Education

  • Brown University, Sc.B., Engineering, 1980
  • Yale University, M.D., 1984

Research interests

Ken Mackie’s research program focuses on cannabinoid receptors, the cell surface receptors responsible for most of the psychoactive and therapeutic actions of cannabis. His group uses a variety of techniques, including electrophysiological, molecular, immunological, and imaging, to better understand how cannabinoid receptors signal and how their signaling interacts with other cellular processes. Much of the current work in his lab centers on endogenous cannabinoids (endocannabinoids), compounds produced by the body that interact with cannabinoid receptors. These molecules have been implicated in processes as diverse as memory, analgesia, anxiety, schizophrenia, and obesity. One recent result from his group suggests that cannabis produces some of its effects by blocking the normal actions of endocannabinoids. This contrasts with the mode of action of opiates, which appear to produce their psychoactivity by mimicking the effects of endogenous opiates (endorphins). Another recent result found that cannabidiol counters some of the deleterious effects of delta-9-tetrahydrocannabinol.

Representative publications

Full list of Ken Mackie’s Publications
  • Lin, X., A.S. Dhopeshwarker, M. Huibregtse, K. Mackie, and A.G. Hohmann, The slowly signaling G protein-biased CB2 cannabinoid receptor agonist LY2828360 suppresses neuropathic pain with sustained efficacy and attenuates morphie tolerance and dependence. Mol Pharmacol, 2017. 93(2):49-62.
  • Westphal, M., M.A. Schafroth, R. Sarott, M. Imhof, C. Bold, P. Leippe, A.Dhopeswarkar, J. Grandner, V. Katritch, K. Mackie, D. trauner, E.M. Carreira, and J.A. Frank, Synthesis of Photoswitchable Delta(9)-Tetrahydrocannabinol Derivatives Enables Optical Control of Cannabinoid Receptor 1 Signaling. J Am Chem Soc, 2017.
  • Ruehle, S., J. Wager-Miller, A. Straiker, J. Farnsworth, M.N. Murphy, S. Loch, K. Monory, K. Mackie, and B. Lutz, Discovery and characterization of two novel CB1 receptor splice variants with modified N-termini in mouse. J Neurochem, 2017. 142(4): p. 521-533.
  • Li, A.L., L.M. Carey, K. Mackie, and A.G. Hohmann, Cannabinoid CB2 Agonist GW405833 Suppresses Inflammatory and Neuropathic Pain through a CB1 Mechanism that is Independent of CB2 Receptors in Mice. J. Pharmacol Exp Ther, 2017. 362(2): p. 296-305
  • Lu, H.C. and K. Mackie. An introduction to the endogenous cannabinoid system. Biol Psychiatry, 2016: 79(7): 516-25.
    Dhopeshwarkar, A., N. Murataeva, A. Makriyannis, A. Straiker, and K. Mackie, Two Janus cannabinoids that are both CB2 agonists and CB1 antagonists. J Pharmacol Exp Ther, 2016. 360(2): p. 300-311.
  • Murataeva, N., A. Dhopeshwarkar, D. Yin, J. Mitjavila, H.B. Bradshaw, A. Straiker, and K. Mackie. Where’s my entourage? The curious case of 2-oleoylglycerol, 2-linolenoylglycerol and 2-palmitoylglycerol, Pharmacol Res, 2016. 110: p.173-80.
  • Dhopeshwarkar, A. and K. Mackie, Functional Selectivity of CB2 Cannabinoid Receptor Ligands at a Canonical and Noncanonical Pathway. J. Pharmacol Exp Ther, 2016. 358(2): p. 342-51.
    Straiker, A., J. Mitjavila, D. Yin, A. Gibson and K. Mackie. Aiming for allosterism: Evaluation of allosteric modulators of CB1 in a neuronal model. Pharmacol Res, 2015. 99: 370-6.
  • Morgan, D.J., B.J. Davis, C.S. Kearn, D. Marcus, A.J.Cook, J. Wager-Miller, A. Straiker, M.H. Myoga, J. Karduck, E. Leishman, L.J. Sim-Selley, T.A. Czyzyk, H.B. Bradshaw, D.E. Selley, and K. Mackie, Mutation of Putative GRK Phosphorylation Sites in the Cannabinoid Receptor 1 (CB1R) Confers Resistance to Cannabinoid Tolerance and Hypersensitivity to Cannabinoids in Mice. J Neurosci, 2014. 34(15): p. 5152-63.
  • Ramikie, T.S., R. Nyilas, R.J. Bluett, J.C. Gamble-George, N.D. Hartley, K. Mackie, M. Watanabe, I. Katona, and S. Patel, Multiple mechanistically distinct modes of endocannabinoid mobilization at central amygdala glutamatergic synapses. Neuron, 2014. 81(5): p.1111-25.
  • O’Donnell, B.F. and K. Mackie, The mismatch negativity: a translational probe of auditory processing in cannabis users. Biol Psychiatry, 2014. 75(6): p. 428-9.
Members from the Mackie Lab in December 2017. Ann Schertz

