cold conditions, a 2.5 mg/kg MDMA, i.p., injection reduced reward thresholds in a manner consistent with the effects of methamphetamine, MDPV or mephedrone (Nguyen et al, 2016). Under Hot conditions, the same MDMA dose only returned reward thresholds to a baseline established under 24 °C without producing a pro-reward effect.

 

This ICSS experiment supports an interpretation of increased MDMA self-administration under high ambient temperature conditions as a normalization of negative affect, rather than an enhancement of the positive, feel-good subjective effects of MDMA.

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September 21, 2017

Locomotor and Reinforcing Effects Of Pentedrone, Pentylone and Methylone

Filed under: Cathinones, Methylone — mtaffe @ 9:59 am

Pentylone and pentedrone are designer drugs within the cathinone stimulant class of drugs that are often referred to as “bathsalts”. These two entities have appeared in the recreational user populations as confirmed by results from ecstasydata.org, a review of trip reports on bluelight.org and erowid.org, as well as in a few scientific reports.

Second-generation substituted cathinone drugs such as pentylone and pentedrone have received less research attention compared with first generation bathsalts such as mephedrone and, in particular, methylone. This is sufficient motivation to explore the abuse liability and other properties of the more recently emerged drugs. In addition, this growing diversity of cathinone derivatives allows us to further determine the role of various structural substitution elements that may be common to both amphetamine and cathinone drugs of abuse. In this study, we investigated the 3,4-methylenedioxy motif  in the contrast of the effects of pentedrone with pentylone. This motif, when added to methamphetamine to produce MDMA, confers reduced rewarding potency and efficacy, reduced locomotor potency, reduced efficacy to induce stereotyped, repetitive behavior and increased thermoregulatory disruption. In contrast, the presence of the 3,4-methylenedioxy substitution produces no change in vivo in the context of the closely related, restricted transporter inhibitor cathinones α-PVP and MDPV which exhibit similar efficacy and potency on both locomotor and self-administration assays in rats . Pentedrone and pentylone also include the extended alkyl-tail carbon chain that is present on MDPV and α-PVP which may be related to the restriction of those drugs to transporter inhibition. This might predict that the 3,4-methylenedioxy motif has minimal impact on these additional compounds (which lack the pyrrolidine ring of MDPV and α-PVP).

The following has recently been accepted for publication:

Javadi-Paydar, M., Nguyen, J.D., Vandewater, S.A., Dickerson, T.J., and Taffe, M.A. Locomotor and Reinforcing Effects Of Pentedrone, Pentylone and Methylone In Rats. Neuropharmacology, doi: https://doi.org/10.1016/j.neuropharm.2017.09.002. [ Publisher Site ][ PubMed ]

We assessed locomotor activity changes produced by i.p. injection of Pentylone and Pentedrone in contrast with the effects of Methylone. This was conducted in a group of female rats (N=8) prepared with radiotelemetry devices which report both both temperature and an activity rate within a housing chamber. These studies found that 1 mg/kg of any of these drugs was insufficient to significantly increase activity, however increases were observed for 5 or 10 mg/kg of each compound. There were similar dose-effect relationships found in a group of male rats.

There was no sign of the type of reduction in activity that is often seen after high dose methamphetamine in the ~5-10 mg/kg range. Such reductions are produced because the rat is engaged in stereotyped, repetitive behaviors (called “stereotypy”) which resolve over the course of about 90-120 minutes, depending on dose, whereupon a boost in activity is often observed. This pattern we are reporting here is, however, fairly consistent with what would be observed for MDMA in this 5-10 mg/kg dose range. So these results are as would be predicted from the pharmacology and by reference to the better-studied entactogen compound, MDMA.

 

We also assessed drug self-administration by way of conducting dose-substitution under Fixed Ratio 1 (FR1) conditions. (Each lever press results in an infusion of drug.). This was conducted in a group of female rats who had been trained originally with alpha-PVP (N=4) or Pentedrone (N=6), but this training history was essentially irrelevant to the dose-response and is not separated for the analysis.

In this figure we depict the mean infusions of the three drugs that are obtained across a range of doses.  A significant difference from vehicle is indicated with *, from the 0.025 mg/kg dose with &, from the 0.05 mg/kg dose with §, from the 0.30 mg/kg dose by % and a significant difference from methylone and α-PHP, respectively, is indicated with #. The takeaway points are first that the ascending and descending limbs of the typical “inverted-U” dose effect function have been captured. This is important to enhance confidence that you are not missing a dose that would engender peak responding. So the essentially parallel curves for Methylone and Pentylone can be interpreted as nearly identical potency of the drugs. Pentylone is more effective, as can be interpreted by the fact the curve is shifted upwards, relative to the one for Methylone. In contrast, the peak for Pentedrone is at a lower dose, indicating that this compound is more potent. The efficacy is not clearly different from either other drug as the curve falls somewhat in between in terms of the peak number of infusions obtained.

