1 00:00:05,080 --> 00:00:25,120 >>I'M CATHERINE LAWS WITH NCCIH 2 00:00:25,120 --> 00:00:56,760 WELCOME TO LECTURE SERIES 3 00:00:56,760 --> 00:00:58,120 >> WELCOME TO THE FIRST LECTURE 4 00:00:58,120 --> 00:01:00,080 SERIES FOR THE SPRING 2021 AND 5 00:01:00,080 --> 00:01:04,920 NCCIH INTEGRATIVE MEDICINE 6 00:01:04,920 --> 00:01:06,040 RESEARCH LECTURE SERIES. 7 00:01:06,040 --> 00:01:09,520 WE'RE PLEASED THAT 8 00:01:09,520 --> 00:01:10,840 DR. CHRISTOPHER MCCURDY AND OUR 9 00:01:10,840 --> 00:01:13,720 VIEWING AUDIENCE COULD JOIN US 10 00:01:13,720 --> 00:01:14,000 TODAY. 11 00:01:14,000 --> 00:01:15,640 SEVERAL KEY RESEARCH INTERESTS 12 00:01:15,640 --> 00:01:17,880 TO NCCIH INCLUDING COMPLEMENTARY 13 00:01:17,880 --> 00:01:19,440 INTEGRATIVE APPROACHES TO HELP 14 00:01:19,440 --> 00:01:20,920 TREAT OPIOID MISUSE ADDICTION 15 00:01:20,920 --> 00:01:23,040 AND SUPPORT RECOVERY, APPROACHES 16 00:01:23,040 --> 00:01:25,080 TO ENHANCE THE MANAGEMENT OF 17 00:01:25,080 --> 00:01:26,720 CHRONIC PAIN, WHICH IS 18 00:01:26,720 --> 00:01:28,640 FREQUENTLY CO-MORBID WITH 19 00:01:28,640 --> 00:01:30,120 PROBLEMS OF OPIATE USE DISORDER, 20 00:01:30,120 --> 00:01:31,720 AND TO DEVELOP TOOLS, MODEL, 21 00:01:31,720 --> 00:01:34,080 MEASURES AND METHODOLOGIES TO 22 00:01:34,080 --> 00:01:36,040 ADVANCE THE SCIENTIFIC STUDY OF 23 00:01:36,040 --> 00:01:37,440 NATURAL PRODUCTS. 24 00:01:37,440 --> 00:01:38,520 YOU CAN FIND MANY OF THESE 25 00:01:38,520 --> 00:01:43,560 TOPICS OUTLINED IN OUR FY FISCAL 26 00:01:43,560 --> 00:01:45,400 YEARS 2021 TO 2025 STRATEGIC 27 00:01:45,400 --> 00:01:45,880 PLAN. 28 00:01:45,880 --> 00:01:47,400 AND I HOPE YOU WILL TAKE A LOOK 29 00:01:47,400 --> 00:01:48,920 AT THAT. 30 00:01:48,920 --> 00:01:51,520 NOW IT'S MY PLEASURE TO 31 00:01:51,520 --> 00:01:54,520 INTRODUCE TODAY'S SPEAKER, 32 00:01:54,520 --> 00:01:56,480 DR. CHRISTOPHER MCCURDY IS A 33 00:01:56,480 --> 00:01:59,880 BROADLY TRAINED MEDICINAL 34 00:01:59,880 --> 00:02:01,080 CHEMIST WHOSE RESEARCH FOCUSES 35 00:02:01,080 --> 00:02:03,080 ON THE DESIGN, SYNTHESIS AND 36 00:02:03,080 --> 00:02:04,120 DEVELOPMENT OF DRUGS TO TREAT 37 00:02:04,120 --> 00:02:05,040 PAIN AND DRUG ABUSE. 38 00:02:05,040 --> 00:02:07,360 HE RECEIVED HIS PH.D. IN ME 39 00:02:07,360 --> 00:02:11,320 DIDDAL 40 00:02:11,320 --> 00:02:13,120 MEDICINAL CHEMISTRY FROM 41 00:02:13,120 --> 00:02:14,600 GEORGIA. 42 00:02:14,600 --> 00:02:15,240 DR. MCCURDY IS CURRENTLY 43 00:02:15,240 --> 00:02:18,160 PROFESSOR OF MEDICINAL CHEMISTRY 44 00:02:18,160 --> 00:02:20,360 AND THE FRANK A. DUCKWORTH 45 00:02:20,360 --> 00:02:21,440 EMINENT SCHOLAR CHAIR, DIRECTOR 46 00:02:21,440 --> 00:02:23,680 OF THE UF TRANSLATIONAL DRUG 47 00:02:23,680 --> 00:02:24,880 DEVELOPMENT CORE AT THE 48 00:02:24,880 --> 00:02:27,160 UNIVERSITY OF FLORIDA. 49 00:02:27,160 --> 00:02:29,280 FOR OVER 20 YEARS, MUCH OF HIS 50 00:02:29,280 --> 00:02:32,360 RESEARCH HAS FOCUSED ON OPIOIDS, 51 00:02:32,360 --> 00:02:33,640 NEUROPEPTIDE FF AND SIGMA 52 00:02:33,640 --> 00:02:36,320 RECEPTOR LIGAND, PROBE DESIGN, 53 00:02:36,320 --> 00:02:39,120 SYNTHESIS, PHARMACOLOGICAL 54 00:02:39,120 --> 00:02:40,920 EVALUATION AND DEVELOPMENT. 55 00:02:40,920 --> 00:02:44,480 MOST NOTABLY, HE HAS DEVELOPED A 56 00:02:44,480 --> 00:02:47,560 PET MRI DOES GNOSTIC AGENT FOR 57 00:02:47,560 --> 00:02:48,760 INDIVIDUALIZING THE ORIGINS OF 58 00:02:48,760 --> 00:02:50,080 CHRONIC NEUROPATHIC PAIN BY 59 00:02:50,080 --> 00:02:51,440 INTERACTING WITH SIGMA RECEPTORS 60 00:02:51,440 --> 00:02:54,320 AT THE SITE OF NERVE DAMAGE. 61 00:02:54,320 --> 00:02:55,760 DR. MCCURDY IS ALSO AN 62 00:02:55,760 --> 00:02:56,880 INTERNATIONALLY RECOGNIZED 63 00:02:56,880 --> 00:03:01,920 EXPERT ON KRAI KRATOM, UNDER 64 00:03:01,920 --> 00:03:03,480 INVESTIGATION FOR OPIATE 65 00:03:03,480 --> 00:03:05,880 WITHDRAWAL SYNDROME. 66 00:03:05,880 --> 00:03:08,560 HE CURRENTLY SERVED AS PRESIDENT 67 00:03:08,560 --> 00:03:10,600 FOR THE ASSOCIATION OF 68 00:03:10,600 --> 00:03:11,440 PHARMACEUTICAL SCIENCE AND ALSO 69 00:03:11,440 --> 00:03:13,080 SERVES AS CO-CHAIR OF THE 70 00:03:13,080 --> 00:03:14,480 SPECIAL INTEREST GROUP ON DRUG 71 00:03:14,480 --> 00:03:16,520 DESIGN AND DISCOVERY OF THE 72 00:03:16,520 --> 00:03:17,520 INTERNATIONAL PHARMACEUTICAL 73 00:03:17,520 --> 00:03:17,800 FEDERATION. 74 00:03:17,800 --> 00:03:19,320 HE WAS ALSO PAST DIRECTOR OF THE 75 00:03:19,320 --> 00:03:21,520 NIH COBRE CENTER FOR RESEARCH 76 00:03:21,520 --> 00:03:23,800 EXCELLENCE IN NATURAL PRODUCTS 77 00:03:23,800 --> 00:03:24,800 NEUROSCIENCE. 78 00:03:24,800 --> 00:03:27,720 DR. MCCURDY RECEIVES NIH FUNDING 79 00:03:27,720 --> 00:03:28,840 FROM NATIONAL INSTITUTE ON DRUG 80 00:03:28,840 --> 00:03:30,920 ABUSE AND THE NATIONAL INSTITUTE 81 00:03:30,920 --> 00:03:32,240 ON NEUROLOGICAL DISORDERS AND 82 00:03:32,240 --> 00:03:32,760 STROKE. 83 00:03:32,760 --> 00:03:34,880 AND WITH THAT, CHRIS, WE VERY 84 00:03:34,880 --> 00:03:36,280 MUCH LOOK FORWARD TO YOUR 85 00:03:36,280 --> 00:03:37,600 PRESENTATION, AND I'LL TURN THE 86 00:03:37,600 --> 00:03:42,560 MIC OVER TO YOU. 87 00:03:42,560 --> 00:03:45,080 >> THANK YOU FOR INVITING ME TO 88 00:03:45,080 --> 00:03:45,560 PRESENT TODAY. 89 00:03:45,560 --> 00:03:47,040 IT'S REALLY QUITE AN HONOR TO BE 90 00:03:47,040 --> 00:03:48,360 ABLE TO SHARE SOME OF THE WORK 91 00:03:48,360 --> 00:03:51,320 THAT WE'VE BEEN DOING WITH YOU. 92 00:03:51,320 --> 00:03:52,840 UNFORTUNATELY I CAN'T SHARE ALL 93 00:03:52,840 --> 00:03:56,760 OF IT BECAUSE WE'VE REALLY DONE 94 00:03:56,760 --> 00:04:00,360 A TREMENDOUS AMOUNT OF WORK IN 95 00:04:00,360 --> 00:04:03,840 THIS AREA DURING THE TIME THAT 96 00:04:03,840 --> 00:04:05,600 WE'VE BEEN SORT OF SEQUESTERED 97 00:04:05,600 --> 00:04:12,440 TO OUR LABS. 98 00:04:12,440 --> 00:04:13,480 COVID HAS NOT BEEN A TERRIBLE 99 00:04:13,480 --> 00:04:14,920 THING FOR US, WE'VE BEEN VERY 100 00:04:14,920 --> 00:04:15,920 PRODUCTIVE AND A LOT OF THAT IS 101 00:04:15,920 --> 00:04:17,440 THANKS TO THE SUPPORT WE RECEIVE 102 00:04:17,440 --> 00:04:20,560 FROM NIH. 103 00:04:20,560 --> 00:04:21,600 SO I'D LIKE TO JUST TELL YOU A 104 00:04:21,600 --> 00:04:23,920 LITTLE BIT ABOUT OUR JOURNEY 105 00:04:23,920 --> 00:04:30,040 WITH THIS PLANT, MITRAGYNA 106 00:04:30,040 --> 00:04:33,160 SPECIOSA, PROPERLY KNOWN AS 107 00:04:33,160 --> 00:04:34,000 KRATOM. 108 00:04:34,000 --> 00:04:35,960 WE WILL GET THROUGH MANY OF THE 109 00:04:35,960 --> 00:04:36,840 ALKALOIDS AND MANY OF THE 110 00:04:36,840 --> 00:04:37,760 POTENTIAL THAT'S THERE BUT I'M 111 00:04:37,760 --> 00:04:39,280 ONLY SCRATCHING THE SURFACE 112 00:04:39,280 --> 00:04:40,560 TODAY JUST DUE TO TIME 113 00:04:40,560 --> 00:04:42,640 RESTRAINTS, AND UNFORTUNATELY, 114 00:04:42,640 --> 00:04:43,920 WE DON'T HAVE ANY HUMAN DATA TO 115 00:04:43,920 --> 00:04:46,560 SHARE WITH YOU JUST YET, BUT 116 00:04:46,560 --> 00:04:48,560 THERE WAS RECENTLY A 117 00:04:48,560 --> 00:04:51,200 PHARMACOKINETICS PAPER PUBLISHED 118 00:04:51,200 --> 00:04:54,680 FROM MARY PAINE'S GROUP FUNDED 119 00:04:54,680 --> 00:04:59,480 OUT OF THIS INSTITUTE, AND I'VE 120 00:04:59,480 --> 00:05:00,760 NOT DIGESTED THAT COMPLETELY SO 121 00:05:00,760 --> 00:05:02,360 I'M NOT GOING TO SHARE THAT DATA 122 00:05:02,360 --> 00:05:05,160 WITH YOU TODAY, BUT I AM AWARE 123 00:05:05,160 --> 00:05:06,360 OF AND PARTICIPATING IN A FEW 124 00:05:06,360 --> 00:05:09,640 OTHER TRIALS THAT ARE GOING ON 125 00:05:09,640 --> 00:05:10,680 IN CANADA, AS WELL AS ONE FUNDED 126 00:05:10,680 --> 00:05:13,080 BY THE FDA THAT WILL BE STARTED 127 00:05:13,080 --> 00:05:16,360 SOMETIME THIS YEAR. 128 00:05:16,360 --> 00:05:17,960 SO WE'LL HOPEFULLY COME BACK 129 00:05:17,960 --> 00:05:19,400 NEXT YEAR OR IN A COUPLE YEARS 130 00:05:19,400 --> 00:05:20,360 AND TELL YOU WHAT WE'VE LEARNED 131 00:05:20,360 --> 00:05:23,240 IN TERMS OF HUMAN SAFETY AND 132 00:05:23,240 --> 00:05:24,440 PHARMACOKINETICS AS WELL AS SOME 133 00:05:24,440 --> 00:05:29,280 POTENTIAL IN THE HUMAN SETTING 134 00:05:29,280 --> 00:05:32,240 FROM SOY ENS. 135 00:05:32,240 --> 00:05:32,680 SCIENCE. 136 00:05:32,680 --> 00:05:34,400 FIRST WE'RE GOING TO TALK MORE 137 00:05:34,400 --> 00:05:35,040 ANECDOTALLY AND I'D LIKE TO 138 00:05:35,040 --> 00:05:36,800 SHARE WITH YOU A LITTLE ON THE 139 00:05:36,800 --> 00:05:38,560 TREE AND ITS ORIGIN. 140 00:05:38,560 --> 00:05:41,520 MITRAGYNA SPECIOSA COMES FROM 141 00:05:41,520 --> 00:05:43,480 THE RUBIACEAE FAMILY WHICH IS 142 00:05:43,480 --> 00:05:45,560 ACTUALLY THE SAME FAMILY THE 143 00:05:45,560 --> 00:05:46,400 COFFEE PLANT IS IN. 144 00:05:46,400 --> 00:05:47,600 WE'VE HEARD THIS COMPARISON MANY 145 00:05:47,600 --> 00:05:47,840 TIMES. 146 00:05:47,840 --> 00:05:51,400 AND THE MOST COMMON FORM OF 147 00:05:51,400 --> 00:05:53,000 CONSUMPTION OF MITRAGYNA 148 00:05:53,000 --> 00:05:55,200 SPECIOSA IS AS A BREWED TEA. 149 00:05:55,200 --> 00:05:56,680 AND I'LL SHOW YOU A LITTLE BIT 150 00:05:56,680 --> 00:06:00,520 OF THAT IN A FEW MINUTES. 151 00:06:00,520 --> 00:06:03,160 THE TREE IS NATIVELY FOUND IN 152 00:06:03,160 --> 00:06:04,760 SOUTHEAST ASIA, PARTICULARLY 153 00:06:04,760 --> 00:06:10,280 THAILAND AND MALAYSIA. 154 00:06:10,280 --> 00:06:13,760 IT'S REALLY IN PENINSULAR 155 00:06:13,760 --> 00:06:15,560 MALAYSIA AND THAILAND WHERE THIS 156 00:06:15,560 --> 00:06:16,560 TREE IS BELIEVED TO HAVE 157 00:06:16,560 --> 00:06:18,560 ORIGINATED FROM. 158 00:06:18,560 --> 00:06:19,880 IT HAS SINCE SPREAD THROUGHOUT 159 00:06:19,880 --> 00:06:22,000 MOST OF SOUTHEAST ASIA INTO IND 160 00:06:22,000 --> 00:06:25,000 KNEE SLA, WHICH 161 00:06:25,000 --> 00:06:25,760 INDONESIA, WHICH IS WHERE MOST 162 00:06:25,760 --> 00:06:28,000 OF THE MATERIAL COMING INTO THE 163 00:06:28,000 --> 00:06:28,880 UNITED STATES IS GROWN TO THIS 164 00:06:28,880 --> 00:06:29,520 DAY. 165 00:06:29,520 --> 00:06:32,600 IT IS REFERRED TO AS KRATOM. 166 00:06:32,600 --> 00:06:36,080 IN THAILAND IT'S ACTUALLY CRAH 167 00:06:36,080 --> 00:06:40,600 TOM AND IN MALAYSIA, IT'S BIAK 168 00:06:40,600 --> 00:06:43,520 BIAK OR KETUM, SO THAT SORT OF 169 00:06:43,520 --> 00:06:45,800 KRATOM KETUM SORT OF VIBE TO IT, 170 00:06:45,800 --> 00:06:49,360 AND WE ALL HAVE HEARD MANY 171 00:06:49,360 --> 00:06:49,760 PRONUNCIATIONS. 172 00:06:49,760 --> 00:06:50,840 THAT'S ONE OF THE MOST FREQUENT 173 00:06:50,840 --> 00:06:52,400 QUESTIONS I'M ASKED, IS WHAT'S 174 00:06:52,400 --> 00:06:53,080 THE RIGHT PRONUNCIATION. 175 00:06:53,080 --> 00:06:58,160 I THINK IT'S MORE LIKE TOMATOES 176 00:06:58,160 --> 00:06:59,960 AND TOMATOES, SO AS LONG AS WE 177 00:06:59,960 --> 00:07:01,000 KNOW WE'RE TALKING ABOUT THE 178 00:07:01,000 --> 00:07:01,680 SAME THING, THAT'S THE MOST 179 00:07:01,680 --> 00:07:02,120 IMPORTANT. 