Narrative biography

Written by: Elisabeth Andrews

In neuroscientist Ken Mackie beats the heart of a physician. His substantial contributions to our current understanding of the endocannabinoid system – which plays significant roles in a wide range of neurological processes including memory, pain, and metabolism – were influenced by 15 years of clinical experience as an anesthesiologist in a Level-1 trauma center in Seattle. 

"Well over half my patients tested positive for THC on their drug screens," he says, referring to the primary psychoactive component of cannabis. "It was clear that many people were using cannabis to try to achieve medical benefits, including managing their pain. For some patients it seemed to be effective, but it wasn't clear how these drugs were working in the body. I wanted to answer this question."

Throughout his time as a clinician, and now in his role as a Gill Chair, Mackie has been a leading force investigating the biological mechanisms and effects of different types of cannabinoids (compounds like those found in cannabis). In addition to uncovering intermediate and long-term effects of exposure to THC and other cannabis-derived compounds like cannabidiol (CBD), his research has also helped describe the presence and function of cannabinoid molecules produced by the body, known as endogenous cannabinoids or endocannabinoids. His work highlights the promise of new therapeutic applications targeting the endocannabinoid system to address a range of problems including chronic pain and obesity, while also revealing potential risks associated with THC exposure.

Mackie's first cannabinoid breakthrough came serendipitously. Following his residency, Mackie joined the lab of Bertil Hille at the University of Washington, whose research focused on signaling activity within neurons. Hille was investigating ion channels, gateways in the membranes of cells that allow passage of ions in and out of cells.  

"That was right at the time that the first cannabinoid receptor had been cloned," Mackie recalls. "So while it had been cloned, we didn’t know what the receptor did."

Working in the Hille lab, Mackie solved this mystery by demonstrating that activation of cannabinoid receptors kept calcium ion channels from opening, thus suppressing neurotransmission and communication between neurons. In effect, cannabinoids serve to "block a message," Mackie explains. For example, a cannabinoid might interrupt a pain signal before it was relayed to the central nervous system.

"Opiates do exactly the same thing to calcium channels and neurotransmission," he adds, "but cannabinoid receptors are expressed on different neurons." Importantly, these receptors are absent from neuronal networks responsible for critical respiratory functions – so, unlike opiates, cannabinoids cannot cause a person to stop breathing. This distinction is one reason cannabinoids may offer an attractive alternative to opiates for pain management. 

Mackie's more recent research at the Gill Center reveals another difference between opiates and cannabinoids: while opioid drugs mimic the activity of the body's endogenous opiates (endorphins), the components of cannabis have a more nuanced relationship to the body's endogenous cannabinoids, either enhancing or blocking their effects. A better understanding of these distinct processes is critical for developing effective therapies; for example, it appears that some negative effects of prenatal THC exposure can be countered with drugs that enhance endocannabinoid signaling.

One of the most important contributions Mackie's lab has made is to investigate the separate and combined effects of the cannabinoids THC, which is psychoactive, and CBD, which is not. While some negative effects can be attributed to THC, CBD appears to counteract many of them. In addition, CBD appears to have other health benefits such as controlling inflammation and reducing epileptic seizures. Moreover, THC may offer its own benefits: Mackie's group has demonstrated that obese mice treated with THC reliably lose weight.

Mackie's overall goal, he says, is for the results of his lab's research to promote informed policies and programs that provide an appropriate response to both the widespread use of cannabis and the potential for cannabinoid-based therapies.

"A lot of people use cannabis; understanding and communicating about its effects is an important social issue," he says. "At the same time, we are finding ways to develop new cannabinoid medications that can improve both health and quality of life. It's an exciting time for the field."