 

Overall this study confirms that differences between Pentylone and Pentedrone are subtle and they exhibit a profile of dose-effect relationships that is as would be predicted for entactogens. Therefore the 3,4-methylenedioxy motif appears to convey little difference in the context of this core structure. There is some evidence for enhanced abuse liability relative to Methylone and this will be of great interest to follow up with additional models. The difference between Pentylone and Methylone lies in the presence of the extended alpha alkyl chain which enhances lipophilicity, potentially letting Pentylone enter the brain more rapidly.

May 22, 2017

Congressional Outreach

Filed under: ASPET, Experimental Biology / ASPET, Op/Ed, Public Health — mtaffe @ 11:53 am

We are very proud to announce that Jacques D. Nguyen, PhD,  was selected by the American Society for Pharmacology and Experimental Therapeutics (ASPET) to participate in their Washington Fellows Program for 2017. Jacques has been a very productive member of the Taffe Laboratory since joining it as a postdoctoral trainee in early 2015 and he still manages to find time to think about broader issues of science policy. He has been an active participant in ASPET as an academic society in addition to presenting work at the annual meetings.

Jacques is pictured, in this photo, preparing to discuss science policy with the staff of a San Diego Congressman,  Rep. Scott Peters.

For a little bit of background, the ASPET Washington Fellows Mission statement:

Program Mission

The mission of the ASPET Washington Fellows Program is to enable developing and early career scientists interested in science policy to learn about and become more engaged in public policy issues.

Fellows will develop an understanding of how public policy decisions made in Washington help shape and impact science policy, such as funding for the National Institutes of Health and other science agencies. Fellows will also learn how to advocate effectively on Capitol Hill and in their home districts.

This program will help fellows develop the skills and insights to become future leaders in science. 

 

April 13, 2017

Pre-Prints

Filed under: Careerism, NIH — mtaffe @ 10:11 am

In 2017 the NIH issued NOT-OD-17-050 Reporting Preprints and Other Interim Research Products to encourage funded investigators to speed the dissemination of tax-payer funded research by citing and claiming pre-prints as products of NIH funding.

The NIH encourages investigators to use interim research products, such as preprints, to speed the dissemination and enhance the rigor of their work. This notice clarifies reporting instructions to allow investigators to cite their interim research products and claim them as products of NIH funding.

Pre-prints are manuscripts (and other interim research products) which have not undergone peer-review and formal acceptance for publication.

The most critical implication of this new policy is for grant preparation.

Interim research products can be cited anywhere other research products are cited.  These sections include the following:

The benefits should be clear. Instead of having to describe work as being “in preparation” or “submitted” one can now point to a link and any interested reviewers can see it for themselves. This will be critical on the CV or Biosketch of junior scientists in transition. The publishing timeline is slow compared to their needs with respect to finding a postdoc appointment after graduate school, winning a fellowship as a postdoc or getting a job offer after postdoctoral training.

This will potentially help all PIs with their grant applications as well. Productivity can be a major point of review for new applicants, for renewal applications and indeed for any application if a PI is perceived to have too much funding. Productivity as reflected in peer reviewed published papers is not always under the direct control of the research team- the publication racket can induce significant unexpected delays. This pre-print policy allows the grant applicant to post pretty much anything that they want. It will potentially function as a hybrid of Preliminary Data and Publications. “Potentially” because there is no obligation for any reviewer to consider these documents.

I have decided to respond to this new initiative, for now, by submitting manuscripts to bioRχiv (http://biorxiv.org). I have found the submission process to be relatively easy on the scale of the usual manuscript submission for publication or to the PMC repository. The first two I submitted were available online within 24 h of my upload.

The critical question for most of us will be to try to determine what our threshold should be for publicizing any pre-print or interim research product. I have come to the conclusion that a manuscript that we have already submitted for publication somewhere clearly fits the bill as a sufficiently complete work to put on a pre-print server. A manuscript that we plan to submit for peer review essentially concurrently is also very clearly sufficient and the only difference here, to my view, is whether we are really, really at a submittable-draft stage or maybe jumping the gun with the pre-print.

The following three manuscripts had already been reviewed by the time I put them up on bioRχiv. I would characterize two of the reviews as being concerned about interpretation of the data in a way that would require a LOT more data to satisfy. This appears to me to satisfy one potential goal of posting pre-prints. I.e., that people can interpret the quality and meaning of the data for themselves before the authors manage to satisfy all theoretical concerns, sidelines or unlikely possibilities that might be required for publication acceptance. The third one is awaiting one more figure of data for the resubmission. We thought we had a decent rebuttal without it, one that would possibly fly with the editor. But we are also generating new data that is relevant. This has been slower to emerge than I had hoped and we have noticed some recent publication activity in this area. Posting this manuscript as a pre-print is essentially putting down a priority marker at this time.