180 00:07:02,120 --> 00:07:05,120 THERE HAVE BEEN REPORTED OVER 40 181 00:07:05,120 --> 00:07:06,240 ALKALOIDS ISOLATED TO DATE. 182 00:07:06,240 --> 00:07:07,680 WE'VE JUST ISOLATED A COUPLE NEW 183 00:07:07,680 --> 00:07:09,960 ONES THAT WE'RE GETTING READY TO 184 00:07:09,960 --> 00:07:11,960 PUBLISH THAT HAVEN'T BEEN 185 00:07:11,960 --> 00:07:15,400 REPORTED BEFORE, SO I THINK THE 186 00:07:15,400 --> 00:07:16,640 LIST KEEPS GROWING, NOT TOO 187 00:07:16,640 --> 00:07:17,880 DIFFERENT FROM WHAT WE SEE IN 188 00:07:17,880 --> 00:07:19,800 THE CANNABIS SPACE WHERE WE KEEP 189 00:07:19,800 --> 00:07:23,840 FINDING MORE AND MORE 190 00:07:23,840 --> 00:07:26,640 CANNABINOIDS. 191 00:07:26,640 --> 00:07:34,240 THE GENUS NAME MITT MI TRA GUY MITRAGYNA COMES 192 00:07:34,240 --> 00:07:35,440 FROM THE SHAPE OF THE LEAF. 193 00:07:35,440 --> 00:07:37,880 IF YOU TURN THIS 90 DEGREES 194 00:07:37,880 --> 00:07:39,000 CLOCKWISE, IT TAKES ON THE SHAPE 195 00:07:39,000 --> 00:07:42,880 OF A BISHOP'S OR MITER'S HAT, 196 00:07:42,880 --> 00:07:44,840 AND THAT'S WHERE THE SPECIES GOT 197 00:07:44,840 --> 00:07:48,480 ITS NAME, FROM MITRAGYNA. 198 00:07:48,480 --> 00:07:50,560 SO I WANT TO SHOW YOU WHAT THE 199 00:07:50,560 --> 00:07:51,280 SORT OF TRADITIONAL VIEW OF THIS 200 00:07:51,280 --> 00:07:54,160 IS AND HOW IT LOOKS IN ITS 201 00:07:54,160 --> 00:07:55,240 NATIVE SETTING. 202 00:07:55,240 --> 00:07:58,200 SO KRATOM HAS BEEN USED BY FIELD 203 00:07:58,200 --> 00:08:01,560 WORKERS IN SOUTHEAST ASIA TO 204 00:08:01,560 --> 00:08:03,680 RELIEVE PAIN, ALSO AS A STIM 205 00:08:03,680 --> 00:08:05,560 LANTD TO 206 00:08:05,560 --> 00:08:07,240 STIMULANT TO IMPROVE THEIR WORK 207 00:08:07,240 --> 00:08:08,760 CAPACITY IN THE HOT TROPICAL 208 00:08:08,760 --> 00:08:09,800 CLIMATE, AND ALSO WHEN THEY 209 00:08:09,800 --> 00:08:11,280 WOULD RUN OUT OF OPIUM, THOSE 210 00:08:11,280 --> 00:08:12,560 THAT USED OPIUM, THEY WOULD USE 211 00:08:12,560 --> 00:08:13,840 THIS IN A LITTLE BIT HIGHER 212 00:08:13,840 --> 00:08:15,760 DOSES TO HELP REDUCE OPIOID 213 00:08:15,760 --> 00:08:16,080 WITHDRAWAL. 214 00:08:16,080 --> 00:08:19,800 AND THAT'S REALLY WHERE WE GOT 215 00:08:19,800 --> 00:08:20,480 INTERESTED IN THIS PROJECT. 216 00:08:20,480 --> 00:08:22,200 NOT JUST THE PAIN ASPECT, BUT 217 00:08:22,200 --> 00:08:25,920 CAN WE SEE AN ALTERNATIVE IN 218 00:08:25,920 --> 00:08:27,800 HELPING WITH OPIOID USE 219 00:08:27,800 --> 00:08:30,080 DISORDERS OR EVEN OPIOID 220 00:08:30,080 --> 00:08:32,160 WITHDRAWAL SYNDROME. 221 00:08:32,160 --> 00:08:32,800 RECENTLY THERE'S BEEN SOME 222 00:08:32,800 --> 00:08:34,680 REPORTS THAT POLYDRUG USER, 223 00:08:34,680 --> 00:08:36,960 PARTICULARLY THOSE USING OPIATES 224 00:08:36,960 --> 00:08:39,560 AND METHAMPHETAMINE, ARE 225 00:08:39,560 --> 00:08:41,000 INTAKING KRATOM TO REALLY REDUCE 226 00:08:41,000 --> 00:08:41,640 THEIR USE. 227 00:08:41,640 --> 00:08:43,080 OF COURSE THIS IS INTERESTING 228 00:08:43,080 --> 00:08:45,480 BECAUSE WE HAVE NOTHING TO 229 00:08:45,480 --> 00:08:47,720 REALLY COMBAT METHAMPHETAMINE OR 230 00:08:47,720 --> 00:08:51,960 COCAINE USE DISORDER EITHER. 231 00:08:51,960 --> 00:08:53,360 SO THIS IS ANOTHER AREA WE'VE 232 00:08:53,360 --> 00:08:54,920 KIND OF JUMPED INTO A LITTLE 233 00:08:54,920 --> 00:08:55,680 BIT. 234 00:08:55,680 --> 00:08:57,480 THE PREDOMINANT ACTIVE 235 00:08:57,480 --> 00:08:59,000 INGREDIENT OR ACTIVE AGENT AT 236 00:08:59,000 --> 00:09:01,480 LEAST THE THOUGHT TO BE ACTIVE 237 00:09:01,480 --> 00:09:06,360 AGENT IN KRATOM IS MITRAGYNINE 238 00:09:06,360 --> 00:09:07,880 THAT ACCOUNTS FOR ANYWHERE FROM 239 00:09:07,880 --> 00:09:14,720 20 TO 66% OF THE TOTALING TOTAL ALKALOID 240 00:09:14,720 --> 00:09:15,120 CONTENT. 241 00:09:15,120 --> 00:09:16,080 I'LL TALK A LITTLE MORE ABOUT 242 00:09:16,080 --> 00:09:17,120 THE TREES THEMSELVES IN A 243 00:09:17,120 --> 00:09:17,560 MOMENT. 244 00:09:17,560 --> 00:09:23,920 THIS IS THE STRUCTURE OF 245 00:09:23,920 --> 00:09:26,280 MITRAGYNINE, AND MOST ALL OF THE 246 00:09:26,280 --> 00:09:27,840 STRUCTURES IN THIS PLANT, ALL 247 00:09:27,840 --> 00:09:34,720 THE ALKALOIDS HAVE THIS BASE 248 00:09:34,720 --> 00:09:35,600 RING STRUCTURE. 249 00:09:35,600 --> 00:09:40,840 THE SECOND THING IS THIS BOTTOM 250 00:09:40,840 --> 00:09:41,600 PORTION OF THE MOLECULE, IF YOU 251 00:09:41,600 --> 00:09:43,560 CAN SEE MY POINTER, WHAT WE CALL 252 00:09:43,560 --> 00:09:54,240 THE BETA METHOXY ACRYLATE, WE'LL 253 00:09:54,240 --> 00:09:55,960 ON THE BOTTOM LEFT-HAND SCREEN 254 00:09:55,960 --> 00:09:58,520 IS THE TREE GROWING IN THE 255 00:09:58,520 --> 00:09:59,920 NATIVE ENVIRONMENT IN THE 256 00:09:59,920 --> 00:10:01,960 FLOWERING STATE. 257 00:10:01,960 --> 00:10:03,400 WE'RE ONLY FOCUSING ON THE 258 00:10:03,400 --> 00:10:03,960 LEAVES TODAY. 259 00:10:03,960 --> 00:10:10,760 THE FLOWERS IS ANOTHER STORY. 260 00:10:10,760 --> 00:10:11,960 AND MAYBE ANOTHER TIME. 261 00:10:11,960 --> 00:10:13,280 THOSE LEAVES ARE HARVESTED FRESH 262 00:10:13,280 --> 00:10:14,600 EACH DAY FROM THE TREE, THEY ARE 263 00:10:14,600 --> 00:10:16,240 CUT WITH SCISSORS AND PUT INTO A 264 00:10:16,240 --> 00:10:17,560 POT OF BOILING WATER, WHERE 265 00:10:17,560 --> 00:10:23,240 THEY'RE BOILED FOR ANYWHERE FROM 266 00:10:23,240 --> 00:10:26,120 2 TO 4 HOURS, USUALLY TWO TO 267 00:10:26,120 --> 00:10:28,320 THREE HOURS MAXIMUM. 268 00:10:28,320 --> 00:10:30,560 IT'S LADLED OUT AND PUT INTO 269 00:10:30,560 --> 00:10:31,560 TRAVELING PACKAGES, WHICH YOU 270 00:10:31,560 --> 00:10:33,160 CAN SEE DOWN AT THE BOTTOM RIGHT 271 00:10:33,160 --> 00:10:35,960 CORNER THERE, EITHER IN PLASTIC 272 00:10:35,960 --> 00:10:39,160 BAGGIES, WHICH IS A COMMON DRINK 273 00:10:39,160 --> 00:10:41,560 CONTAINER IN MALAYSIA, OR IT'S 274 00:10:41,560 --> 00:10:44,440 PUT INTO PLASTIC BOTTLES. 275 00:10:44,440 --> 00:10:46,080 AND THEN I WANTED TO SHOW YOU 276 00:10:46,080 --> 00:10:47,880 WHAT A STREETSIDE STAND LOOKS 277 00:10:47,880 --> 00:10:49,080 LIKE, AND THAT'S PRETTY MUCH 278 00:10:49,080 --> 00:10:51,720 WHAT YOU SEE THERE IN THE MIDDLE 279 00:10:51,720 --> 00:10:55,600 OF THE SCREEN NEXT TO THE 280 00:10:55,600 --> 00:10:56,160 MITRAGYNINE STRUCTURE. 281 00:10:56,160 --> 00:10:59,200 THESE ARE NOT VERY HEAVILY 282 00:10:59,200 --> 00:10:59,560 ADVERTISED. 283 00:10:59,560 --> 00:11:02,480 IT'S ILLEGAL TO SELL THIS IN THE 284 00:11:02,480 --> 00:11:06,200 PUBLIC IN MALAYSIA. 285 00:11:06,200 --> 00:11:10,360 BUT IT'S NOT HARD TO FIND, AND 286 00:11:10,360 --> 00:11:12,120 THE FINES FOR SELLING SUCH ARE 287 00:11:12,120 --> 00:11:13,560 REALLY NOT PROHIBITIVE TO PEOPLE 288 00:11:13,560 --> 00:11:14,920 DOING IT, BECAUSE THEY CAN MAKE 289 00:11:14,920 --> 00:11:17,560 MORE MONEY SELLING. 290 00:11:17,560 --> 00:11:20,080 MOST EVERY SINGLE HOUSE IN 291 00:11:20,080 --> 00:11:21,960 MALAYSIA IN THIS AREA HAS A TREE 292 00:11:21,960 --> 00:11:23,240 IN THEIR OWN PROPERTY. 293 00:11:23,240 --> 00:11:24,680 IT'S LEGAL TO USE IF YOU GROW 294 00:11:24,680 --> 00:11:28,720 YOUR OWN. 295 00:11:28,720 --> 00:11:30,160 AND CONSUME YOUR OWN IN YOUR 296 00:11:30,160 --> 00:11:30,800 HOUSEHOLD, BUT ALMOST EVERY 297 00:11:30,800 --> 00:11:32,200 SINGLE HOUSE THAT WE ENCOUNTERED 298 00:11:32,200 --> 00:11:34,400 HAD AT LEAST ONE TREE IN THE 299 00:11:34,400 --> 00:11:36,320 YARD. 300 00:11:36,320 --> 00:11:37,720 KRATOM USE IN THE UNITED STATES 301 00:11:37,720 --> 00:11:40,560 IS A TOTALLY DIFFERENT STORY. 302 00:11:40,560 --> 00:11:42,560 AND THIS IS WHAT WE SEE. 303 00:11:42,560 --> 00:11:44,760 IT'S WIDELY AVAILABLE ON THE 304 00:11:44,760 --> 00:11:46,960 INTERNET. 305 00:11:46,960 --> 00:11:48,480 SMOKE AND VAPE SHOPS. 306 00:11:48,480 --> 00:11:50,440 AND THIS DATA IS A LITTLE BIT 307 00:11:50,440 --> 00:11:52,880 OLD NOW, BUT THE AMERICAN KRATOM 308 00:11:52,880 --> 00:11:54,960 ASSOCIATION REPORTED BACK ABOUT 309 00:11:54,960 --> 00:11:56,040 THREE YEARS AGO NOW THAT THERE 310 00:11:56,040 --> 00:11:58,760 WAS ALMOST 2,000 METRIC TONS 311 00:11:58,760 --> 00:12:01,000 EXPORTED INTO THE U.S. EVERY 312 00:12:01,000 --> 00:12:01,360 MONTH. 313 00:12:01,360 --> 00:12:04,160 AND SO IF WE DO A QUICK 314 00:12:04,160 --> 00:12:05,920 CALCULATION ABOUT A TYPICAL DOSE 315 00:12:05,920 --> 00:12:09,920 BEING 3 TO 5 GRAMS, IT SUGGESTS 316 00:12:09,920 --> 00:12:10,600 THERE'S PROBABLY IN THE 317 00:12:10,600 --> 00:12:12,160 NEIGHBORHOOD OF 15 MILLION USERS 318 00:12:12,160 --> 00:12:13,680 IN THE UNITED STATES. 319 00:12:13,680 --> 00:12:15,520 THERE HAVE BEEN SOME MORE 320 00:12:15,520 --> 00:12:16,600 CONSERVATIVE REPORTS THAT HAVE 321 00:12:16,600 --> 00:12:19,760 COME OUT RECENTLY THAT ACTUALLY 322 00:12:19,760 --> 00:12:22,360 INDICATE THERE'S PROBABLY TWO TO 323 00:12:22,360 --> 00:12:22,960 3 MILLION USERS. 324 00:12:22,960 --> 00:12:24,960 BUT BASED ON TALKING WITH 325 00:12:24,960 --> 00:12:27,040 VENDORS AND THE AMERICAN KRATOM 326 00:12:27,040 --> 00:12:28,720 ASSOCIATION, I THINK THAT NUMBER 327 00:12:28,720 --> 00:12:33,080 IS NORTH OF 10 MILLION FOR SURE. 328 00:12:33,080 --> 00:12:34,200 THIS IS WHAT THE PRODUCTS LOOK 329 00:12:34,200 --> 00:12:34,800 LIKE HERE. 330 00:12:34,800 --> 00:12:37,480 WE'VE GOT CRUSHED LEAVES, WE'VE 331 00:12:37,480 --> 00:12:40,320 GOT PHARMACEUTICALLY 332 00:12:40,320 --> 00:12:41,360 ENCAPSULATED EXTRACTS AND 333 00:12:41,360 --> 00:12:44,880 PRODUCT, WE'VE GOT ENERGY SHOTS, 334 00:12:44,880 --> 00:12:47,160 AND THEN JUST FINALLY GROUND 335 00:12:47,160 --> 00:12:47,960 POWDERS. 336 00:12:47,960 --> 00:12:50,600 THIS IS ALL UNDER AN IMPORT BAN 337 00:12:50,600 --> 00:12:52,280 FROM THE FDA, SO IT'S NOT EVEN 338 00:12:52,280 --> 00:12:53,800 SUPPOSED TO BE COMING IN TO THE 339 00:12:53,800 --> 00:12:54,280 COUNTRY. 340 00:12:54,280 --> 00:12:55,440 YET MOST OF IT COMES IN THE 341 00:12:55,440 --> 00:13:00,080 COUNTRY UNDER THE GUISE OF 342 00:13:00,080 --> 00:13:05,760 SODIUM ALGINATE OR SEA WE'D, WEED, A 343 00:13:05,760 --> 00:13:06,880 FOOD THICKENING AGENT USED QUITE 344 00:13:06,880 --> 00:13:09,160 COMMONLY IN THE CULINARY 345 00:13:09,160 --> 00:13:11,160 INDUSTRY, SO IT COMES IN AS A 346 00:13:11,160 --> 00:13:14,120 GREEN POWDER, IT LOOKS JUST LIKE 347 00:13:14,120 --> 00:13:16,640 SODIUM ALGINATE AS WELL, AND SO 348 00:13:16,640 --> 00:13:18,480 IT'S NO SURPRISE THAT MUCH OF 349 00:13:18,480 --> 00:13:22,080 IT'S GETTING THROUGH UNDETECTED. 350 00:13:22,080 --> 00:13:24,040 AND IN SOME CASES, IT LITERALLY 351 00:13:24,040 --> 00:13:26,240 COMES IN UNDER WET SEAWEED, AND 352 00:13:26,240 --> 00:13:29,680 THAT'S BEEN A PROBLEM WITH 353 00:13:29,680 --> 00:13:32,800 SALMONELLA AND OTHER ISSUES THAT 354 00:13:32,800 --> 00:13:36,400 HAVE LED TO SOME RECALLS. 355 00:13:36,400 --> 00:13:40,360 SO WHAT ABOUT KRATOM AND 356 00:13:40,360 --> 00:13:41,000 MITRAGYNINE? 357 00:13:41,000 --> 00:13:42,400 WE'RE GOING TO FOCUS ON 358 00:13:42,400 --> 00:13:43,960 MITRAGYNINE, IT'S THE MOST 359 00:13:43,960 --> 00:13:45,040 ABUNDANT ALKALOID IN THE PLANT 360 00:13:45,040 --> 00:13:48,080 SO THE MOST EASILY EXTRACTED, 361 00:13:48,080 --> 00:13:49,120 PURIFIED AND STUDIED. 362 00:13:49,120 --> 00:13:52,280 WE KNOW THAT VERY FEW DEATHS ARE 363 00:13:52,280 --> 00:13:53,760 ATTRIBUTABLE TO A KRATOM PRODUCT 364 00:13:53,760 --> 00:13:58,160 ALONE. 365 00:13:58,160 --> 00:13:59,360 AND EVEN THOSE THAT ARE 366 00:13:59,360 --> 00:14:00,480 ATTRIBUTED TO KRATOM ALONE, 367 00:14:00,480 --> 00:14:01,840 THERE COULD BE EXTREME 368 00:14:01,840 --> 00:14:02,360 CIRCUMSTANCES. 