Javadi-Paydar, M., Nguyen, J.D., Grant, Y., Vandewater, S.A., Cole, M., and Taffe, M.A. Effects Of Δ9-THC And Cannabidiol Vapor Inhalation In Male And Female Rats.  bioRχiv, 2017, Posted April 18, 2017 doi:

Taffe, M.A. Wheel running increases hyperthermia and mortality rate following 3,4-methylenedioxymethamphetamine (MDMA) in rats. bioRχiv, 2017, Posted April 11, 2017 doi:

Aarde, S.M., Huang, P-K  and Taffe, M.A. High Ambient Temperature Facilitates The Acquisition Of 3,4-Methylenedioxymethamphetamine (MDMA) Self-Administration. bioRχiv, 2017, Posted April 4, 2017 doi:

 

March 19, 2017

Vaccination against methamphetamine works in female rats

Filed under: Methamphetamine, Vaccines, Vape inhalation, Vapor Inhalation — mtaffe @ 9:32 am

We have shown that a vaccine designed to blunt the effects of methamphetamine works in male rats in two prior publications, summarized here and here. We have also had success showing that vaccines directed against the synthetic cathinones MDPV (“bathsalts”) and alpha-PVP (“flakka”) work to reduce the effects of those drugs. A brief video outlining the approach to generating vaccines that might be helpful for drug abused created by NIDA can be found here.

The following has recently been accepted for publication:

Nguyen, J.D., Bremer, P.T., Hwang, C.S., Vandewater, S.A., Collins, K.C., Creehan, K.M., Janda, K.D. and Taffe, M.A. Effective active vaccination against methamphetamine in female rats, Drug Alcohol Depend, 2017, 175:179-186. [Publisher Site] [PubMed]

In this study we show that an increase in the amount that female rats move around their cages after an injection of methamphetamine is reduced in the MH6-KLH vaccinated rats.

As you can see in the explainer video, the main principle of anti-drug vaccination is that antibodies can bind some of the drug molecules (methamphetamine in this case) in the bloodstream, thereby preventing them from getting into the brain. This capacity to retain methamphetamine is relatively fixed at a given point in the vaccine sequence, thus administering a sufficiently high dose can (should) overcome the protection.

In our data, the effects of the vaccine were dose dependent. This is Figure 4 from the paper which depicts locomotor activity rates (counts per minute) in the MH6-KLH and KLH groups in the first and second hours after injection of methamphetamine in three doses [Significant differences from the Vehicle and 0.25 mg/kg within Group and Hour are indicated by §, from Vehicle (only) by # and from the 0.5 mg/kg condition by &. ]. There is a dose-dependent increase in activity rate compared with the vehicle injection condition. With respect to the active vaccination group, complete protection was found at the 0.25 mg/kg dose and partial protection at 0.5 mg/kg compared with the KLH group; the two groups were about the same after 1.0 mg/kg was injected. This further enhances our ability to interpret these data as a specific effect of the vaccination and to determine where the threshold for effective protection may lie.

There was another finding in this study which was slightly disappointing in terms of the vaccine study but greatly enhanced our understanding of another thing that we have been working on, namely vapor inhalation techniques to deliver drugs to rats for various research purposes. Most specifically we showed that e-cigarette type vapor inhalation of methamphetamine (and MDPV and mephedrone) increases the activity of male rats to a similar extent as it does when injected (blogpost overview). We used this model in the present study as well and confirmed that just as with male rats, the female rats activity in the cage was increased after vapor inhalation of methamphetamine to about the same extent as after the injected doses. Therefore up to this point in time we were assuming that the dose delivered to the rat was approximately similar when similar behavioral results were produced.

Unfortunately there was no difference in the effects of inhaled methamphetamine across the vaccinated and control groups of rats. We originally interpreted this as potentially a difference in the rate of drug penetration into the brain which minimized the ability of the vaccine-generated antibodies to prevent locomotor effects.

Upon reviewer request we then examined the blood levels of methamphetamine after injection (0.25, 1.0 mg/kg, i.p.) and the inhalation condition in a different group of unvaccinated female rats. We found that methamphetamine was about ten times higher in the blood after inhalation versus injection in this new study. This of course explains why the vaccinated group was not protected, i.e., the dose under inhalation was far past the ability of the antibodies to sequester in the bloodstream.

The curious thing is still why a similar level of locomotor activity was produced at the 10-fold difference in methamphetamine levels. Very likely this is due to the rate at which drug is delivered to the animal- in our inhalation model this takes place over 30 minutes whereas an injection takes seconds. Obviously one of our next avenues of research is to better determine the way that drug levels increase in the blood during vapor inhalation.

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]

 

December 9, 2016

Vaccination against the effects of MDPV (“bathsalts”) and alpha-PVP (“flakka”)

Filed under: alpha-PVP, Cathinones, MDPV, Vaccines — mtaffe @ 10:10 am

The substituted cathinone stimulants 3,4-methylenedioxypyrovalerone (MDPV) and alpha-pyrrolidinopentiophenone(alpha-PVP) have emerged as significant public health concerns in recent years. These drugs turned out to be monoamine transporter inhibitors with high selectivity for the dopamine transporter. These two compounds lack the monoamine releasing properties of methamphetamine, MDMA and other recently popular cathinone derivatives such as mephedrone and methylone. As we’ve shown, both MDPV and alpha-PVP are highly reinforcing in the rat self-administration paradigm and increase locomotor behavior when injected non-contingently or inhaled with e-cig technology. Although these drugs are still in the early stages of market penetration, the data from our lab as well as several other labs suggest that these will have high abuse liability. Effective countermeasures are therefore likely to be needed in the future.

One method to counteract effects of psychoactive drugs that has been attempted is vaccination; an explainer video from NIDA is available here. In this strategy a drug-like chemical structure is attached to a large protein that generates an immune response. When successful, this immune response creates antibodies that circulate in the blood with the capacity to recognize and bind to the target drug molecule. If this is done to effective levels, the administration of a given dose of drug leads to a reduced response, due to part of the drug dose being bound to antibodies in the bloodstream which prevents from entering the brain.

A paper describing an initial effort to develop a vaccine to provide protection against the effects of MDPV and alpha-PVP has recently been accepted for publication. As with all of our vaccine work to date, this was conducted in collaboration with the Janda laboratory at TSRI.

Nguyen, J.D., Bremer, P.T., Ducime, Creehan, K.M., Kisby, B.R., Taffe, M.A. and Janda, K.D. Active vaccination attenuates the psychostimulant effects of α-PVP and MDPV in rats, Neuropharmacology, 2017, 116:1-8. [PubMed][Publisher Site]

In this study, Paul Bremer and Alex Ducime created vaccine candidates designed to generate antibodies against MDPV and alpha-PVP, respectively. Initially, three groups of male rats were vaccinated to evaluate the MDPV-specific, alpha-PVP-specific vaccines against a group vaccinated with the immunogenic protein (keyhole limpet hemocyanin; KLH). The antibodies in the MDPV-vaccinated group showed high affinity for MDPV but not for alpha-PVP or methamphetamine. Likewise, the antibodies in the alpha-PVP group were selective for alpha-PVP over MDPV or methampetamine.

Brent Kisby, an undergraduate on an extended internship, in combination with Kevin Creehan and Jacques Nguyen first determined if these rats would exhibit functional protection against drug exposure. We selected a wheel-activity response to drug injection (see Huang et al, 2012) because this had proved effective at screening anti-methamphetamine candidate vaccines in our prior study (Miller et al, 2013).
nguyen17-alphavaccfig3-wheel This figure (click to enlarge) shows wheel activity (quarter revolutions) in the four hours following injection with four doses of alpha-PVP (Panels A, B) or four doses of MDPV (Panels C, D). The left hand panels depict the effects of drug in the KLH-only control groups while the right hand panels depict the effects of drug in the respective alpha-PVP-KLH and MDPV-KLH vaccine groups. The asterix indicates a significant change of activity relative to the vehicle (saline) injection condition. The takeaway message here is that doses of alpha-PVP (0.5, 1.0 mg/kg, i.p.) and MDPV (1.0 mg/kg, i.p.) which increase wheel activity in the control group do not do so in the respective vaccine group. The vaccine can be partially surmounted since the 5 mg/kg dose of each drug increased activity in the vaccinated rats, although this increase was numerically lower and lasted less long in the MDPV-KLH and alpha-PVP-KLH animals compared with the control group.