369 00:14:02,360 --> 00:14:05,120 ONE IN TERMS OF OVERDOSING OR 370 00:14:05,120 --> 00:14:06,440 VERY HIGH DOSES, AND I'LL TALK 371 00:14:06,440 --> 00:14:07,640 ABOUT THAT AT THE VERY END OF 372 00:14:07,640 --> 00:14:10,400 THE TALK. 373 00:14:10,400 --> 00:14:13,560 OR IT COULD BE ADULT RATED WITH 374 00:14:13,560 --> 00:14:14,360 UNKNOWN SYNTHETIC COMPOUNDS. 375 00:14:14,360 --> 00:14:16,520 WE'VE ALSO REPORTED SOME ADULT 376 00:14:16,520 --> 00:14:19,360 RANGE OF MOTION OF KRATOM WITH 377 00:14:19,360 --> 00:14:20,760 OXYCODONE AND MORPHINE THAT'S 378 00:14:20,760 --> 00:14:21,920 BEEN AVAILABLE IN THE 379 00:14:21,920 --> 00:14:22,400 MARKETPLACE. 380 00:14:22,400 --> 00:14:24,000 AND WHY SOMEONE WOULD SPEND THE 381 00:14:24,000 --> 00:14:25,520 MONEY TO GO THROUGH AND PUT A 382 00:14:25,520 --> 00:14:29,960 MORE EXPENSIVE OPIATE INTO A 383 00:14:29,960 --> 00:14:33,600 PRODUCT THAT'S VERY INEXPENSIVE 384 00:14:33,600 --> 00:14:34,720 IS SOMETHING JUST SEEMING TO ME 385 00:14:34,720 --> 00:14:38,400 TO BE NEFARIOUS AND SINISTER. 386 00:14:38,400 --> 00:14:40,400 BUT IT HAPPENS. 387 00:14:40,400 --> 00:14:43,560 MITRAGYNINE, WE KNOW IS A 388 00:14:43,560 --> 00:14:44,320 PARTIAL MU OPIOID AGONIST. 389 00:14:44,320 --> 00:14:46,280 IT CAUSES ABOUT 40% MAXIMAL 390 00:14:46,280 --> 00:14:48,000 EFFECT IN G PROTEIN ACTIVATION, 391 00:14:48,000 --> 00:14:49,520 AND THE EXCITEMENT ABOUT IT WAS 392 00:14:49,520 --> 00:14:51,640 THAT IT'S ALSO A BIASED AGONIST. 393 00:14:51,640 --> 00:14:54,160 IN OTHER WORDS, IT SIGNALS ONLY 394 00:14:54,160 --> 00:14:55,760 THROUGH THE G PROTEIN MECHANISM, 395 00:14:55,760 --> 00:15:00,360 IT DOESN'T RECRUIT BETA 396 00:15:00,360 --> 00:15:00,800 ARRESTIN. 397 00:15:00,800 --> 00:15:01,320 WHY IS THAT IMPORTANT? 398 00:15:01,320 --> 00:15:02,720 A LOT OF MOLECULES ARE UNDER 399 00:15:02,720 --> 00:15:04,000 INVESTIGATION AND DEVELOPMENT AS 400 00:15:04,000 --> 00:15:06,720 OPIOIDS WITH LOW RESPIRATORY 401 00:15:06,720 --> 00:15:09,960 DEPRESSIVE AND CONS CONSTIPATION 402 00:15:09,960 --> 00:15:11,320 EFFECTS BECAUSE IT'S BELIEVED 403 00:15:11,320 --> 00:15:14,800 THAT NOT RECRUITING BETA 404 00:15:14,800 --> 00:15:16,640 ARRESTIN ACTUALLY PUSHES AWAY 405 00:15:16,640 --> 00:15:17,480 SOME OF THE LIABILITIES AND SIDE 406 00:15:17,480 --> 00:15:17,880 EFFECTS. 407 00:15:17,880 --> 00:15:21,520 SO A LOT OF THAT WORK FIRST CAME 408 00:15:21,520 --> 00:15:25,400 OUT FROM A LAB AT COLUMBIA. 409 00:15:25,400 --> 00:15:29,480 THEY'VE BEEN WORK HARD ON THIS 410 00:15:29,480 --> 00:15:33,960 AS WELL , 411 00:15:33,960 --> 00:15:35,720 REALLY BEEN PRODUCING SOME GREAT 412 00:15:35,720 --> 00:15:39,320 MATERIAL THAT WE TEND TO GO BACK 413 00:15:39,320 --> 00:15:40,760 AND FORTH IN THE LITERATURE ON. 414 00:15:40,760 --> 00:15:41,640 IT'S BEEN FUN. 415 00:15:41,640 --> 00:15:43,160 WHAT ABOUT THE THERAPEUTIC 416 00:15:43,160 --> 00:15:43,720 POTENTIAL, THOUGH? 417 00:15:43,720 --> 00:15:47,720 WE'VE LOOKED AT IT PRIMARILY 418 00:15:47,720 --> 00:15:53,120 FROM THE SOURCE OF AN OPIOID 419 00:15:53,120 --> 00:15:54,960 DETOXIFICATION, SO HAVING THE 420 00:15:54,960 --> 00:15:56,160 POTENTIAL TO REPLACE SEVERAL 421 00:15:56,160 --> 00:15:56,440 MEDICATIONS. 422 00:15:56,440 --> 00:15:57,560 I'M GOING TO SHOW YOU IT'S MUCH 423 00:15:57,560 --> 00:15:59,640 MORE DISRUPTIVE THAN JUST OPIOID 424 00:15:59,640 --> 00:15:59,920 ACTIVITY. 425 00:15:59,920 --> 00:16:01,760 IN FACT, I THINK IT'S REALLY 426 00:16:01,760 --> 00:16:03,240 SOMETHING THAT IS CAUSING A LOT 427 00:16:03,240 --> 00:16:04,760 OF PROBLEMS ON HOW TO DEAL WITH 428 00:16:04,760 --> 00:16:08,520 THIS ON MANY LEVELS, BECAUSE OF 429 00:16:08,520 --> 00:16:10,800 THE FAIRLY DISRUPTIVE 430 00:16:10,800 --> 00:16:13,320 PHARMACOLOGY THAT IT'S CAUSING. 431 00:16:13,320 --> 00:16:17,480 IT HAS ADD ADRENERGIC ACTIVITIES AS 432 00:16:17,480 --> 00:16:18,160 WELL AS OTHERS. 433 00:16:18,160 --> 00:16:19,600 BUT IF YOU COMBINE ALL OF THOSE 434 00:16:19,600 --> 00:16:20,360 INTO ONE PRODUCT, YOU MIGHT BE 435 00:16:20,360 --> 00:16:22,840 ABLE TO IMPROVE MEDICATION 436 00:16:22,840 --> 00:16:26,000 ADHERENCE AND COMPLETION OF 437 00:16:26,000 --> 00:16:27,440 DETOXIFICATION. 438 00:16:27,440 --> 00:16:29,120 WE ALSO HAVE LOOKED AT IT WITH 439 00:16:29,120 --> 00:16:31,960 NIDA AS A POTENTIAL MEDICATION 440 00:16:31,960 --> 00:16:32,400 ASSISTED THERAPY. 441 00:16:32,400 --> 00:16:36,000 IT IS USED INFORMALLY TO REDUCE 442 00:16:36,000 --> 00:16:38,680 OPIOID USE AND KRATOM WITHDRAWAL 443 00:16:38,680 --> 00:16:39,840 IS MILD. 444 00:16:39,840 --> 00:16:42,440 REALLY ON THE SUBJECTIVE OPIATE 445 00:16:42,440 --> 00:16:43,360 WITHDRAWAL SCALE, IT'S IN THE 446 00:16:43,360 --> 00:16:46,280 UPPER END OF MILD BUT IT'S NOT 447 00:16:46,280 --> 00:16:50,240 IMMODERATE AND IT'S CERTAINLY 448 00:16:50,240 --> 00:16:53,000 NOT INSEVERE, POLYDRUG USERS 449 00:16:53,000 --> 00:16:55,680 REPORT KRATOM ALSO MAY REDUCE 450 00:16:55,680 --> 00:16:58,520 METH AM FEET FEATHER MEAN 451 00:16:58,520 --> 00:16:59,280 METHAMPHETAMINE USE. 452 00:16:59,280 --> 00:17:01,560 THE BIGGEST PROBLEM TO STARTING 453 00:17:01,560 --> 00:17:03,200 EXPLORING IS HAVING A 454 00:17:03,200 --> 00:17:04,800 STANDARDIZED PRODUCT TO REALLY 455 00:17:04,800 --> 00:17:08,720 GET INTO CLINICAL TRIALS AND 456 00:17:08,720 --> 00:17:09,840 EVALUATE ANY OF THESE 457 00:17:09,840 --> 00:17:10,600 THERAPEUTIC POTENTIALS. 458 00:17:10,600 --> 00:17:12,600 THERE ARE OTHER THERAPEUTIC 459 00:17:12,600 --> 00:17:13,400 POTENTIAL, I THINK, THAT CAN 460 00:17:13,400 --> 00:17:17,360 COME OUT OF THIS IN TERMS OF 461 00:17:17,360 --> 00:17:20,040 NOVEL ANALGESIA MEASURES AS WELL 462 00:17:20,040 --> 00:17:22,160 AS POTENTIAL ANTIDEPRESSANTS AND 463 00:17:22,160 --> 00:17:24,520 MOOD ELEVATING ELEMENTS. 464 00:17:24,520 --> 00:17:25,720 AND I'LL DISSECT A LITTLE BIT OF 465 00:17:25,720 --> 00:17:27,760 THAT AS WE GO. 466 00:17:27,760 --> 00:17:29,400 ONE OF THE GREAT THINGS ABOUT 467 00:17:29,400 --> 00:17:30,120 THE UNIVERSITY OF FLORIDA IS 468 00:17:30,120 --> 00:17:33,160 THAT WE HAVE OUR AGRICULTURAL 469 00:17:33,160 --> 00:17:37,600 SCHOOL AND OUR HEALTH SCIENCES 470 00:17:37,600 --> 00:17:38,560 ALL BASED IN THE GAINESVILLE 471 00:17:38,560 --> 00:17:40,280 CAMPUS, WHICH IS ONE OF ONLY 472 00:17:40,280 --> 00:17:41,520 THREE UNIVERSITIES IN THE 473 00:17:41,520 --> 00:17:45,040 COUNTRY THAT HAS THAT ABILITY, 474 00:17:45,040 --> 00:17:46,480 AND SO I'VE REALLY BEEN 475 00:17:46,480 --> 00:17:48,000 FORTUNATE TO FORM A GREAT 476 00:17:48,000 --> 00:17:50,520 COLLABORATIVE RELATIONSHIP WITH 477 00:17:50,520 --> 00:17:51,880 BRIAN PIERSON HERE, WHO IS 478 00:17:51,880 --> 00:17:55,200 LOCATED IN OUR CAMPUS JUST 479 00:17:55,200 --> 00:17:56,400 OUTSIDE OF ORLANDO, AND THESE 480 00:17:56,400 --> 00:18:00,840 ARE KRATOM TREES THAT WE'RE 481 00:18:00,840 --> 00:18:01,760 GROWING IN THAT CENTER. 482 00:18:01,760 --> 00:18:04,520 WE HAVE ABOUT 100 TREES IN 483 00:18:04,520 --> 00:18:07,960 GROUND, AND WE HAVE HUNDREDS, 484 00:18:07,960 --> 00:18:10,160 CLOSE TO A THOUSAND TREES IN 485 00:18:10,160 --> 00:18:11,640 GREENHOUSE, WHICH IF YOU CAN SEE 486 00:18:11,640 --> 00:18:19,360 MY PICTURE WHERE I'M SPEAKING 487 00:18:19,360 --> 00:18:21,680 AT, IT'S A GREENHOUSE FULL OF 488 00:18:21,680 --> 00:18:21,880 TREES. 489 00:18:21,880 --> 00:18:22,560 INTERESTINGLY ENOUGH, WE WILL TO 490 00:18:22,560 --> 00:18:24,120 WAIT UNTIL WE HAD ENOUGH BIOMASS 491 00:18:24,120 --> 00:18:25,560 TO REALLY ANALYZE THESE TREES 492 00:18:25,560 --> 00:18:26,960 AND WHAT WE'VE LEARNED IS WE 493 00:18:26,960 --> 00:18:29,120 HAVE THREE EXISTING CHEMO TYPES. 494 00:18:29,120 --> 00:18:31,160 SO NOT DIFFERENT, AGAIN, FROM 495 00:18:31,160 --> 00:18:34,960 CANNABIS, WHERE WE HAVE A HIGH 496 00:18:34,960 --> 00:18:35,600 MITRAGYNINE-PRODUCING CHEMOTYPE, 497 00:18:35,600 --> 00:18:38,160 AND WE HAVE A CHEMOTYPE THAT 498 00:18:38,160 --> 00:18:38,760 PRODUCES ALMOST NO MITRAGYNINE 499 00:18:38,760 --> 00:18:39,960 AND THEN WE HAVE SOMETHING THAT 500 00:18:39,960 --> 00:18:42,320 SEEMS TO BE IN BETWEEN. 501 00:18:42,320 --> 00:18:47,200 WE'RE WORKING TO LOOK AT THE 502 00:18:47,200 --> 00:18:47,960 BIOSYNTHETIC PATHWAYS WITHIN 503 00:18:47,960 --> 00:18:48,480 THIS PLANT. 504 00:18:48,480 --> 00:18:50,800 WE'RE ALSO WORKING WITH PLANT 505 00:18:50,800 --> 00:18:51,400 GENETICISTS HERE AT THE 506 00:18:51,400 --> 00:18:52,240 UNIVERSITY OF FLORIDA TO REALLY 507 00:18:52,240 --> 00:18:55,200 START TO UNDERSTAND WHAT THE 508 00:18:55,200 --> 00:18:57,480 DIFFERENCES ARE IN DOING DEEP 509 00:18:57,480 --> 00:19:01,040 DIVE DNA BARCODING TO REALLY SEE 510 00:19:01,040 --> 00:19:02,480 HOW CLOSELY RELATED THESE 511 00:19:02,480 --> 00:19:03,520 DIFFERENT CHEMO TYPES ARE. 512 00:19:03,520 --> 00:19:05,480 BUT ANYWAY, THAT BEING SAID, 513 00:19:05,480 --> 00:19:08,200 IT'S BECAUSE OF THE INTEREST IN 514 00:19:08,200 --> 00:19:09,920 TRYING TO GET A HOME GROWN 515 00:19:09,920 --> 00:19:11,320 SPECIES SO THAT WE MIGHT BE ABLE 516 00:19:11,320 --> 00:19:12,760 TO DEVELOP A PRODUCT THAT'S MORE 517 00:19:12,760 --> 00:19:16,560 SIMILAR TO THE TRADITIONAL USE 518 00:19:16,560 --> 00:19:19,840 FOR STUDY IN THE UNITED STATES 519 00:19:19,840 --> 00:19:21,680 THAN HAVING TO RELY ON THESE 520 00:19:21,680 --> 00:19:23,480 DRIED LEAF MATERIALS, WHICH BY 521 00:19:23,480 --> 00:19:26,240 THE WAY UNDERGO POST HARVEST 522 00:19:26,240 --> 00:19:29,800 OXIDATION AND SO YOU CAN IMAGINE 523 00:19:29,800 --> 00:19:32,000 JUST THINKING ABOUT THE DRIED 524 00:19:32,000 --> 00:19:33,640 LEAF VERSUS A FRESH LEAF, YOU'VE 525 00:19:33,640 --> 00:19:34,600 GOT OXIDATIVE CHEMISTRIES THAT 526 00:19:34,600 --> 00:19:36,040 HAVE TAKEN PLACE AND MANY TIMES 527 00:19:36,040 --> 00:19:39,200 HAVE CHANGED THE COMPOSITION OF 528 00:19:39,200 --> 00:19:41,360 THE ALKALOIDAL CONTENT, AND 529 00:19:41,360 --> 00:19:42,720 WE'LL TALK A LITTLE BIT ABOUT 530 00:19:42,720 --> 00:19:44,560 THAT AS WELL. 531 00:19:44,560 --> 00:19:48,360 SO WE'VE ISOLATED MORE THAN THIS 532 00:19:48,360 --> 00:19:49,720 NOW, BUT WE'VE DEFINITELY GOTTEN 533 00:19:49,720 --> 00:19:53,000 ALL OF THE MAJOR ALKALOIDS OUT 534 00:19:53,000 --> 00:19:54,480 OF THE PLANT, AND WE'VE GOTTEN 535 00:19:54,480 --> 00:19:56,440 MANY OF THE MINOR ALKALOIDS OUT 536 00:19:56,440 --> 00:19:58,920 AS WELL, AND WE'VE LEARNED A 537 00:19:58,920 --> 00:20:01,760 TREMENDOUS AMOUNT ABOUT THESE. 538 00:20:01,760 --> 00:20:03,480 WE'VE BEEN ABLE TO HAVE THE 539 00:20:03,480 --> 00:20:05,000 LUXURY OF SCREENING EACH OF 540 00:20:05,000 --> 00:20:10,160 THESE COMPOUNDS THROUGH A DRUG 541 00:20:10,160 --> 00:20:11,680 TARGET PANEL AND WE'VE LEARNED A 542 00:20:11,680 --> 00:20:11,840 LOT. 543 00:20:11,840 --> 00:20:12,840 AND I'LL SHARE A COUPLE OF THOSE 544 00:20:12,840 --> 00:20:15,520 WITH YOU, BUT NOT ALL OF THEM. 545 00:20:15,520 --> 00:20:17,040 AS WE GO THROUGH THIS. 546 00:20:17,040 --> 00:20:19,040 I'VE GROUPED THESE COMPOUNDS 547 00:20:19,040 --> 00:20:24,040 MORE OR LESS, THESE 12 OVER 548 00:20:24,040 --> 00:20:25,280 HERE, THAT ARE NATURALLY 549 00:20:25,280 --> 00:20:28,680 OCCURRING IN THE PLANT, AND THEN 550 00:20:28,680 --> 00:20:29,960 THE THREE ON THE RIGHT SIDE OF 551 00:20:29,960 --> 00:20:32,280 THE SCREEN ARE ONES WE'VE 552 00:20:32,280 --> 00:20:33,720 SYNTHESIZED TO HAVE IN LARGE 553 00:20:33,720 --> 00:20:37,920 ENOUGH QUANTITY. 