This promising result led to the design of an intravenous self-administration study to test the ability of alpha-PVP-KLH vaccination to alter the course of self-administration. Jacques Nguyen and Kevin Creehan headed up this study.
A group of rats were first trained to self-administer alpha-PVP, prior to any vaccination. This is only the second study to publish the acquisition of alpha-PVP self-administration in an animal model (see Aarde et al, 2015) and we found that a 0.1 mg/kg/infusion dose was required to produce good acquisition in Sprague-Dawley male rats. Thereafter the rats were placed on hiatus from drug self-administration and given a 5 week protocol of three immunizations, divided into two groups- one receiving KLH only and the other receiving alpha-PVP-KLH vaccine. We showed first that on return to self-administration at a reduced per-infusion dose of 0.025 mg/kg/infusion the alpha-PVP-KLH vaccinated animals self-administered more drug. This result is consistent with the circulating antibodies producing partial reduction of the dose as it was self-administered and the corresponding behavioral compensation to produce similar brain levels of drug.
nguyen17-fig7-prepostAfter three weeks the animals were given a booster immunization which resulted in about a doubling of the circulating antibody level (titer). This resulted in no change in the KLH-only animals’ drug intake, however the alpha-PVP-KLH animals changed from a mean of 17-20 infusions per session to a mean of about 4-5 infusions per session, a significant reduction in self administration. This lasted for 15 sessions and is depicted in the figure (click to enlarge) as Post4-Post8 bins of three sequential sessions.

As discussed in the paper this is an initial feasibility study but it shows the potential of the anti-drug immunotherapy strategy to be effective against the effects of both MDPV and alpha-PVP. This should encourage additional work to determine the extent and nature of the protection against these substituted cathinone stimulants that can be achieved with vaccines.

These studies were funded by USPHS grants DA024705, DA042211 and DA037709.
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Additional Reading: A list of our cathinone-related publications can be found here.

December 3, 2016

New Chapter on Entactogen Self-Administration

Filed under: 4-MMC/Mephedrone, alpha-PVP, Cathinones, MDPV, Methylone — mtaffe @ 2:48 pm

We have recently published a short review on the self-administration of entactogen psychostimulants.

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. Curr Top Behav Neurosci. 2016 Dec 2. [Epub ahead of print] [PubMed][Publisher Site]

This is part of a Current Topics in Behavioral Neuroscience book on New and Emerging Psychoactive Substances organized by Mike Baumann of the NIDA IRP who has been publishing a lot of work on synthetic cathinones lately. Eventually the Chapters will be collected into a book and assigned unique pagination.

For now you can look chronologically in the pre-publication OnlineFirst list.

The first chapter of the series that was published was:
Schifano et al “NPS: Medical Consequences Associated with Their Intake” [link]

The cannabinoids are covered:
Wiley, Marusich and Thomas Combination Chemistry: Structure–Activity Relationships of Novel Psychoactive Cannabinoids [link]

All told there will be around a dozen chapters, I think most of them are on the pre-print list already. Happy reading!

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.

September 20, 2016

Just. Keep. Swimming.

Filed under: 4-MMC/Mephedrone, Cathinones, MDPV, NIH — mtaffe @ 1:07 pm

In the prior post I tried to give some flavor of the sort of grant submission effort that it has taken for me to keep my lab afloat to this point in time. That description gave an overview of my rough success rates which hovers somewhere in the high teens, not too far away from the aggregate NIH success rate over a similar interval of time.

As I point out to trainees now and again, there is no reason for any of us to think we are somehow special in securing grant funding. The NIH system of extramural funding has been under high stress in the past 10-15 years and there are far more deserving proposals being submitted than can be funded.

In this post, I want to outline the course of a particular research program of mine.

In early 2010 I became aware of a new recreational drug called mephedrone, (aka meow-meow or plant-food) which was very popular in the UK. It was not legally controlled and it seemed to emerge in a bit of a MDMA drought in that country. I soon found that 4-methylmethcathinone was the drug of interest, that the core molecule of cathinone was very similar to amphetamine and that it appeared to be only one of several substituted cathinones which were circulating. I did a bit of searching on PubMed and rapidly concluded that very little science had been published with any of the cathinones after a brief interest in methcathinone and cathinone in the 80s. From what little pharmacological evidence was available, combined with human subjective trip reports I could find online, it was pretty clear that we were facing a reboot of the substituted amphetamine era of the 1980s.

Mephedrone had first come to media attention around 2008 with an overdose in Sweden and had gradually grown in popularity through 2009 and into 2010. The UK government was alerted, trying to complete legal controls and had to rely on very imprecise reviews of the available knowledge.

I found this professionally embarrassing that so little was known. We spent so much effort on methamphetamine and MDMA and here, one to two years into a novel drug phenomenon we knew nothing. Nobody was presenting data at the scientific meetings I was attending, either.

I was also very interested scientifically precisely because of my interest in that prior episode of substituted amphetamine popularity and in the clear “winner”, i.e., MDMA or Ecstasy. This highly popular new drug, mephedrone, was being used by MDMA type populations in the MDMA type environment with many of them explicitly saying they were looking for a MDMA substitute. This drew my attention. There was also a very clear under-current that this mephedrone stuff was like a poor echo of MDMA but watch out for the compulsive use risk. Users were suggesting that this compound was perhaps more like a traditional psychostimulant than MDMA is.

This realization came as I was working on a final revision of an R01 proposal I was submitting on the topic of the abuse liability of MDMA, why it differs from a traditional psychostimulant like methamphetamine and how various situational or experiential factors may make MDMA more compulsively abused. The A1 had received a 21 %ile with pretty minor criticisms so of course there was no way I was going to start dragging in new drugs for the A2 (which I submitted in April of 2010).

Instead I started plotting an assault on specific funding for these novel cathinone drugs. I contacted my Program Officer who, having driven some funding opportunities for MDMA back in the day, was of course interested. But this was 2010. And there was about zero enthusiasm down in the NIDA trenches for anything that wasn’t already on NIDA Director Volkow’s current priority list. In emails and eventually in person at CPDD that year, I bounced around from one NIDA person to another and came up with a similar story. Nobody was enthusiastic about generating any special interest. “Get a fundable score and we’ll talk” was the size of it. There was even a hilarious (not really) standoff between DEA who were demanding data from NIDA (for their intent to Schedule some of these drugs) and the latter’s demand that DEA pay for it and sure, they’d see what they could do.

I got friendly with some DEA scientists to find out what was being seen in the US since law enforcement detection usually runs far ahead of any epidemiology in the peer reviewed literature. From this I deduced that mephedrone was actually pretty rare in the US but that MDPV was going to be a thing.

As we all know, Preliminary Data was going to be required to get a grant funded. But that requires….the drugs!

NIDA drug supply wouldn’t provide any of these new drugs. The usual commercial suppliers didn’t have them either.

Luckily, I was working with a couple of investigators in the department of Chemistry. One of them, Tobin Dickerson, took a look at what I needed and said “Looks pretty simple, how’s next Thursday?”. Boom! We were in business.

Our first grant proposal on this topic was submitted in October of 2010 and focused on mephedrone/4-MMC. It included self-administration data, thermoregulation and activity data, metabolism and PK data from Karen Houseknecht at UNE, microdialysis data on dopamine and serotonin responses generated with Larry Parsons’ lab and receptor/transporter screening from Bryan Roth’s Psychoactive Drug Screening Program at UNC. We proposed self-administration investigations, physiological endpoints and PK. In recognition that there were going to be many other substituted cathinone derivatives of interest we proposed a bit of structure-activity manipulation to start looking at whether specific chemical alterations conferred enhanced/decreased risk for adverse outcomes. In retrospect, putting all this together in the early days of this drug trend was probably one of the best things I’ve ever done in terms of a scientific program.

It was triaged. The app went to MNPS study section instead of BRLE (which we had requested) or even NMB, probably because of all the PK and the structure/activity content. Even though the focus was really on the novelty and the abuse liability/risks. We got 4-6s on the Innovation and 5s on the approach. But really, reading on and between the lines of the critiques it was all about “Problem? What problem?“. This could have occurred at any study section.

One has to be a bit sanguine about the inherent conservatism of the NIH grant process. It was absolutely true that there was not as yet overwhelming evidence of broad use of substituted cathinones, no evidence of large numbers of addicted people in serious life crisis and no evidence of weird/unique dangers akin to the serotonergic neurotoxicity that attends high-dose repeated MDMA exposure to drive enthusiasm.

But still. We weren’t the only ones who could see the importance of this. And as I started to present our data at meetings, I would run into colleagues who were also interested in studying these drugs. And their efforts at grant funding were to sound very familiar over the coming years.

The A1 for this initial proposal was submitted July of 2011 and likewise triaged by MNPS. There was still a lot of kvetching about “Problem? What problem?” but also some typical grant stuff. “Too descriptive”. “What’s the hypothesis”. Etc. This is always a problem for how I look at science, of course, but in this case it was kind of annoying since very little was known about any of these drugs yet, and we did have a clear hypothesis under investigation. [Related papers: Huang et al, 2012; Wright, Angrish et al, 2012; Miller et al, 2013; Aarde, Angrish et al, 2013]

I next incorporated cathinone studies on a competing continuation application for a prior MDMA-focused project that admittedly had issues with its chance of being renewed, even before I added cathinones. The first one went in July 2011 and was triaged by BRLE. The A1 went in March 2012 and got a 42 %ile. As far as the inclusion of substituted cathiones goes, it was mixed. Some reviewers saw this as a positive but some also made comments to the effect of “Problem? What problem?” and “Why don’t you have clearer hypotheses?”. Seeing a pattern? [Related paper: Wright, Vandewater et al, 2012]