554 00:20:37,920 --> 00:20:38,560 7 HYDROXYMITRAGYNINE, THE ONE AT 555 00:20:38,560 --> 00:20:39,440 THE TOP RIGHT OF THE SCREEN, IS 556 00:20:39,440 --> 00:20:40,640 THE ONE THAT'S ATTRACTED THE 557 00:20:40,640 --> 00:20:43,520 SECOND MOST AMOUNT OF ATTENTION 558 00:20:43,520 --> 00:20:44,160 BESIDES MITRAGYNINE. 559 00:20:44,160 --> 00:20:47,760 WE DO KNOW THAT IT IS A 560 00:20:47,760 --> 00:20:48,080 METABOLITE. 561 00:20:48,080 --> 00:20:50,120 IT IS A METABOLITE THAT CAN BE 562 00:20:50,120 --> 00:20:51,480 FORMED IN THE INTESTINE AND IN 563 00:20:51,480 --> 00:20:51,960 THE LIVER. 564 00:20:51,960 --> 00:20:53,600 I'LL SHOW YOU A LITTLE DATA ON 565 00:20:53,600 --> 00:20:55,400 THAT. 566 00:20:55,400 --> 00:20:58,600 AND WE ALSO KNOW THAT IT CAN BE 567 00:20:58,600 --> 00:20:59,760 FORMED UPON DRYING OF THE 568 00:20:59,760 --> 00:21:00,240 LEAVES. 569 00:21:00,240 --> 00:21:02,400 SO WE DO NOT BELIEVE THAT IT 570 00:21:02,400 --> 00:21:05,360 ACTUALLY EXISTS IN THE TREE IN 571 00:21:05,360 --> 00:21:08,680 FRESH LEAF SAMPLES FROM NOT ONLY 572 00:21:08,680 --> 00:21:11,840 OUR GROWINGS BUT THE HARVEST AND 573 00:21:11,840 --> 00:21:13,560 COLLABORATIONS WE'VE HAD IN PLA 574 00:21:13,560 --> 00:21:16,120 LAY 575 00:21:16,120 --> 00:21:19,080 MALAYSIA, WE'VE NOT DETECTED 576 00:21:19,080 --> 00:21:20,080 7 HYDROXYMITRAGYNINE IN FRESH 577 00:21:20,080 --> 00:21:20,560 LEAF MATERIAL. 578 00:21:20,560 --> 00:21:21,600 THAT BECOMES A LITTLE MORE THAN 579 00:21:21,600 --> 00:21:23,440 LATER ON. 580 00:21:23,440 --> 00:21:28,600 AND THEN MYTH PSEUDOINDOXYL WAS 581 00:21:28,600 --> 00:21:30,120 FIRS REPORTED AS A FUNGAL 582 00:21:30,120 --> 00:21:33,800 ISOLATE AND A VERY APPROPRIATE 583 00:21:33,800 --> 00:21:35,560 MU OPIOID AGONIST, AND WE WANTED 584 00:21:35,560 --> 00:21:36,320 TO SYNTHESIZE THAT. 585 00:21:36,320 --> 00:21:41,840 YOU CAN SIBT SIZE SYNTHESIZE THAT FROM TH E 586 00:21:41,840 --> 00:21:42,360 7 HYDROXYCOMPOUND WITH A 587 00:21:42,360 --> 00:21:43,400 CLINICAL ARRANGEMENT AND WE CAN 588 00:21:43,400 --> 00:21:45,640 NOW AFFORD THAT IN LARGE ENOUGH 589 00:21:45,640 --> 00:21:46,640 MATERIALS AND QUANTITIES TO 590 00:21:46,640 --> 00:21:48,160 STUDY AS WELL AS SOME OF OUR 591 00:21:48,160 --> 00:21:49,280 COLLABORATORS OR COMPETITORS 592 00:21:49,280 --> 00:21:50,760 HAVE BEEN DOING. 593 00:21:50,760 --> 00:21:52,560 BUT I MENTIONED EARLIER, YOU CAN 594 00:21:52,560 --> 00:21:54,480 SEE IN ALL OF THESE MOLECULES, 595 00:21:54,480 --> 00:22:02,840 WE HAVE THIS BETA METHOXY 596 00:22:02,840 --> 00:22:03,560 ACCUMULATE STRUCTURE. 597 00:22:03,560 --> 00:22:05,040 IT MAY BE TO BENEFIT THE PLANT, 598 00:22:05,040 --> 00:22:06,360 IT'S PROBABLY NOT TO BENEFIT 599 00:22:06,360 --> 00:22:06,640 HUMANS. 600 00:22:06,640 --> 00:22:08,440 SO WE'VE BEEN LOOKING AT SOME OF 601 00:22:08,440 --> 00:22:09,520 THAT AND UNDERSTANDING WHAT 602 00:22:09,520 --> 00:22:10,680 MIGHT BE GOING ON THERE. 603 00:22:10,680 --> 00:22:12,160 AND I WON'T GO INTO DETAILS ON 604 00:22:12,160 --> 00:22:16,040 THAT JUST BECAUSE OF TIME. 605 00:22:16,040 --> 00:22:18,240 IF YOU LOOK AT MITRAGYNINE, THE 606 00:22:18,240 --> 00:22:24,600 MAJOR COMPOUND THREUR THROUGH THE 607 00:22:24,600 --> 00:22:27,920 EUROFIN SCREEN, IT ONLY HITS -- 608 00:22:27,920 --> 00:22:33,000 INTERESTINGLY ENOUGH, -- ALONG 609 00:22:33,000 --> 00:22:37,520 WITH THE DREADED HERG CHANNEL 610 00:22:37,520 --> 00:22:39,400 AND THAT'S IT, 10 MICROMOLAR. 611 00:22:39,400 --> 00:22:40,680 IF WE TAKE THOSE HITS WHERE 612 00:22:40,680 --> 00:22:43,080 WE'VE DISPLACED 50% OF THE RADIO 613 00:22:43,080 --> 00:22:44,360 LIGAND AND GO DOWN TO THE 614 00:22:44,360 --> 00:22:49,200 SECONDARY SCREEN THAT 100 615 00:22:49,200 --> 00:22:51,400 NANOMOLAR, THIS COMPOUND LOOKS 616 00:22:51,400 --> 00:22:53,360 VERY BENIGN, IT DOESN'T SEEM TO 617 00:22:53,360 --> 00:22:54,560 INTERACT WITH ANY TARGET. 618 00:22:54,560 --> 00:22:57,480 WE DID GO AND CALCULATE OUT FULL 619 00:22:57,480 --> 00:22:58,560 KI VALUES AT ALL OF THESE 620 00:22:58,560 --> 00:22:59,120 TARGETS. 621 00:22:59,120 --> 00:23:01,760 I'M ONLY GO TO SHOW YOU THE 622 00:23:01,760 --> 00:23:04,080 OPIOID AND ALPHA ADRENERGIC 623 00:23:04,080 --> 00:23:04,560 HERE. 624 00:23:04,560 --> 00:23:06,000 AND IT'S NOT SPECTACULAR. 625 00:23:06,000 --> 00:23:10,360 THE KI VALUE AT MU IS 136, KAPPA 626 00:23:10,360 --> 00:23:11,680 ONE WITH IT SEVEN, IT DOESN'T 627 00:23:11,680 --> 00:23:14,000 BIND TO DELTA, AND ITS 628 00:23:14,000 --> 00:23:15,880 MICROMOLAR AFFINITY AT 629 00:23:15,880 --> 00:23:16,520 ADRENERGIC RECEPTORS. 630 00:23:16,520 --> 00:23:18,520 IT DOES HAVE PARTIAL AGONIST 631 00:23:18,520 --> 00:23:20,000 EFFECT AT THE MU OPIOID AS WELL 632 00:23:20,000 --> 00:23:23,760 AS THE ALPHA-1 AND ALPHA 633 00:23:23,760 --> 00:23:24,400 2 ADRENERGIC RECEPTORS. 634 00:23:24,400 --> 00:23:26,160 WE DO HAVE SOME IN VIVO EVIDENCE 635 00:23:26,160 --> 00:23:29,960 TO SUGGEST THAT IT HAS ALPHA 636 00:23:29,960 --> 00:23:31,440 2 ACTIVITY, AGONIST ACTIVITY AS 637 00:23:31,440 --> 00:23:32,960 WELL, AND THAT'S THROUGH DRUG 638 00:23:32,960 --> 00:23:33,960 DISCRIMINATION, WHICH I DON'T 639 00:23:33,960 --> 00:23:35,920 HAVE TIME TO SHOW YOU TODAY 640 00:23:35,920 --> 00:23:36,680 EITHER. 641 00:23:36,680 --> 00:23:37,840 INTERESTINGLY ENOUGH, IF YOU 642 00:23:37,840 --> 00:23:42,720 LOOK AT POISON CONTROL DATA, 643 00:23:42,720 --> 00:23:43,680 KRATOM OVERDOSES RESEMBLE 644 00:23:43,680 --> 00:23:44,440 STIMULANTS, NOT OPIOIDS. 645 00:23:44,440 --> 00:23:46,280 SO THEY LOOK MUCH MORE LIKE A 646 00:23:46,280 --> 00:23:49,680 STIM LAND 647 00:23:49,680 --> 00:23:50,840 STIMULANT OVERDOSE, A COCAINE 648 00:23:50,840 --> 00:23:51,200 OVERDOSE. 649 00:23:51,200 --> 00:23:52,880 THERE IS NOT THE RESPIRATORY 650 00:23:52,880 --> 00:23:54,040 DEPRESSION YOU WOULD EXPECT AS A 651 00:23:54,040 --> 00:23:56,120 FREQUENT CALL-IN FOR POISON 652 00:23:56,120 --> 00:23:57,160 CONTROL CENTERS OR SOME OF THE 653 00:23:57,160 --> 00:23:58,760 OTHER ISSUES THAT YOU MIGHT SEE 654 00:23:58,760 --> 00:24:00,880 WITH OPIATE OVERDOSE. 655 00:24:00,880 --> 00:24:04,360 SO WE WANTED TO PROBE THAT A 656 00:24:04,360 --> 00:24:05,440 LITTLE FURTHER AND WHAT WE WERE 657 00:24:05,440 --> 00:24:07,560 ABLE TO DO IS LOOK AT HOT PLATE 658 00:24:07,560 --> 00:24:10,400 ASSESSMENT, SO FOR ANALGESIA, 659 00:24:10,400 --> 00:24:11,600 EVERYONE HAS FOCUSED ON 660 00:24:11,600 --> 00:24:13,520 MITRAGYNINE HAVING OPIOID 661 00:24:13,520 --> 00:24:15,200 ACTIVITY, OPIOID ACTIVITY. 662 00:24:15,200 --> 00:24:18,280 SO INDEED, IF WE TAKE WILD TYPE 663 00:24:18,280 --> 00:24:21,120 C57 BLACK 6 MICE AND GIVE THEM 664 00:24:21,120 --> 00:24:23,640 100 MG PER KILOGRAM, WE CAN GET 665 00:24:23,640 --> 00:24:25,720 100% ANALGESIC EFFICACY IN 10 666 00:24:25,720 --> 00:24:27,480 MINUTES BY SUBCUTANEOUS 667 00:24:27,480 --> 00:24:28,480 INJECTION OF MITRAGYNINE. 668 00:24:28,480 --> 00:24:31,520 THAT LAST FOR S FOR ABOUT AN HOUR 669 00:24:31,520 --> 00:24:33,160 UNTIL IT DISSIPATES OFF. 670 00:24:33,160 --> 00:24:37,840 WHAT WE WANTED WANTED TO SEE WAS WHAT 671 00:24:37,840 --> 00:24:39,440 ELSE WAS GOING ON, SO WE STUCK 672 00:24:39,440 --> 00:24:41,480 SOME COMPOUND IN MU OPIOID 673 00:24:41,480 --> 00:24:43,560 RECEPTOR KNOCKOUT MICE, AND 100 674 00:24:43,560 --> 00:24:45,240 MG PER KILOGRAM, WHICH IS GREEN, 675 00:24:45,240 --> 00:24:48,160 WE SEE NO EFFECT. 676 00:24:48,160 --> 00:24:49,440 AT 125 MG PER KILOGRAM, WE SEE 677 00:24:49,440 --> 00:24:51,400 MAYBE A BUMP OR A TREND UP AT 10 678 00:24:51,400 --> 00:24:54,520 MINUTES, BUT REALLY NOTHING. 679 00:24:54,520 --> 00:24:57,920 BUT WHEN WE JUMP TO 200 MG PER 680 00:24:57,920 --> 00:24:59,200 KILOGRAM, WE START TO SEE AN 681 00:24:59,200 --> 00:25:02,960 ALMOST 30 TO 40% SUSTAINED 682 00:25:02,960 --> 00:25:04,560 ANALGESIA THAT DROPS OFF AGAIN 683 00:25:04,560 --> 00:25:05,880 RIGHT AROUND AN HOUR AND WE 684 00:25:05,880 --> 00:25:06,680 WANTED TO PROBE WHAT THAT WAS 685 00:25:06,680 --> 00:25:07,000 DOING. 686 00:25:07,000 --> 00:25:08,640 SO WE TOOK THOSE SAME MICE AND 687 00:25:08,640 --> 00:25:14,880 WE TREATED THEM AHEAD OF TIME 688 00:25:14,880 --> 00:25:16,440 AND YOU CAN SEE WE ALMOST 689 00:25:16,440 --> 00:25:18,320 COMPLETELY ATTENUATE THAT 690 00:25:18,320 --> 00:25:19,160 ANALGESIC EFFECT. 691 00:25:19,160 --> 00:25:21,160 SO THERE APPEARS TO BE A MIXTURE 692 00:25:21,160 --> 00:25:26,080 OF OPIOID AND ADRENERGIC 693 00:25:26,080 --> 00:25:26,920 ACTIVITY, AND HOPEFULLY BY THE 694 00:25:26,920 --> 00:25:28,800 END OF THIS, WE'LL CONVINCE YOU 695 00:25:28,800 --> 00:25:30,680 THERE'S SOME SEROTONERGIC 696 00:25:30,680 --> 00:25:32,880 ACTIVITY WITHIN THE PLANT AS 697 00:25:32,880 --> 00:25:34,280 WELL AS ANALGESIC PROMISE. 698 00:25:34,280 --> 00:25:36,480 SO THIS IS JUST 699 00:25:36,480 --> 00:25:36,960 MITRAGYNINE-ISOLATED. 700 00:25:36,960 --> 00:25:39,000 I LIKE TO SAY THAT KRATOM IS A 701 00:25:39,000 --> 00:25:41,520 COMPLEX SYMPHONY ORCHESTRA OF 702 00:25:41,520 --> 00:25:42,840 ALKALOIDS AND WHAT WE GENERALLY 703 00:25:42,840 --> 00:25:45,640 TEND TO DO IN SCIENCE IS PLUCK 704 00:25:45,640 --> 00:25:46,440 EACH INSTRUMENT OUT AND LISTEN 705 00:25:46,440 --> 00:25:48,360 TO IT AT FULL BLAST AND FORGET 706 00:25:48,360 --> 00:25:51,560 ABOUT THE SYMPHONY THAT IT 707 00:25:51,560 --> 00:25:52,560 NATURALLY OCCURS IN. 708 00:25:52,560 --> 00:25:54,240 SO PLEASE TAKE ALL OF THIS DATA 709 00:25:54,240 --> 00:25:56,000 IN THAT SORT OF CONTEXT. 710 00:25:56,000 --> 00:25:57,760 WE'RE LOOKING AT THESE THINGS ON 711 00:25:57,760 --> 00:25:58,400 FULL BLAST. 712 00:25:58,400 --> 00:26:03,000 THESE ARE BIG DOSES, 713 00:26:03,000 --> 00:26:04,760 100 MILLIGRAMS PER KG TO ACHIEVE 714 00:26:04,760 --> 00:26:08,680 THAT IN ACTUAL HUMAN TAKING 715 00:26:08,680 --> 00:26:12,000 KRATOM JUST STRAIGHT, IT WOULD 716 00:26:12,000 --> 00:26:12,920 MAKE THEM VOMIT LONG BEFORE THEY 717 00:26:12,920 --> 00:26:16,760 WOULD GET TO THAT LEVEL OF 718 00:26:16,760 --> 00:26:17,560 EFFICACY. 719 00:26:17,560 --> 00:26:18,720 I DO ALWAYS LIKE TO POINT OUT 720 00:26:18,720 --> 00:26:21,400 THAT THE MOST COMPREHENSIVE TO 721 00:26:21,400 --> 00:26:24,040 DATE STUDY OF MITRAGYNINE ITSELF 722 00:26:24,040 --> 00:26:28,320 WAS DONE BY MACKO AND HIS 723 00:26:28,320 --> 00:26:29,920 COLLEAGUES AT SMITH KLINE AND 724 00:26:29,920 --> 00:26:31,280 FRENCH BACK IN 1972. 725 00:26:31,280 --> 00:26:32,400 THIS PUBLICATION CAME OUT, THEY 726 00:26:32,400 --> 00:26:34,680 WERE REALLY PURSUING THIS AS A 727 00:26:34,680 --> 00:26:36,200 NEW ANALGESIC TO PUT INTO THE 728 00:26:36,200 --> 00:26:39,280 MARKETPLACE TO COMPETE WITH 729 00:26:39,280 --> 00:26:41,680 CODEINE, BECAUSE THEY SAW THAT 730 00:26:41,680 --> 00:26:43,440 THERE WERE SOME SIMILARITIES 731 00:26:43,440 --> 00:26:46,360 PARTICULARLY IN THE 732 00:26:46,360 --> 00:26:50,520 ANTINOCICEPTIVE AND ANTITUSSIVE 733 00:26:50,520 --> 00:26:52,760 EFFECT TO CODEINE. 734 00:26:52,760 --> 00:26:56,080 SO IT HAD LESS EFFECTS ON 735 00:26:56,080 --> 00:26:59,240 GASTRIC MOTILITY AND PRESS 736 00:26:59,240 --> 00:27:08,360 RESPIRATORY DEPRESSION. 737 00:27:08,360 --> 00:27:09,760 NSAIDS TOOK OFF AND THEY DECIDED 738 00:27:09,760 --> 00:27:10,680 TO ABANDON THIS PROJECT. 739 00:27:10,680 --> 00:27:12,160 IF YOU'RE INTERESTED IN THE 740 00:27:12,160 --> 00:27:14,680 HISTORY OF THIS, I WOULD HIGHLY 741 00:27:14,680 --> 00:27:15,760 PREM 742 00:27:15,760 --> 00:27:17,520 RECOMMEND PICKING UP THIS PAPER. 743 00:27:17,520 --> 00:27:20,280 I DID MENTION 744 00:27:20,280 --> 00:27:21,000 7 HYDROXYMITRAGYNINE. 745 00:27:21,000 --> 00:27:22,960 I'VE BEEN WORKING IN OPIOID 746 00:27:22,960 --> 00:27:28,760 CHEMISTRY SINCE MY POSTDOC AT 747 00:27:28,760 --> 00:27:31,680 MINNESOTA FOR -- GOSH, IT'S BEEN 748 00:27:31,680 --> 00:27:32,920 ALMOST 25-PLUS YEARS NOW, AND I 749 00:27:32,920 --> 00:27:38,160 NEVER HAVE SEEN AN OPIOID SCREEN 750 00:27:38,160 --> 00:27:39,560 THROUGH EUROFINS PANEL THAT CAME 751 00:27:39,560 --> 00:27:41,640 BACK ONLY OPIOID AT 10 752 00:27:41,640 --> 00:27:41,960 MICROMOLAR. 753 00:27:41,960 --> 00:27:43,600 THIS COMPOUND AT 10 MICROMOLAR 754 00:27:43,600 --> 00:27:44,920 ONLY HITS OPIOID RECEPTORS. 755 00:27:44,920 --> 00:27:51,160 IT HITS ALL THREE MUDDLE TA MU DELTA AND 756 00:27:51,160 --> 00:27:52,880 KAPPA, AND WHEN WE GOT THE 757 00:27:52,880 --> 00:27:54,360 ACTUAL KI VALUE, YOU CAN SEE 758 00:27:54,360 --> 00:27:57,360 THAT JUST THE SIMPLE EDITION OF 759 00:27:57,360 --> 00:28:00,160 A HYDROXY GROUP IN THE 760 00:28:00,160 --> 00:28:01,760 7 POSITION COMPLETELY CHANGES 761 00:28:01,760 --> 00:28:02,600 THE THREE-DIMENSIONAL STRUCTURE 762 00:28:02,600 --> 00:28:09,120 OF THE MOLECULE. 763 00:28:09,120 --> 00:28:10,760 SO THIS IS WHY WE'VE BEEN SO 764 00:28:10,760 --> 00:28:13,160 CONCERNED ABOUT THIS MOLECULE. 765 00:28:13,160 --> 00:28:14,720 AS I SAID, WE DON'T SEE IT IN 766 00:28:14,720 --> 00:28:15,560 THE FRESH LEAF MATERIAL. 767 00:28:15,560 --> 00:28:18,480 WE DID SEE IT IN THE HIGH LEVELS 768 00:28:18,480 --> 00:28:19,960 FOR A NUMBER OF YEARS AND 769 00:28:19,960 --> 00:28:21,920 PRODUCTS THAT WE ANALYZED IN THE 770 00:28:21,920 --> 00:28:22,080 U.S. 771 00:28:22,080 --> 00:28:23,360 I'M HOPEFUL THAT THE RESEARCH 772 00:28:23,360 --> 00:28:25,040 THAT WE PUBLISHED AND MANY OF 773 00:28:25,040 --> 00:28:26,720 THE THINGS THAT WE'VE DONE HAVE 774 00:28:26,720 --> 00:28:29,720 REALLY GUIDED THE COMMUNITY INTO 775 00:28:29,720 --> 00:28:32,040 LOOKING FOR PRODUCTS THAT ARE 776 00:28:32,040 --> 00:28:35,160 ALMOST NON-DETECTABLE TO 777 00:28:35,160 --> 00:28:36,520 7 HYDROXY, AND WE'VE SEEN THAT 778 00:28:36,520 --> 00:28:39,360 TREND IN A LOT OF THE 779 00:28:39,360 --> 00:28:39,960 MARKETPLACE NOW. 780 00:28:39,960 --> 00:28:41,640 SO MANY PRODUCTS THAT WE 781 00:28:41,640 --> 00:28:43,720 ANALYZE, WE CAN'T DETECT 782 00:28:43,720 --> 00:28:44,560 7 HYDROXYMITRAGYNINE IN THEM ANY 783 00:28:44,560 --> 00:28:45,480 LONGER. 784 00:28:45,480 --> 00:28:46,560 HOWEVER, THERE'S STILL SOME 785 00:28:46,560 --> 00:28:50,960 PRODUCTS OUT THERE THAT HAVE 786 00:28:50,960 --> 00:28:51,920 HIGH LEVEL. 787 00:28:51,920 --> 00:28:53,000 AND THIS IS THE BUYER BEWARE 788 00:28:53,000 --> 00:28:54,320 SORT OF THE ENVIRONMENT THAT 789 00:28:54,320 --> 00:28:54,760 WE'RE IN. 790 00:28:54,760 --> 00:28:56,840 YOU JUST DON'T KNOW WHAT YOU'RE 791 00:28:56,840 --> 00:28:58,040 GETTING WHEN YOU BUY THESE 792 00:28:58,040 --> 00:28:59,120 PRODUCTS AND THERE'S NO 793 00:28:59,120 --> 00:29:00,000 REGULATION AROUND THEM, SO IT'S 794 00:29:00,000 --> 00:29:01,560 VERY HARD TO TELL. 795 00:29:01,560 --> 00:29:02,960 THERE'S NO STANDARDIZATION PUT 796 00:29:02,960 --> 00:29:03,960 INTO PLACE, AND THIS IS 797 00:29:03,960 --> 00:29:08,640 SOMETHING THAT WE REALLY AIM TO 798 00:29:08,640 --> 00:29:10,200 LEARN AND AIM TO INFORM THE 799 00:29:10,200 --> 00:29:11,880 PUBLIC OF WITH THEIR TAX DOLLARS 800 00:29:11,880 --> 00:29:13,680 THAT HAVE BEEN PAYING FOR A LOT 801 00:29:13,680 --> 00:29:16,440 OF THIS WORK. 802 00:29:16,440 --> 00:29:18,720 SO WE LOOK AT WHAT IS THE 803 00:29:18,720 --> 00:29:21,280 SUBSTITUTION OF MITRAGYNINE AND 804 00:29:21,280 --> 00:29:22,440 7 HYDROXYMITRAGYNINE FOR 805 00:29:22,440 --> 00:29:26,840 MORPHINE, AND SO WITH SCOTT 806 00:29:26,840 --> 00:29:28,960 HEMBY'S HELP, WE PUBLISHED A 807 00:29:28,960 --> 00:29:30,280 NICE PAPER IN 2019 WHERE WE 808 00:29:30,280 --> 00:29:31,640 LOOKED AT SELF-ADMINISTRATION OF 809 00:29:31,640 --> 00:29:33,600 MORPHINE AND WE GENERATE A 810 00:29:33,600 --> 00:29:40,920 TYPICAL INVERTED UNITED U-SHAPED CURVE, 811 00:29:40,920 --> 00:29:41,960 THE ANIMALS ARE EITHER MORE 812 00:29:41,960 --> 00:29:44,320 DRUNK OR MORE IMPAIRED AND DON'T 813 00:29:44,320 --> 00:29:45,440 TEND TO ADMINISTER MORE. 814 00:29:45,440 --> 00:29:47,960 WHAT WE DID WITH THESE ANIMALS 815 00:29:47,960 --> 00:29:51,160 ARE HABITUATE TODAY THAT IS THEN 816 00:29:51,160 --> 00:29:52,320 SUBSTITUTING MITRAGYNINE ACROSS 817 00:29:52,320 --> 00:29:53,360 VARIOUS CONCENTRATIONS AND WE 818 00:29:53,360 --> 00:29:54,360 DON'T REALLY SEE ANY DIFFERENCE 819 00:29:54,360 --> 00:29:58,160 FROM SALINE IN THOSE INFUSIONS, 820 00:29:58,160 --> 00:30:01,720 BUT WHEN WE GIVE 821 00:30:01,720 --> 00:30:03,000 7 HYDROXYMITRAGYNINE, IT READILY 822 00:30:03,000 --> 00:30:04,640 SUBSTITUTES AND MORE POTENTLY 823 00:30:04,640 --> 00:30:07,320 SUBSTITUTES FOR MORPHINE IN 824 00:30:07,320 --> 00:30:10,920 SELF-ADMINISTRATION ASSAYS, 825 00:30:10,920 --> 00:30:11,280 INDICATING THAT 826 00:30:11,280 --> 00:30:12,440 7 HYDROXYMITRAGYNINE IS 827 00:30:12,440 --> 00:30:14,600 POTENTIALLY AN ABUSABLE AND 828 00:30:14,600 --> 00:30:15,840 ADDICTIVE COMPOUND WHEREAS 829 00:30:15,840 --> 00:30:18,440 MITRAGYNINE MAY OR MAY NOT BE 830 00:30:18,440 --> 00:30:21,360 ABUSABLE AND ADDICTIVE, WE'VE 831 00:30:21,360 --> 00:30:24,360 PROBED THIS FURTHER, BUT 832 00:30:24,360 --> 00:30:26,320 JONATHAN KATZ AND HIS COLLEAGUES 833 00:30:26,320 --> 00:30:27,960 AT THE NATIONAL INSTITUTE ON 834 00:30:27,960 --> 00:30:29,040 DRUG ABUSE'S INTRAMURAL PROGRAM 835 00:30:29,040 --> 00:30:31,720 DEMONSTRATED THAT MITRAGYNINE 836 00:30:31,720 --> 00:30:33,400 ALONE COULD BLOCK 837 00:30:33,400 --> 00:30:40,880 SELF-ADMINISTRATION OF HEROIN IN 838 00:30:40,880 --> 00:30:42,440 RATS, AND IT DOESN'T SEEM TO BE 839 00:30:42,440 --> 00:30:44,880 ABLE TO BLOCK THE INFUSIONS OF 840 00:30:44,880 --> 00:30:45,240 METHAMPHETAMINE. 841 00:30:45,240 --> 00:30:48,760 SO IT WORKS FOR HEROIN BUT NOT 842 00:30:48,760 --> 00:30:49,440 METHAMPHETAMINE, WHICH IS A 843 00:30:49,440 --> 00:30:50,880 LITTLE BIT IN CONTRAST TO WHAT 844 00:30:50,880 --> 00:30:53,120 WE SAW WITH THE HUMAN REPORTS 845 00:30:53,120 --> 00:30:55,200 THAT ARE HUMANS CONSUMING 846 00:30:55,200 --> 00:30:57,080 KRATOM, AND AGAIN, KRATOM IS 847 00:30:57,080 --> 00:30:58,040 DIFFERENT THAN JUST MITRAGYNINE. 848 00:30:58,040 --> 00:31:02,000 WE'RE SEEING A REDUCTION IN 849 00:31:02,000 --> 00:31:09,120 METHAMPHETAMINE USE. 850 00:31:09,120 --> 00:31:13,160 SO IF WE LOOK AT MITRAGYNINE 851 00:31:13,160 --> 00:31:16,840 SUBCUTANEOUSLY DOSED, IT IS NOT 852 00:31:16,840 --> 00:31:19,360 NEARLY AS POTENT AS MORPHINE AS 853 00:31:19,360 --> 00:31:24,560 AN ANALGESIC IN THE WARM WATER 854 00:31:24,560 --> 00:31:25,840 TAIL-WITHDRAWAL TEST BUT 855 00:31:25,840 --> 00:31:26,840 7 HYDROXY IS DEFINITELY MORE 856 00:31:26,840 --> 00:31:29,760 POTENT THAN THIS, THAN MORPHINE. 857 00:31:29,760 --> 00:31:33,160 BUT WHAT WE FOUND TO BE VERY 858 00:31:33,160 --> 00:31:35,960 INTERESTING IS -- AND THIS WAS 859 00:31:35,960 --> 00:31:39,000 REPORTED IN THE MACKO PAPERBACK 860 00:31:39,000 --> 00:31:40,160 IN 1972, IS THAT IF MITRAGYNINE 861 00:31:40,160 --> 00:31:41,600 IS GIVEN ORALLY, IT'S MORE 862 00:31:41,600 --> 00:31:44,440 POTENT AND ACTUALLY EQUIPOTENT 863 00:31:44,440 --> 00:31:46,960 TO CODEINE OR MORPHINE IN SOME 864 00:31:46,960 --> 00:31:47,520 CASES. 865 00:31:47,520 --> 00:31:52,520 AND HERE WE COULD SEE ONE 866 00:31:52,520 --> 00:31:54,240 DELIVERED ORALLY, MITRAGYNINE IS 867 00:31:54,240 --> 00:31:55,560 SUBSTANTIALLY MORE POTENT AND IN 868 00:31:55,560 --> 00:31:57,640 FACT AT THE COUPLE HIGHER DOSES 869 00:31:57,640 --> 00:32:01,360 OVERLAPS RIGHT ON TO MORPHINE'S 870 00:32:01,360 --> 00:32:02,360 EFFICACY. 871 00:32:02,360 --> 00:32:03,360 IN CONTRAST TO THAT, WE LOOKED 872 00:32:03,360 --> 00:32:05,960 AT DELIVERING KRATOM, THE WHOLE 873 00:32:05,960 --> 00:32:07,200 PLANT MATERIAL, ORALLY. 874 00:32:07,200 --> 00:32:09,960 WE DO THIS AS -- WE MAKE A TEA, 875 00:32:09,960 --> 00:32:14,960 WE FREEZE DRY THAT TEA SO WE 876 00:32:14,960 --> 00:32:16,560 RECONSTITUTE THE TEA, WE BASE 877 00:32:16,560 --> 00:32:17,640 THAT ON MITRAGYNINE CONTENTS SO 878 00:32:17,640 --> 00:32:19,120 THAT THE MITRAGYNINE CONTENT IS 879 00:32:19,120 --> 00:32:21,080 EQUIVALENT TO WHAT WAS GIVEN 880 00:32:21,080 --> 00:32:25,160 INDIVIDUALLY AND THEN YOU CAN 881 00:32:25,160 --> 00:32:29,200 SEE HERE THE ANALGESIA IS NOT 882 00:32:29,200 --> 00:32:30,720 QUITE AS ROW BUST, BUT IT DOES 883 00:32:30,720 --> 00:32:32,360 GET THERE. 884 00:32:32,360 --> 00:32:35,680 THIS IS REALLY BECAUSE WE KNOW 885 00:32:35,680 --> 00:32:38,760 THAT MYTH IS METABOLIZED IN THE 886 00:32:38,760 --> 00:32:42,240 LIVER, BUT IT'S ALSO 887 00:32:42,240 --> 00:32:42,760 INTESTINALLY METABOLIZED. 888 00:32:42,760 --> 00:32:47,080 SO THIS KIND OF POINTS TO THE 889 00:32:47,080 --> 00:32:51,880 DISTRICT OF WHICH CYTOCHROME 890 00:32:51,880 --> 00:32:53,960 P50s ARE INVOLVED, WE KNOW IT 891 00:32:53,960 --> 00:32:56,560 HEAVILY INVOLVED IN THE 892 00:32:56,560 --> 00:32:57,360 METABOLISM OF MITRAGYNA SPECIOSA 893 00:32:57,360 --> 00:32:57,560 KORTH. 894 00:32:57,560 --> 00:32:59,640 WHAT YOU CAN SEE HERE IN RED IS 895 00:32:59,640 --> 00:33:00,560 DEPLETION OF THE PARENT 896 00:33:00,560 --> 00:33:01,760 COMPOUND, AT THE SAME TIME WE'RE 897 00:33:01,760 --> 00:33:03,240 MONITORING FOR THAT IN THE LCMS, 898 00:33:03,240 --> 00:33:04,960 WE'RE MONITORING FOR THE 899 00:33:04,960 --> 00:33:07,440 PRESENCE OF -- FORMATION OF 900 00:33:07,440 --> 00:33:08,320 7 HYDROXYMITRAGYNINE, SO WE 901 00:33:08,320 --> 00:33:11,240 DIDN'T PUT 7 HYDROXYS&P IN THESE 902 00:33:11,240 --> 00:33:12,200 PREPARATIONS BUT WE CAN 903 00:33:12,200 --> 00:33:16,200 DEFINITELY DETECT AN INCREASING 904 00:33:16,200 --> 00:33:18,320 AMOUNT OF THE LIVER MICRO SOME 905 00:33:18,320 --> 00:33:21,240 AND THE INTESTINAL MICRO SOME 906 00:33:21,240 --> 00:33:21,560 PREPARATIONS. 