I had been doing some work on methamphetamine vaccines with the Janda lab, where my collaborator on the cathinones had done his doctoral studies. As a newish PI, he’d been trying to get away from that area of work (successfully) but here I was dragging him back into work on drug abuse. So it seemed natural for us to put in a vaccine proposal in October, 2012. This time we were focused on MDPV because it was becoming clear in our ongoing studies that this was much more like a traditional psychostimulant with a high potential for addiction in humans. Triaged. With reviewers throwing 6s and a 7 and an 8! Ouch. Well, it certainly wasn’t my strongest proposal but, more to the point, there wasn’t much complaint about the drug choice. Maybe because the rest of it drew so much fire, I couldn’t say. [Related paper: Aarde, Huang et al, 2013]

[Updated: I forgot about this one] I tried a slightly different strategy at this point, submitting a new proposal in October 2012 that wasn’t focused on the cathinones, per se. Instead, this was a proposal about another topic in substance abuse research (one which had background, we’d been working a little bit on it, had a pub, etc, etc) where we just used MDPV self-administration as the drug model. Our most recent Preliminary Data were from this so why not, right? The PMDA study section triaged it- one reviewer threw a 9 for approach and a 7 for significance but the other three reviewers were throwing 3s and 4s mostly. Leaving aside the hater reviewer who went off hilariously on ad hominem attacks and thoroughly unjustified complaints (going by my rather considerable collection of grant reviews testifying to my minimal competence level), the remaining three reviewers ranged from slightly skeptical (insufficient justification for selecting MDPV as the model) to out and out objecting (“…should be examined using a drug that has well characterized patterns of self-administration in the laboratory“). Needless to say when I put the revision in it did not include a cathinone as the model. [Related papers: Aarde, Huang et al, 2015; Aarde, Miller et al, 2015]

In Feb 2013 we submitted a new approach to the cathinones, now with the take on Hypothesis B, as opposed to the Hypothesis A that underlay most of our arguments up to this point. Triaged by NMB. Things were improving slightly, however. A little bit of kvetching over methodology but for the most part no complaining about the relevance of studying these emerging drugs. A fascinating new all-reviewers complaint was included about our structure-activity studies somehow informing clandestine chemists how to make better (or worse from another point of view) drugs. [Related paper: Aarde, Creehan et al, 2015]

Of course by this point we had started publishing papers on cathinone-related topics. Our first ones must have appeared online in early 2012 with print versions issued in fall of 2012. I think we had 6 papers published by the end of 2013. I’ve added citations to the above to indicate the approximate stage of Preliminary Data that were available and relevant at each grant submission- obviously the papers appeared later in most cases.

I’m not entirely sure I remember why but we submitted a different take to the question in November 2013. This one backed off of Hypothesis B and struck out on a tack that tried to address what was now a diverse set of substituted cathinones on the open market. This was promptly triaged by BRLE. One reviewer was convinced that we’d never publish many papers. Most of the rest was the usual ticky tack stuff about “why didn’t you do it this way?” and questions that really can only be resolved by getting in there and doing the work. In a word, empirical. By this point, reviewers were viewing the attention to these novel drugs as a strength, no more comments about demonstrating the scope of the real world problem.

In February of 2014, NIDA posted a new funding opportunity announcement on synthetic drugs, the R01 version was PAR-14-106. Actually, it was initially posted as a PA, withdrawn and reposted as a PAR “to allow a Special Emphasis Panel to provide peer review of the applications”. Why? Who knows. But as soon as the original PA was posted I sent an email to the Program Officer in charge that included my summary statements to that point in time and an observation that throwing these apps into regular study sections was unlikely to produce fundable scores. If you are keeping track, nearly everything I had submitted was triaged, except the A1 for my competing continuation (which you might view as a sympathy scoring/discussion).

Up to that point in time, if you search RePORTER for funded grant projects on “mdpv, methylone, mephedrone or cathinone” for fiscal years 2010-2014 you would first find 2 pre-doc fellowships and one post-doc fellowship. Next you would notice that one R01 was funded in FY2012 via a conflict special emphasis panel for a study section chair, one R01 was funded in FY2014 on human epidemiology through a regular standing study section and one R21 was funded through BRLE for FY2012. In addition, five NIDA intramural labs started mentioning these key words and are located by this search.

The point here is that clearly my colleagues who were also submitting grants on cathinone-related topics were having a similar lack of success. We talk at meetings so, trust me, there were several quite accomplished PIs who were applying during this interval of time as well.