907 00:33:21,560 --> 00:33:23,360 SO WE WANTED TO LOOK AT 908 00:33:23,360 --> 00:33:24,320 PHARMACOKINETIC PARAMETERS 909 00:33:24,320 --> 00:33:27,760 REALLY OF MITRAGYNINE AND HOWMP 910 00:33:27,760 --> 00:33:29,480 7 HYDROXYMITRAGYNINE IS BEING 911 00:33:29,480 --> 00:33:31,760 PRODUCED AFTER A SINGLE DOSE 912 00:33:31,760 --> 00:33:37,360 OR -- EITHER ORALLY OR IV TO 913 00:33:37,360 --> 00:33:39,120 RATS, IN THIS CASE THEY WERE ALL 914 00:33:39,120 --> 00:33:40,880 FEMALE RATS. 915 00:33:40,880 --> 00:33:42,840 WE DON'T SEE MUCH OF A SEX 916 00:33:42,840 --> 00:33:45,440 DIFFERENCE IN THE 917 00:33:45,440 --> 00:33:46,080 PHARMACOKINETICS. 918 00:33:46,080 --> 00:33:47,640 WE DO SEE SOME SEX DIFFERENCE 919 00:33:47,640 --> 00:33:51,520 BETWEEN SPECIES, BUT I DON'T 920 00:33:51,520 --> 00:33:55,160 HAVE TIME TO GO INTO THAT TODAY 921 00:33:55,160 --> 00:33:55,360 EITHER. 922 00:33:55,360 --> 00:33:57,360 THE BOTTOM LINE IS, THE 923 00:33:57,360 --> 00:33:59,360 TAKE-HOME MESSAGE, ORALLY WE 924 00:33:59,360 --> 00:34:00,680 CONVERT ABOUT 9% OF THE 925 00:34:00,680 --> 00:34:05,160 MITRAGYNINE DOSE TO 7 HYDROXY, 926 00:34:05,160 --> 00:34:07,960 VERSUS IV, THERE'S ONLY ABOUT A 927 00:34:07,960 --> 00:34:14,520 3 1/2% CONVERSION TO 7 HYDROXY. 928 00:34:14,520 --> 00:34:16,720 WE ALSO FOUND THAT 929 00:34:16,720 --> 00:34:17,600 7 HYDROXYMITRAGYNINE IS TOTALLY 930 00:34:17,600 --> 00:34:19,200 UNSTABLE IN HUMAN PLASMA. 931 00:34:19,200 --> 00:34:20,720 SO WE WERE DOING PLASMA 932 00:34:20,720 --> 00:34:24,160 STABILITY STUDIES BECAUSE WE 933 00:34:24,160 --> 00:34:26,560 WANTED TO DO A LOT OF STUDIES 934 00:34:26,560 --> 00:34:27,680 WITH 7 HYDROXYMITRAGYNINE IN 935 00:34:27,680 --> 00:34:27,920 ANIMALS. 936 00:34:27,920 --> 00:34:30,640 WE WERE DOING CROSS-SPECIES 937 00:34:30,640 --> 00:34:32,720 PLASMA STABILITY STUDIES. 938 00:34:32,720 --> 00:34:37,200 AND THIS ACTUALLY -- WE FOUND 939 00:34:37,200 --> 00:34:39,200 THAT MITRAGYNINE IS CONVERTED IN 940 00:34:39,200 --> 00:34:42,840 THE LIVER TO 941 00:34:42,840 --> 00:34:46,680 7 HYDROXYMITRAGYNINE. 942 00:34:46,680 --> 00:34:50,680 BUT IN PLASMA, 943 00:34:50,680 --> 00:34:51,600 7 HYDROXYMITRAGYNINE ACTUALLY 944 00:34:51,600 --> 00:34:54,400 UNDERGOA THIS IS SEMI PINNACLE 945 00:34:54,400 --> 00:34:55,240 REARRANGEMENT. 946 00:34:55,240 --> 00:34:56,720 IT IS PROTEIN DRIVEN, WE DON'T 947 00:34:56,720 --> 00:34:58,000 KNOW WHAT PROTEIN DOES IT YET, 948 00:34:58,000 --> 00:35:02,960 BUT THIS PRODUCES MITRAGYNINE 949 00:35:02,960 --> 00:35:03,960 PSEUDOINDOXYL, WHICH HAS NEVER 950 00:35:03,960 --> 00:35:05,000 BEEN DETECTED FROM THE PLANT 951 00:35:05,000 --> 00:35:06,880 BEFORE, AND AGAIN, IT'S NOT FROM 952 00:35:06,880 --> 00:35:09,000 THE PLANT, THIS IS A METABOLITE 953 00:35:09,000 --> 00:35:10,240 THAT HUMANS ARE EVEN FORMING AND 954 00:35:10,240 --> 00:35:13,280 IT SEEMS TO BE A HUMAN-SPECIFIC 955 00:35:13,280 --> 00:35:14,000 METABOLITE, SO IF YOU LOOK AT 956 00:35:14,000 --> 00:35:15,360 THE INSERT OF THE GRAPH ON THE 957 00:35:15,360 --> 00:35:18,080 RIGHT, WE WERE ACTUALLY SEEING 958 00:35:18,080 --> 00:35:22,720 THIS METABOLITE PRESENT BY 959 00:35:22,720 --> 00:35:24,120 TREMENDOUS AMOUNTS VERSUS MOUSE, 960 00:35:24,120 --> 00:35:27,480 RAT, DOG OR MONKEY. 961 00:35:27,480 --> 00:35:28,600 TREMENDOUS AMOUNTS IN HUMANS. 962 00:35:28,600 --> 00:35:30,840 I ACTUALLY MADE THE LAB SCALE UP 963 00:35:30,840 --> 00:35:33,640 THIS REACTION SO WE COULD 964 00:35:33,640 --> 00:35:35,280 ISOLATE ENOUGH TO PERFORM NMR, 965 00:35:35,280 --> 00:35:38,480 AND THAT'S WHERE WE CAME, 966 00:35:38,480 --> 00:35:42,920 BECAUSE THE MASS WAS IDENTICAL 967 00:35:42,920 --> 00:35:44,160 TO 7 HYDROXYMITRAGYNINE BUT THE 968 00:35:44,160 --> 00:35:45,520 RETENTION TIMES CHANGED, SO WE 969 00:35:45,520 --> 00:35:47,200 KNEW THERE WAS SOMETHING THERE. 970 00:35:47,200 --> 00:35:50,960 ANYWAY, THEY ENDED UP PUBLISHING 971 00:35:50,960 --> 00:35:53,800 THIS AND GOT US A LITTLE COVER 972 00:35:53,800 --> 00:35:54,240 FEATURE. 973 00:35:54,240 --> 00:35:55,560 AND THIS HAS BEEN INTERESTING 974 00:35:55,560 --> 00:35:57,960 WORK WHICH LED US TO MORE 975 00:35:57,960 --> 00:35:58,640 QUESTIONS. 976 00:35:58,640 --> 00:36:02,480 SO WHAT'S GOING ON WHEN WE GIVE 977 00:36:02,480 --> 00:36:04,120 MITRAGYNINE ORALLY, AND HOW MUCH 978 00:36:04,120 --> 00:36:05,440 7 HYDROXY ARE REPRODUCING AND 979 00:36:05,440 --> 00:36:06,680 WHAT'S PRESENT IN THE PLASMA 980 00:36:06,680 --> 00:36:08,200 VERSUS THE BRAIN. 981 00:36:08,200 --> 00:36:10,480 AND SO WE TOOK THE ED50 FROM 982 00:36:10,480 --> 00:36:12,560 SOME OF OUR ANALGESIA STUDIES IN 983 00:36:12,560 --> 00:36:18,240 MICE, AND WE DOSED THOSE MICE 984 00:36:18,240 --> 00:36:20,040 AND WE COLLECTED PLASMA AND 985 00:36:20,040 --> 00:36:22,760 BRAIN AT VARIOUS TIME POINTS, 986 00:36:22,760 --> 00:36:26,160 AND WE DOSED THEM WITH 987 00:36:26,160 --> 00:36:27,000 MITRAGYNINE, NOT 7 HYDROXY, B 988 00:36:27,000 --> 00:36:28,520 BUT WHAT WE WANTED TO SEE WAS 989 00:36:28,520 --> 00:36:31,360 HOW MUCH 7 HYDROXY WAS PRESENT 990 00:36:31,360 --> 00:36:32,160 IN THOSE ANIMALS. 991 00:36:32,160 --> 00:36:33,800 YOU CAN SEE THE BRAIN TO PLASMA 992 00:36:33,800 --> 00:36:38,400 RATIO OF MITRAGYNINE ITSELF IS 993 00:36:38,400 --> 00:36:41,960 ABOUT 2.4 AND THE BRAIN TO 994 00:36:41,960 --> 00:36:46,560 PLASMA RATIO OF 7 HYDROXY IS 995 00:36:46,560 --> 00:36:47,000 ABOUT 1.65. 996 00:36:47,000 --> 00:36:48,960 SO THERE'S MORE 7 HYDROXY IN THE 997 00:36:48,960 --> 00:36:50,160 BRAIN THAN IN THE PLASMA, 998 00:36:50,160 --> 00:36:50,960 THERE'S MORE MITRAGYNINE IN THE 999 00:36:50,960 --> 00:36:54,240 BRAIN THAN IN THE PLASMA. 1000 00:36:54,240 --> 00:36:55,960 I THINK WHAT REALLY SURPRISED US 1001 00:36:55,960 --> 00:36:59,960 WAS THAT WE TOOK THIS AND THEN 1002 00:36:59,960 --> 00:37:05,640 DECIDED TO LOOK AT THE ED50 OF 7 HYDROXYMI TRAGYNINE ORALLY, AND 1003 00:37:05,640 --> 00:37:09,840 WE SAW THE REVERSE. 1004 00:37:09,840 --> 00:37:10,880 SO 7 HYDROXYMITRAGYNINE DOESN'T 1005 00:37:10,880 --> 00:37:13,000 SEEM TO CROSS THE BLOOD-BRAIN 1006 00:37:13,000 --> 00:37:14,720 BARRIER AS EFFICIENTLY. 1007 00:37:14,720 --> 00:37:16,360 THE BRAIN TO PLASMA RATIO IS 1008 00:37:16,360 --> 00:37:17,880 LESS THAN 1, SO THERE'S MORE IN 1009 00:37:17,880 --> 00:37:19,760 THE PLASMA THAN IN THE BRAIN, 1010 00:37:19,760 --> 00:37:21,160 AND WE KNEW THAT THE METABOLITE 1011 00:37:21,160 --> 00:37:25,560 COULD BE GENERATED, THIS 1012 00:37:25,560 --> 00:37:28,160 MITRAGYNINE PSEUDOINDOXYL, 1013 00:37:28,160 --> 00:37:29,560 ALBEIT IN LOW AMOUNTS, WE STILL 1014 00:37:29,560 --> 00:37:31,000 SAW IT IN THE MOUSE AND WE SAW 1015 00:37:31,000 --> 00:37:32,840 IT HAVE THE SAME ISSUE, MORE OF 1016 00:37:32,840 --> 00:37:34,040 IT'S IN THE PLASMA THAN IN THE 1017 00:37:34,040 --> 00:37:34,280 BRAIN. 1018 00:37:34,280 --> 00:37:37,880 IN FACT, IT'S EXTREMELY LOW 1019 00:37:37,880 --> 00:37:38,080 RATIO. 1020 00:37:38,080 --> 00:37:40,960 AND WHAT WE BELIEVE THAT'S GOING 1021 00:37:40,960 --> 00:37:42,520 ON THERE, WHEN WE START DOING A 1022 00:37:42,520 --> 00:37:44,880 LITTLE BIT OF PHARMACOKINETIC 1023 00:37:44,880 --> 00:37:46,840 MODELING, WE LOOKED AT 1024 00:37:46,840 --> 00:37:47,600 MITRAGYNINE'S CONCENTRATION 1025 00:37:47,600 --> 00:37:50,960 VERSUS ITS EFFECT SO WE COULD 1026 00:37:50,960 --> 00:37:54,120 CALCULATE THE LOG BRAIN CONS 16 1027 00:37:54,120 --> 00:37:56,160 TRAITED OVER THE EFFECT AND WE 1028 00:37:56,160 --> 00:37:58,080 COULD GENERATE A RANGE OF 1029 00:37:58,080 --> 00:37:58,680 PHARMACOLOGICAL RESPONSE, AND 1030 00:37:58,680 --> 00:38:00,240 THAT MAPPED REALLY NICELY ON TO 1031 00:38:00,240 --> 00:38:01,680 OUR ACTUAL OBSERVED VALUES. 1032 00:38:01,680 --> 00:38:03,280 BUT WHAT'S MORE IMPORTANT IS, 1033 00:38:03,280 --> 00:38:05,960 WHEN WE LOOKED AT THE EFFICACY 1034 00:38:05,960 --> 00:38:07,960 OF 7 HYDROXYMITRAGYNINE VERSUS 1035 00:38:07,960 --> 00:38:10,000 ITS EFFECT, AND YOU CAN SEE THAT 1036 00:38:10,000 --> 00:38:12,240 IN THE BLUE WITH THE RED, AND 1037 00:38:12,240 --> 00:38:14,680 THE RED ARE THE OBSERVED, WHAT 1038 00:38:14,680 --> 00:38:17,920 WAS REASSURING TO US IS THAT THE 1039 00:38:17,920 --> 00:38:19,160 MAXIMUM 7 HYDROXY CONCENTRATION 1040 00:38:19,160 --> 00:38:23,680 THAT CAN BE GENERATED AFTER 1041 00:38:23,680 --> 00:38:25,480 MITRAGYNINE ADMINISTRATION IS 1042 00:38:25,480 --> 00:38:29,120 FAR BELOW WHERE THE EFFICACY 1043 00:38:29,120 --> 00:38:29,680 COULD BE FOUND. 1044 00:38:29,680 --> 00:38:31,240 SO THIS WAS JUST PUBLISHED IN 1045 00:38:31,240 --> 00:38:31,520 FEBRUARY. 1046 00:38:31,520 --> 00:38:33,280 THIS WAS SOME OF THE HOTTEST NEW 1047 00:38:33,280 --> 00:38:33,720 DATA. 1048 00:38:33,720 --> 00:38:34,800 THIS IS REFUTING SOME WORK 1049 00:38:34,800 --> 00:38:38,600 THAT'S COME OUT SAYING THAT 1050 00:38:38,600 --> 00:38:39,400 7 HYDROXYMITRAGYNINE IS 1051 00:38:39,400 --> 00:38:41,320 RESPONSIBLE FOR KRATOM'S 1052 00:38:41,320 --> 00:38:43,160 ANALGESIC EFFECTS, OR 1053 00:38:43,160 --> 00:38:44,560 MITRAGYNINE'S ANALGESIC EFFECTS. 1054 00:38:44,560 --> 00:38:46,440 AND WE DON'T BELIEVE THAT TO BE 1055 00:38:46,440 --> 00:38:48,360 THE CASE, WE DON'T BELIEVE THE 1056 00:38:48,360 --> 00:38:51,800 AMOUNT THAT'S GENERATED THROUGH 1057 00:38:51,800 --> 00:38:54,400 METABOLISM IS PHARMACOLOGICALLY 1058 00:38:54,400 --> 00:38:54,840 RELEVANT. 1059 00:38:54,840 --> 00:38:56,840 THERE ARE SOME QUESTIONS AS TO 1060 00:38:56,840 --> 00:38:57,920 WHY MITRAGYNINE -- WHEN 1061 00:38:57,920 --> 00:38:59,160 MITRAGYNINE IS GIVEN BY ITSELF, 1062 00:38:59,160 --> 00:39:02,640 YOU SEE HIGHER BRAIN TO PLASMA 1063 00:39:02,640 --> 00:39:04,160 RATIOS THAN WHEN 7 HYDROXYIS 1064 00:39:04,160 --> 00:39:07,200 GIVEN BY ITSELF, BUT WE'VE BEEN 1065 00:39:07,200 --> 00:39:08,120 DEALING WITH THOSE AND I'LL BE 1066 00:39:08,120 --> 00:39:09,360 HAPPY TO ANSWER ANY QUESTIONS 1067 00:39:09,360 --> 00:39:11,200 AROUND THOSE. 1068 00:39:11,200 --> 00:39:13,360 JUST JUMPING BACK ON THE 1069 00:39:13,360 --> 00:39:14,080 CYTOCHROME P450s, I KNOW WE'RE 1070 00:39:14,080 --> 00:39:15,240 GETTING CLOSE TO TIME AND I WANT 1071 00:39:15,240 --> 00:39:27,360 TO JUMP AHEAD, 1072 00:39:27,360 --> 00:39:28,200 7 HYDROXYMITRAGYNINE IS A 1073 00:39:28,200 --> 00:39:28,920 RESULTANT FROM THAT. 1074 00:39:28,920 --> 00:39:31,560 WE HAVE SEEN A TOTAL OF 12 1075 00:39:31,560 --> 00:39:35,760 METABOLITES IN MICROSOME STUDIES 1076 00:39:35,760 --> 00:39:38,120 AND 31 METABOLITES IN 1077 00:39:38,120 --> 00:39:39,520 HEPATOCYTES, AND THOSE ARE HUMAN 1078 00:39:39,520 --> 00:39:41,560 LIVER MICRO SOMES AND 1079 00:39:41,560 --> 00:39:41,880 HEPATOCYTES. 1080 00:39:41,880 --> 00:39:45,080 WE ALSO WANTED TO LOOK AT CYP 1081 00:39:45,080 --> 00:39:45,360 INHIBITION. 1082 00:39:45,360 --> 00:39:46,720 I HAVEN'T TALKED ABOUT ANY OF 1083 00:39:46,720 --> 00:39:50,360 THESE OTHER ALKALOIDS YET, SO 1084 00:39:50,360 --> 00:39:51,680 I'M GOING TO GO BACK HERE. 1085 00:39:51,680 --> 00:39:52,960 WHAT WE SAW WAS REALLY THERE'S 1086 00:39:52,960 --> 00:39:55,760 NOT ANY SIGNIFICANT INHIBITION 1087 00:39:55,760 --> 00:39:58,760 OF CYTOCHROME P450s, BUT WE DO 1088 00:39:58,760 --> 00:40:02,440 SEE MODERATE INHIBITION OF 1089 00:40:02,440 --> 00:40:03,360 CYP2D6 WITH MITRAGYNINE, THE 1090 00:40:03,360 --> 00:40:04,400 MAJOR ALKALOID, AND THIS COULD 1091 00:40:04,400 --> 00:40:06,080 BE SWA RESPONSIBLE FOR WHY WE'VE 1092 00:40:06,080 --> 00:40:09,920 SEEN SOME ADVERSE EVENTS WITH 1093 00:40:09,920 --> 00:40:14,160 OTHER CMS DRUGS THAT ARE 1094 00:40:14,160 --> 00:40:16,360 METABOLIZED AND CLEARED THROUGH 1095 00:40:16,360 --> 00:40:17,000 CYP2D6. 1096 00:40:17,000 --> 00:40:18,920 WE HAVEN'T DONE ANY DETAILED 1097 00:40:18,920 --> 00:40:19,960 STUDIES ON THAT TO PROVE THAT 1098 00:40:19,960 --> 00:40:21,400 THERE ARE ANY ISSUES OR 1099 00:40:21,400 --> 00:40:23,240 RECOMMENDATIONS TO AVOWED THOSE 1100 00:40:23,240 --> 00:40:24,440 THINGS. 1101 00:40:24,440 --> 00:40:24,760 AVOID THOSE 1102 00:40:24,760 --> 00:40:25,200 THINGS. 1103 00:40:25,200 --> 00:40:27,160 FOR THE MOST PART, ANY ALKALOIDS 1104 00:40:27,160 --> 00:40:28,280 WITHIN KRATOM DON'T HAVE ISSUES 1105 00:40:28,280 --> 00:40:28,720 EITHER. 1106 00:40:28,720 --> 00:40:31,840 SO JUST A QUICK TAKE-HOME OF 1107 00:40:31,840 --> 00:40:32,800 MITRAGYNINE, IT'S AN ATYPICAL 1108 00:40:32,800 --> 00:40:34,160 OPIOID WITH NON-OPIOID 1109 00:40:34,160 --> 00:40:34,480 PHARMACOLOGY. 1110 00:40:34,480 --> 00:40:35,560 IT SHARES SOME OF THE EFFECTS 1111 00:40:35,560 --> 00:40:37,160 BUT NOT ALL OF THE EFFECTS WITH 1112 00:40:37,160 --> 00:40:38,640 MU AGONISTS, AND I HAVEN'T BEEN 1113 00:40:38,640 --> 00:40:40,560 ABLE TO SHOW YOU ALL THE DATA WE 1114 00:40:40,560 --> 00:40:40,920 HAVE. 1115 00:40:40,920 --> 00:40:43,640 IT'S VERY LOW POTENCY AND LOW 1116 00:40:43,640 --> 00:40:44,400 EFFICACY. 1117 00:40:44,400 --> 00:40:47,360 IT HAS THE LESS TOLERANCE THAN 1118 00:40:47,360 --> 00:40:54,840 MORPHINE AT EQUIANALGESIC DOSES. 1119 00:40:54,840 --> 00:41:00,200 IT HAS LESS DEPENDENCE THAN 1120 00:41:00,200 --> 00:41:01,960 MORPHINE, IT HAS DIFFERENT 1121 00:41:01,960 --> 00:41:03,160 DISKRIM NATIVE STIMULUS EFFECTS 1122 00:41:03,160 --> 00:41:05,240 FROM MORPHINE, LESS TOLERANCE, 1123 00:41:05,240 --> 00:41:07,200 ABUSE AND DEPENDENCE LIABILITY 1124 00:41:07,200 --> 00:41:09,400 THAN OTHER OPIOID ANALGESICS. 1125 00:41:09,400 --> 00:41:11,560 IT DOES NOT APPEAR TO HAVE ABUSE 1126 00:41:11,560 --> 00:41:14,320 OR ADDICTION POTENTIAL AND 1127 00:41:14,320 --> 00:41:15,520 REDUCES MORPHINE AND HEROIN 1128 00:41:15,520 --> 00:41:16,680 INTAKE IN RATS, AND THESE ARE, 1129 00:41:16,680 --> 00:41:18,920 OF COURSE, DESIRED 1130 00:41:18,920 --> 00:41:19,880 CHARACTERISTICS FOR 1131 00:41:19,880 --> 00:41:21,440 PHARMACOTHERAPIES FOR OPIATE 1132 00:41:21,440 --> 00:41:22,960 ADDICTION AND WITHDRAWAL. 1133 00:41:22,960 --> 00:41:23,800 THAT'S JUST MITRAGYNINE BY 1134 00:41:23,800 --> 00:41:25,480 ITSELF AS THAT LOUD TRUMPET THAT 1135 00:41:25,480 --> 00:41:27,480 IT WANTS TO BE. 1136 00:41:27,480 --> 00:41:29,440 WHAT ABOUT 7 HYDROXYMITRAGYNINE? 1137 00:41:29,440 --> 00:41:31,360 IT SHOULD BE CONSIDERED A KRATOM 1138 00:41:31,360 --> 00:41:32,800 CONSTITUENT WITH HIGH ABUSE 1139 00:41:32,800 --> 00:41:33,160 POTENTIAL. 1140 00:41:33,160 --> 00:41:34,760 IT MAY ALSO INCREASE THE INTAKE 1141 00:41:34,760 --> 00:41:35,440 OF OTHER OPIATES. 1142 00:41:35,440 --> 00:41:36,680 I DIDN'T TALK ABOUT THAT BUT IN 1143 00:41:36,680 --> 00:41:39,160 THE STUDY WE HAVE PUBLISHED IN 1144 00:41:39,160 --> 00:41:41,360 ADDICTION BIOLOGY WITH SCOTT 1145 00:41:41,360 --> 00:41:47,160 HEMBY, WE DID SEE INCREASED 1146 00:41:47,160 --> 00:41:48,920 INTAKE OF OPIATES AFTER 1147 00:41:48,920 --> 00:41:51,560 ADMINISTRATION OF 1148 00:41:51,560 --> 00:41:52,560 7 HYDROXYMITRAGYNINE. 1149 00:41:52,560 --> 00:41:58,120 IT'S A VERY SELECTIVE OPIOID 1150 00:41:58,120 --> 00:42:02,080 LIGAND, AND THE EXTENT THAT THAT MG 1151 00:42:02,080 --> 00:42:04,480 IS CONVERTED -- SO WHAT ABOUT 1152 00:42:04,480 --> 00:42:04,960 KRATOM, THOUGH? 1153 00:42:04,960 --> 00:42:05,960 WE'VE BEEN TALKING ABOUT JUST A 1154 00:42:05,960 --> 00:42:06,840 COUPLE OF THE ONES THAT WE'VE 1155 00:42:06,840 --> 00:42:08,520 BEEN EASILY ISOLATED AND WHERE 1156 00:42:08,520 --> 00:42:10,120 CAN WE GO WITH THIS, AND I 1157 00:42:10,120 --> 00:42:11,320 REALIZE I ONLY HAVE A COUPLE OF 1158 00:42:11,320 --> 00:42:12,320 MINUTES, SO I'M GOING TO JUMP 1159 00:42:12,320 --> 00:42:13,720 THROUGH SOME OF THIS VERY 1160 00:42:13,720 --> 00:42:17,480 QUICKLY JUST TO SHOW YOU THAT IT 1161 00:42:17,480 --> 00:42:20,040 SEEMS TO HAVE AN ANALGESIC 1162 00:42:20,040 --> 00:42:22,040 SEALING, SO WE'RE LOOKING AT 1163 00:42:22,040 --> 00:42:25,480 ONE, TWO AND FOUR GRAMS PER KG 1164 00:42:25,480 --> 00:42:27,360 DOSE TO THESE MICE ORALLY. 1165 00:42:27,360 --> 00:42:30,320 WE DON'T SEEM TO GET ABOVE 60% 1166 00:42:30,320 --> 00:42:32,160 EFFICACY IN THERE. 1167 00:42:32,160 --> 00:42:37,640 KRATOM TEA WILL HAVE A GOOD HOUR 1168 00:42:37,640 --> 00:42:38,920 TO 90 MINUTES OF EFFICACY 1169 00:42:38,920 --> 00:42:42,120 DEPENDING ON THE DOSE THAT YOU 1170 00:42:42,120 --> 00:42:44,080 GIVE, AND IF YOU GIVE VERY LOW 1171 00:42:44,080 --> 00:42:48,240 DOSE, WE SEE REALLY NO ANALGESIC 1172 00:42:48,240 --> 00:42:48,920 EFFICACY. 1173 00:42:48,920 --> 00:42:50,160 YOU CAN READ MORE DETAILS IN 1174 00:42:50,160 --> 00:42:51,560 DRUG AND ALCOHOL DEEPEN DENSE ON 1175 00:42:51,560 --> 00:42:55,120 THESE. 1176 00:42:55,120 --> 00:42:55,480 DEPENDENCE ON 1177 00:42:55,480 --> 00:42:56,720 THESE. 1178 00:42:56,720 --> 00:43:01,160 WE DO KNOW THE ANALGESIA IS 1179 00:43:01,160 --> 00:43:03,120 MEDIATED THROUGH -- LOOKING AT 1180 00:43:03,120 --> 00:43:05,080 ONLY ADRENERGIC ACTIVITY OF 1181 00:43:05,080 --> 00:43:06,760 MITRAGYNINE IN MU KNOCKOUT MICE, 1182 00:43:06,760 --> 00:43:10,160 BUT HERE YOU CAN SEE IN THE WILD 1183 00:43:10,160 --> 00:43:11,920 TYPE MOUSE, WE CAN GET ABOUT 1184 00:43:11,920 --> 00:43:15,160 THAT 60% ANALGESIA, AND MU 1185 00:43:15,160 --> 00:43:20,680 KNOCKOUTS AND KA TA KAPPA KNOCKOUTS, 1186 00:43:20,680 --> 00:43:21,520 WE DON'T COMPLETELY LOSE IT. 1187 00:43:21,520 --> 00:43:22,560 SOMETHING WEIRD IS GOING ON IN 1188 00:43:22,560 --> 00:43:23,680 THE DELTA KNOCKOUT MOUSE. 1189 00:43:23,680 --> 00:43:25,880 AND IF WE COMBINE THE MU 1190 00:43:25,880 --> 00:43:29,960 KNOCKOUT MOUSE WITH NOR -- WE 1191 00:43:29,960 --> 00:43:32,840 CAN PRETTY MUCH ELIMINATE THE 1192 00:43:32,840 --> 00:43:35,120 FULL ANALGESIC EFFICACY OF THAT 1193 00:43:35,120 --> 00:43:36,320 1-GRAM PER KG ORALLY. 1194 00:43:36,320 --> 00:43:40,920 WE DO KNOW IT LACKS A 1195 00:43:40,920 --> 00:43:46,160 CONDITIONED PLACE PREFERENCE, IT 1196 00:43:46,160 --> 00:43:48,240 DOES NOT APPEAR TO HAVE ANY 1197 00:43:48,240 --> 00:43:53,800 SEDATIVE MEASURES AS MEASURED IN 1198 00:43:53,800 --> 00:43:56,400 AN ASSAY, AND IT DOES NOT APPEAR 1199 00:43:56,400 --> 00:43:58,160 TO REDUCE RESPIRATIONS, WHICH IS 1200 00:43:58,160 --> 00:44:01,680 ONE OF THE THINGS THAT HAS BEEN 1201 00:44:01,680 --> 00:44:04,360 TAUGHTED SORT 1202 00:44:04,360 --> 00:44:07,240 TOUTED ANECDOTALLY THAT IT HAS 1203 00:44:07,240 --> 00:44:08,360 LESS RESPIRATORY DEPRESSION, 1204 00:44:08,360 --> 00:44:09,680 WE'VE SEEN THAT ACTUALLY IN THE 1205 00:44:09,680 --> 00:44:10,840 ANIMAL PLO DELLS. 1206 00:44:10,840 --> 00:44:16,120 WE'VE ALSO SCENERY DUCKS OF 1207 00:44:16,120 --> 00:44:17,320 NALOXONE WITHDRAWAL. 1208 00:44:17,320 --> 00:44:20,160 I'M NOT GOING TO GO INTO THIS 1209 00:44:20,160 --> 00:44:21,600 BUT THERE IS SOME DEFINITE 1210 00:44:21,600 --> 00:44:22,480 EFFICACY THAT WE'VE SEEN, BUT I 1211 00:44:22,480 --> 00:44:23,520 THINK THE MOST IMPORTANT THING 1212 00:44:23,520 --> 00:44:25,640 TO FINISH WITH IS WHAT'S GOING 1213 00:44:25,640 --> 00:44:26,760 ON PHARMACOKINETICALLY, PAND 1214 00:44:26,760 --> 00:44:29,560 WHAT WE SEE NOW IN THE ANIMAL 1215 00:44:29,560 --> 00:44:31,720 MODELS, WE'RE STARTING TO NOW 1216 00:44:31,720 --> 00:44:33,720 GET DATA IN HUMANS, SO IT'S 1217 00:44:33,720 --> 00:44:35,360 GETTING TO BE A REALLY NEXUS 1218 00:44:35,360 --> 00:44:37,840 POINT FOR US AND AN EXCITING 1219 00:44:37,840 --> 00:44:39,440 TIME TO SEE IF THE ANIMAL MODELS 1220 00:44:39,440 --> 00:44:40,640 ARE GOING TO BE REALLY 1221 00:44:40,640 --> 00:44:41,760 PREDICTIVE OF WHAT'S HAPPENING 1222 00:44:41,760 --> 00:44:43,240 IN THE HUMAN. 1223 00:44:43,240 --> 00:44:47,080 WE'VE GIVEN THIS KRATOM TEA, YOU 1224 00:44:47,080 --> 00:44:49,000 CAN SEE 7 HYDROXYMITRAGYNINE IS 1225 00:44:49,000 --> 00:44:51,560 BELOW LIMITS OF DETECTION, AND 1226 00:44:51,560 --> 00:44:54,120 WE DO SEE SOME OF THE OTHER 1227 00:44:54,120 --> 00:44:55,320 ALKALOIDS THAT ARE PRESENT. 1228 00:44:55,320 --> 00:44:57,400 WE DO SEE MITRAGYNINE AS THE 1229 00:44:57,400 --> 00:44:59,760 MAJOR ALKALOID AND AS THE MAJOR 1230 00:44:59,760 --> 00:45:01,240 EXPOSED ALKALOID WITHIN THE 1231 00:45:01,240 --> 00:45:02,720 PLASMA. 1232 00:45:02,720 --> 00:45:13,880 WE ALSO SEE SPECIOCILLATINE, AND 1233 00:45:13,880 --> 00:45:15,160 TWO OTHER ALONG THE BOTTOM WHERE 1234 00:45:15,160 --> 00:45:19,320 IT SAYS CONTENT OF INDIVIDUAL 1235 00:45:19,320 --> 00:45:21,600 ALKALOIDS. 1236 00:45:21,600 --> 00:45:24,040 TWO OF THE MORE MAJOR ALKALOIDS 1237 00:45:24,040 --> 00:45:25,320 IN THIS, WE DON'T SEE THEM IN 1238 00:45:25,320 --> 00:45:27,800 THE PLASMA, BUT THAT'S BECAUSE 1239 00:45:27,800 --> 00:45:29,360 THEY DISAPPEAR WITHIN THE FIRST 1240 00:45:29,360 --> 00:45:29,880 HOUR. 1241 00:45:29,880 --> 00:45:33,200 AND SO WE REALLY DON'T HAVE DATA 1242 00:45:33,200 --> 00:45:34,840 TO QUANTIFY THAT THEY'RE GONE, 1243 00:45:34,840 --> 00:45:36,480 THEY'RE CLEARED, BUT THEY HAVE 1244 00:45:36,480 --> 00:45:39,360 ACTIVE METABOLITES SO STAY 1245 00:45:39,360 --> 00:45:42,280 TUNED. 1246 00:45:42,280 --> 00:45:46,440 WHAT ABOUT THE SPESH YOE 1247 00:45:46,440 --> 00:45:46,720 CIALATINE. 1248 00:45:46,720 --> 00:45:49,600 THE ONLY DIFFERENCE IS THE THREE 1249 00:45:49,600 --> 00:45:51,920 HYDROGEN POSITION, SO INSTEAD OF 1250 00:45:51,920 --> 00:45:53,360 BEING ALPHA, WE'VE MOVED TO THE 1251 00:45:53,360 --> 00:45:54,040 BETA POSITION. 1252 00:45:54,040 --> 00:45:55,880 THIS CAUSES A COMPLETE CHANGE IN 1253 00:45:55,880 --> 00:45:59,240 THREE DIMENSION NAT ARCHITECTURE 1254 00:45:59,240 --> 00:46:01,120 AND VERY SIMILAR 1255 00:46:01,120 --> 00:46:02,320 THREE-DIMENSIONAL ARCHITECTURE 1256 00:46:02,320 --> 00:46:04,040 TO THAT 7 YOU HYDROXYMITRAGYNINE 1257 00:46:04,040 --> 00:46:05,160 MOLECULE I TALKED ABOUT EARLIER 1258 00:46:05,160 --> 00:46:11,880 AS BEING PROBLEMATIC. 1259 00:46:11,880 --> 00:46:13,200 FORTUNATELY IT ONLY HAS PARTIAL 1260 00:46:13,200 --> 00:46:14,960 AGONIST EFFECT AT THE MU OPIOID 1261 00:46:14,960 --> 00:46:17,360 RECEPTOR AND DOESN'T APPEAR TO 1262 00:46:17,360 --> 00:46:18,840 HAVE EFFECT ALTHOUGH IT BINDS TO 1263 00:46:18,840 --> 00:46:19,040 KAPPA. 1264 00:46:19,040 --> 00:46:20,760 SO THIS IS SOMETHING WE'RE ALSO 1265 00:46:20,760 --> 00:46:22,720 PROBING AND LOOKING FORWARD TO 1266 00:46:22,720 --> 00:46:23,280 UNDERSTANDING. 