We submitted a new version of the Hypothesis B proposal in June 2014 for this new PAR. It got a 25%ile so we resubmitted it in March 2015 again to the PAR. It got a 24%ile. No movement. The resume of discussion for the first version complained about minor technical issues, interdependence of Aims (this is grantsmithing stuff) and “sloppy constructed, lacking clarity and consistency”. This latter bit was interesting since one of the prior reviews of this Hypothesis B lauded it for clarity and fantastic grantsmithing. It happens. Oh, and by now we were trying to get out ahead of the looming SABV initiative and mentioned including female and male rats. Got killed for “design concerns”. The resume of discussion for the second one was a classic case of “we don’t have any real complaints but there are one or more grants better than yours in the list so we have to find something”. Very frustrating. Oh, and we were offered the opportunity to propose a R56 Bridge on the last version of this (yay!) to focus on the sex-differences and improve our hypotheses…..but it wasn’t selected for funding. Another half-submission in late 2015.

In between these submission we put in an R21 on vapor inhalation of cathinones in Jun of 2015 to be reviewed by the SEP. It received a 39 impact score with concerns mostly focused on the novel inhalation model. So no real issues with the cathinone topic itself, after all it was a synthetic drugs SEP! [Related paper: Nguyen, Aarde et al, 2016]

By this time, the MDMA-related grant I mentioned at the top was due for a competing continuation application, which went in November 2015. You may be wondering by now how we were able to sustain the effort to generate new preliminary data and such for all of these applications and, ultimately, papers. Well, our MDMA grant was funded pretty soon after we got really interested in the cathinones. There was a lot of dovetailing of the topic domains, as I mentioned, the mephedrone compound was originally reported as being sort of MDMA-like, but with enhanced abuse liability. Methylone eventually emerged as the direct cathinone cousin of MDMA. So it actually made a lot of sense to draw these together for the competing continuation. It got a 27%ile from BRLE and the reviewers were totally on board with the inclusion of new cathinone experiments as well as the harmony of what we’ve been doing over the past 4 years with the original MDMA proposal (which was originally designed before these designer cathinones appeared in user groups). This put us up to something like 4 straight applications discussed after our initial run of 6 7 triages interrupted only by one kiss-your-sister score of a -06A1 application. Progress! [Related papers: Creehan et al, 2015; Vandewater et al, 2015; Nguyen, Grant et al, 2016]

The stalling of the Hypothesis B proposal at an unfundable 24-25/%ile was frustrating, but what can you do? The ideas seemed to have legs and the complaints were not substantial. We put it back in as new application in October 2015, for the SEP once more. It got an 18%ile. Definitely outside the likely payline for the year*. So I revised and resubmitted it in August 2016. Sixth time (honestly I’m losing track at this point) is the charm for Hypothesis B?

So here we are in September of 2016. We’ve been working on this topic for over 5 years and submitting grants for almost 5 years. We’ve had thirteen papers and I’ve submitted thirteen fourteen grant applications (my collaborator has put in a few more during this interval as well).

NIDA eventually created a FOA for synthetic drugs (not just cathinones, includes cannabinoids and opioids as well). The degree to which this was influenced by our advocacy and publications, I don’t know but it had to have helped. Certainly our early triaged summary statement results were key to getting a SEP convened for this purpose. They’ve funded, by my count, two R15s, one R21 and one R03 via regular study sections and one R21 via SEP for a more general funding opportunity announcement. The PAR on synthetic drugs resulted in the funding of an R21 and four R01s on synthetic cathinones since being issued, that is 6 possible funding rounds to this date*.

We recently received word that the aforementioned October 2015 submission of the Hypothesis B proposal will be funded.

Time to REALLY get to work!

 

__

Addendum: We never work alone on these projects and it has been a large team effort. Deepshikha Angrish synthesized compounds in the Dickerson lab in the early days. Deborah Barlow in the Houseknecht lab was essential for the PK work. Matt Buczynski jumped right on a key early neuropharmacology experiment in the Parsons laboratory. Jerry Wright, Shawn Aarde (in particular), Michelle Miller and Jacques Nguyen are postdocs that did heavy lifting on this topic in my group. My laboratory’s incredible technicians Sophia Vandewater, Kevin Creehan and former technician PK Huang (now a graduate student elsewhere) likewise did great work.

 

*There is an interesting vignette in here about the effectiveness of convening SEPs for PARs. My three scores for Hypothesis B in this SEP (which doesn’t have standing members but is convened per-round) ranged from 31-36. At one point the PO seemed to let slip that my 31 was the top score in that round for the SEP. Going from the PO’s general demeanor in discussing how the FOA was going, and the rather thin list of funded grants (not many cannabinoid or opioid ones emerged either), I conclude that reviewers are not issuing clearly-fundable scores in every round. And not many fundable scores all together over 6 rounds. This is somewhat puzzling**.

 

**In FY2014 alone, NIDA funded 37 new R01s that included cocaine as a keyword and 13 with heroin. Eighteen competing continuation R01s with either heroin or cocaine referenced. Of course there would be far more that were in the middle of non-competing intervals of funding.

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