1267 00:46:23,280 --> 00:46:24,560 BUT LET ME COME BACK TO THE 1268 00:46:24,560 --> 00:46:26,880 OTHER TWO MAJOR ALKALOIDS IN THE 1269 00:46:26,880 --> 00:46:27,120 PLANT -- 1270 00:46:27,120 --> 00:46:29,480 >> CHRIS, WE HAVE ABOUT 1271 00:46:29,480 --> 00:46:31,000 2 MINUTES BEFORE WE GO INTO Q & 1272 00:46:31,000 --> 00:46:31,160 A. 1273 00:46:31,160 --> 00:46:32,880 >> I'LL BLOW RIGHT THROUGH THIS. 1274 00:46:32,880 --> 00:46:38,640 SO WE'VE GOT -- THIS MOLECULE, 1275 00:46:38,640 --> 00:46:42,080 PAYNANTHINE AND SPEESH YOE 1276 00:46:42,080 --> 00:46:44,040 GYNINE, THE ONLY DIFFERENCE IS 1277 00:46:44,040 --> 00:46:44,720 THE DOUBLE BOND. 1278 00:46:44,720 --> 00:46:46,680 THESE MOLECULES HAVE VERY HIGH 1279 00:46:46,680 --> 00:46:47,680 AFFINITY, IN FACT, SOME OF THE 1280 00:46:47,680 --> 00:46:48,960 HIGHEST AFFINITY FOR ANY TARGETS 1281 00:46:48,960 --> 00:46:51,840 WE'VE SEEN FROM THE NATURALLY 1282 00:46:51,840 --> 00:46:56,680 OCCURRING ALKALOIDS. 1283 00:46:56,680 --> 00:47:04,960 #-H T2 A AND B. 1284 00:47:04,960 --> 00:47:06,640 THESE MAY BE AN TACKNISTS WHICH 1285 00:47:06,640 --> 00:47:09,000 COULD BE BENEFICIAL. 1286 00:47:09,000 --> 00:47:11,640 35H IT 1A WE DO HAVING ANIST 1287 00:47:11,640 --> 00:47:12,080 ACTIVITY. 1288 00:47:12,080 --> 00:47:13,720 I'M NOT GOING TO SHOW YOU MUCH 1289 00:47:13,720 --> 00:47:14,920 IN VIVO DATA THERE BUT I DO WANT 1290 00:47:14,920 --> 00:47:19,440 TO SHOW YOU THAT WE LOOKED AT 1291 00:47:19,440 --> 00:47:20,840 ANALGESIC MEASURES OF THESE 1292 00:47:20,840 --> 00:47:22,280 COMPOUNDS THAT HAVE NO OPIOID 1293 00:47:22,280 --> 00:47:25,120 ACTIVITY AND WE SEE THAT THEY 1294 00:47:25,120 --> 00:47:27,320 CAN PRODUCE 100% MAXIMAL 1295 00:47:27,320 --> 00:47:29,360 POSSIBLE EFFECT IN ANALGESIA 1296 00:47:29,360 --> 00:47:30,760 MEASURES, MEDIATED COMPLETELY 1297 00:47:30,760 --> 00:47:35,560 THROUGH SEROTONIN 5HT1A 1298 00:47:35,560 --> 00:47:36,440 RECEPTORS AND THEY CAN BE 1299 00:47:36,440 --> 00:47:40,800 BLOCKED WITH THE SLEK TUN 1300 00:47:40,800 --> 00:47:41,160 100A635. 1301 00:47:41,160 --> 00:47:45,400 SO THIS IS AN EXCITING AVENUE 1302 00:47:45,400 --> 00:47:47,680 FOR NON-OPIOID ANALGESICS 1303 00:47:47,680 --> 00:47:48,560 POTENTIALLY. 1304 00:47:48,560 --> 00:47:54,320 I WON'T GO INTO THESE 1305 00:47:54,320 --> 00:47:56,600 CLINICAL -- -- NANOGRAMS PER 1306 00:47:56,600 --> 00:48:02,560 MILLILITER, REGULARLY USING THAI 1307 00:48:02,560 --> 00:48:03,800 GROUP OF KRATOM USERS. 1308 00:48:03,800 --> 00:48:05,680 WHAT WE SAW IN DEATH CASES WERE 1309 00:48:05,680 --> 00:48:12,760 LEVELS AT 1800-NANOGRAM PER ML, 1310 00:48:12,760 --> 00:48:14,440 ALMOST 200 TIMES HIGHER THAN 1311 00:48:14,440 --> 00:48:15,640 PEAK PLASMA CONCENTRATIONS SEEN 1312 00:48:15,640 --> 00:48:17,720 IN REGULAR KRATOM USERS IN 1313 00:48:17,720 --> 00:48:19,000 THAILAND. 1314 00:48:19,000 --> 00:48:20,520 AND SO FINALLY WRAPPING UP, 1315 00:48:20,520 --> 00:48:23,640 THERE'S A LONG HISTORY OF SAFE 1316 00:48:23,640 --> 00:48:25,160 USE IN THE TRADITIONAL MANNER 1317 00:48:25,160 --> 00:48:26,560 FROM SOUTHEAST ASIA BUT WE'VE 1318 00:48:26,560 --> 00:48:27,960 HAD A WIDE RANGE OF ADVERSE 1319 00:48:27,960 --> 00:48:28,880 EVENTS IN THE WESTERN WORLD. 1320 00:48:28,880 --> 00:48:30,560 THE ALKALOIDS ARE STRUCTURALLY 1321 00:48:30,560 --> 00:48:31,960 DIFFERENT FROM OPIATES AND, 1322 00:48:31,960 --> 00:48:34,640 THEREFORE, HAVE DIFFERENT 1323 00:48:34,640 --> 00:48:35,120 PHARMACOKINETIC AND 1324 00:48:35,120 --> 00:48:35,680 PHARMACODYNAMIC PROPERTIES. 1325 00:48:35,680 --> 00:48:36,640 PRODUCTS IN THE UNITED STATES 1326 00:48:36,640 --> 00:48:38,160 ARE DEFINITELY NOT THE SAME AS 1327 00:48:38,160 --> 00:48:40,800 THE TRADITIONALLY UTILIZED FRESH 1328 00:48:40,800 --> 00:48:42,120 LEAF PREPARATIONS, AND WE STILL 1329 00:48:42,120 --> 00:48:43,360 HAVE A LOT OF GAPS IN THE 1330 00:48:43,360 --> 00:48:45,040 SCIENCE AROUND THIS PLANT, AND 1331 00:48:45,040 --> 00:48:48,080 HOPEFULLY WE CAN CONTINUE TO 1332 00:48:48,080 --> 00:48:49,000 REALLY START SOLVING SOME OF 1333 00:48:49,000 --> 00:48:50,840 THOSE GAPS. 1334 00:48:50,840 --> 00:48:53,000 BUT WE FEEL THAT THIS IS A 1335 00:48:53,000 --> 00:48:55,320 POSSIBLE SOLUTION TO THE OPIOID 1336 00:48:55,320 --> 00:48:56,640 EPIDEMIC, AND IT COULD COME FROM 1337 00:48:56,640 --> 00:48:58,400 NATURE WHERE IT ORIGINATED FROM. 1338 00:48:58,400 --> 00:48:59,920 SO WITH THAT, I HAVE TO THANK 1339 00:48:59,920 --> 00:49:03,320 EVERYBODY THAT DID ALL THE WORK 1340 00:49:03,320 --> 00:49:06,200 >> ONE QUICK QUESTION ABOUT THE 1341 00:49:06,200 --> 00:49:09,120 MITRAGYNINE VERSUS THE TEA, THE 1342 00:49:09,120 --> 00:49:11,400 KRATOM EXTRACT. 1343 00:49:11,400 --> 00:49:12,640 I'M THINKING TO SORT OF TAKE A 1344 00:49:12,640 --> 00:49:13,560 PAGE FROM THE CANNABIS WORLD 1345 00:49:13,560 --> 00:49:15,120 ABOUT THE ENTOURAGE EFFECT, IT 1346 00:49:15,120 --> 00:49:16,160 DOESN'T LOOK LIKE YOU'RE GETTING 1347 00:49:16,160 --> 00:49:17,840 THAT, ALTHOUGH YOU'RE SHOWING 1348 00:49:17,840 --> 00:49:22,880 SOME CONSTITUENTS BUT OFF TARGET 1349 00:49:22,880 --> 00:49:23,440 ANALGESIC PROPERTIES AT THE 1350 00:49:23,440 --> 00:49:24,960 SAIRT NERGIC RECEPTOR. 1351 00:49:24,960 --> 00:49:25,960 SO WHAT DO YOU THINK IS GOING ON 1352 00:49:25,960 --> 00:49:26,640 THERE, AND WOULD THERE BE 1353 00:49:26,640 --> 00:49:28,840 COMBINATIONS OF KRATOM THAT 1354 00:49:28,840 --> 00:49:29,840 MIGHT HAVE THIS SORT OF 1355 00:49:29,840 --> 00:49:32,040 ENTOURAGE TYPE EFFECT FOR 1356 00:49:32,040 --> 00:49:32,920 ANALGESIA OR WHAT ARE YOUR 1357 00:49:32,920 --> 00:49:33,440 THOUGHTS ON THAT? 1358 00:49:33,440 --> 00:49:34,280 >> IT'S A GOOD QUESTION. 1359 00:49:34,280 --> 00:49:36,920 IN FACT, I'M A FULL BELIEVER IN 1360 00:49:36,920 --> 00:49:38,200 THE SYMPHONY ORCHESTRA ANALOGY, 1361 00:49:38,200 --> 00:49:40,880 SO I REALLY THINK THAT THE 1362 00:49:40,880 --> 00:49:45,280 ENTOURAGE EFFECT IS THERE. 1363 00:49:45,280 --> 00:49:46,360 AND WE'RE SEEING DIFFERENT 1364 00:49:46,360 --> 00:49:47,760 THINGS COME INTO PLAY AND I JUST 1365 00:49:47,760 --> 00:49:50,960 DIDN'T HAVE TIME TO GO INTO ALL 1366 00:49:50,960 --> 00:49:52,120 OF THE DIFFERENT ALKALOIDS AND 1367 00:49:52,120 --> 00:49:53,440 ALL THE PHARMACOLOGIES THAT KIND 1368 00:49:53,440 --> 00:49:56,080 OF GIVE YOU A LITTLE GLIMPSE OF 1369 00:49:56,080 --> 00:49:57,680 WHAT'S THERE. 1370 00:49:57,680 --> 00:50:00,400 BUT I THINK MITRAGYNINE BY 1371 00:50:00,400 --> 00:50:01,400 ITSELF IS A FASCINATING MOLECULE 1372 00:50:01,400 --> 00:50:03,560 AND IT MAY HAVE A LIMITED 1373 00:50:03,560 --> 00:50:07,200 THERAPEUTIC APPLICATION. 1374 00:50:07,200 --> 00:50:10,240 VERSUS KRATOM AS A WHOLE, MAY 1375 00:50:10,240 --> 00:50:13,400 HAVE A LOT MORE AVENUES TO 1376 00:50:13,400 --> 00:50:16,000 PURSUE IN TERMS OF MANY 1377 00:50:16,000 --> 00:50:16,440 APPLICATIONS. 1378 00:50:16,440 --> 00:50:18,240 THERE'S SO MUCH ANECDOTAL 1379 00:50:18,240 --> 00:50:21,200 EVIDENCE OUT THERE IN TREATMENT 1380 00:50:21,200 --> 00:50:24,800 OF CARDIOVASCULAR DISEASE, OF 1381 00:50:24,800 --> 00:50:28,200 DIABETES, YOU KNOW, OBVIOUSLY OF 1382 00:50:28,200 --> 00:50:30,200 PAIN, THERE'S JUST MANY AVENUES 1383 00:50:30,200 --> 00:50:32,480 WE HAVEN'T BEEN ABLE TO TREAD 1384 00:50:32,480 --> 00:50:33,720 INTO YET. 1385 00:50:33,720 --> 00:50:35,680 MOOD ENHANCEMENT IS ONE OF THE 1386 00:50:35,680 --> 00:50:38,600 THINGS THAT MAYBE SOME OF THE 1387 00:50:38,600 --> 00:50:39,680 SEROTONERGIC AND ADRENERGIC 1388 00:50:39,680 --> 00:50:42,080 EFFECTS ARE PLAYING INTO. 1389 00:50:42,080 --> 00:50:45,680 I'M EXCITED BECAUSE THOSE 1390 00:50:45,680 --> 00:50:47,280 COMPOUNDS APPEAR TO BE MUCH MORE 1391 00:50:47,280 --> 00:50:50,080 ENRICHED IN SOME OF THE 1392 00:50:50,080 --> 00:50:51,120 CHEMOTYPES THAT INDIVIDUALS THAT 1393 00:50:51,120 --> 00:50:52,520 ARE CONSUMING THOSE THAT DONATED 1394 00:50:52,520 --> 00:50:54,520 THOSE TO THE UNIVERSITY OF 1395 00:50:54,520 --> 00:50:56,640 FLORIDA REALLY SAID THAT THEY 1396 00:50:56,640 --> 00:51:00,600 HAD POSITIVE MENTAL EFFECTS FROM 1397 00:51:00,600 --> 00:51:01,720 THOSE TREES. 1398 00:51:01,720 --> 00:51:05,000 SO WE JUST HAVEN'T PURSUED THAT, 1399 00:51:05,000 --> 00:51:06,280 AND AS YOU MIGHT IMAGINE, WE'RE 1400 00:51:06,280 --> 00:51:10,920 IN THE PROCESS RIGHT NOW, OUR 1401 00:51:10,920 --> 00:51:12,000 R01 FUNDING IS REALLY TO START 1402 00:51:12,000 --> 00:51:13,560 INVESTIGATING WHAT I CALL LEAVE 1403 00:51:13,560 --> 00:51:14,320 ONE OUT PHARMACOLOGY. 1404 00:51:14,320 --> 00:51:16,400 NOW THAT WE KNOW WHAT'S PRESENT 1405 00:51:16,400 --> 00:51:18,800 FROM THE FULL KRATOM TEA 1406 00:51:18,800 --> 00:51:20,800 EXPOSURE INTO THE ANIMALS' 1407 00:51:20,800 --> 00:51:22,760 PLASMA AND BRAIN, WE CAN START 1408 00:51:22,760 --> 00:51:24,440 TAKING THOSE PURIFIED MOLECULES 1409 00:51:24,440 --> 00:51:27,800 IN THE SAME RATIOS AND THEN 1410 00:51:27,800 --> 00:51:29,080 START PLAYING AROUND WITH THAT 1411 00:51:29,080 --> 00:51:32,040 TO SEE IF THERE IS AN 1412 00:51:32,040 --> 00:51:32,520 ENTOURAGE-LIKE EFFECT. 1413 00:51:32,520 --> 00:51:33,800 OR IF WE'RE COMPLETELY MISSING 1414 00:51:33,800 --> 00:51:35,080 THE BOAT, RIGHT? 1415 00:51:35,080 --> 00:51:37,040 WE'RE FOCUSED ON ALKALOIDS. 1416 00:51:37,040 --> 00:51:38,160 WE'RE LOOKING LIKE THE GUY THAT 1417 00:51:38,160 --> 00:51:40,800 DROPPED HIS KEYS IN THE DARK, 1418 00:51:40,800 --> 00:51:41,800 WE'RE LOOKING UNDER THE LAMP 1419 00:51:41,800 --> 00:51:45,080 POST BECAUSE THE LIGHT IS THERE, 1420 00:51:45,080 --> 00:51:46,680 BUT THE KEYS MAY BE OFF IN A 1421 00:51:46,680 --> 00:51:48,440 DARK CORNER SOMEWHERE. 1422 00:51:48,440 --> 00:51:50,680 SO THERE'S TREMENDOUS AMOUNT OF 1423 00:51:50,680 --> 00:51:52,800 WORK TO BE DONE. 1424 00:51:52,800 --> 00:51:53,960 >> ABSOLUTELY. 1425 00:51:53,960 --> 00:51:55,800 I'LL HOLD MY SECOND QUESTION 1426 00:51:55,800 --> 00:51:57,120 BECAUSE I KNOW THERE'S A LOT OF 1427 00:51:57,120 --> 00:52:00,520 OTHERS THAT HAVE QUESTIONS. 1428 00:52:00,520 --> 00:52:01,520 THANK YOU, THAT WAS GREAT. 1429 00:52:01,520 --> 00:52:02,600 >> HELENE, DO YOU HAVE A 1430 00:52:02,600 --> 00:52:03,680 QUESTION OR DO YOU WANT PLE TO 1431 00:52:03,680 --> 00:52:05,560 MOVE TO AUDIENCE QUESTIONS? 1432 00:52:05,560 --> 00:52:07,000 >> WELL, SURE, I HAVE A 1433 00:52:07,000 --> 00:52:07,240 QUESTION. 1434 00:52:07,240 --> 00:52:09,200 I'M PARTICULARLY INTERESTED IN 1435 00:52:09,200 --> 00:52:12,880 ADRENERGIC EFFECTS, BECAUSE 1436 00:52:12,880 --> 00:52:15,200 TYPICALLY, RIGHT, THIS DRUG -- 1437 00:52:15,200 --> 00:52:17,000 THE PLANT, THE TEA, AM I CORRECT 1438 00:52:17,000 --> 00:52:19,240 THAT IT'S PRIMARILY USED AS A 1439 00:52:19,240 --> 00:52:19,800 STIMULANT? 1440 00:52:19,800 --> 00:52:22,000 LIKE FOR PEOPLE USE THEM LIKE 1441 00:52:22,000 --> 00:52:23,520 FOR, YOU KNOW, IN THE FIELDS 1442 00:52:23,520 --> 00:52:25,080 WHEN THEY WANT TO WORK LONGER 1443 00:52:25,080 --> 00:52:26,200 HOURS WITHOUT GETTING TIRED, A 1444 00:52:26,200 --> 00:52:31,840 LITTLE BIT LIKE CHEWING COCOA 1445 00:52:31,840 --> 00:52:32,080 LEAVES? 1446 00:52:32,080 --> 00:52:34,200 >> EXACTLY. 1447 00:52:34,200 --> 00:52:35,000 IT'S FASCINATING BECAUSE IT 1448 00:52:35,000 --> 00:52:37,000 SEEMS TO BE MORE STIM LANTD-LIKE 1449 00:52:37,000 --> 00:52:41,080 AT LOWER DOSES AND MORE OPIATE 1450 00:52:41,080 --> 00:52:42,280 LIKE OR EU FORTUNATE AT HIGHER 1451 00:52:42,280 --> 00:52:42,720 DOSES. 1452 00:52:42,720 --> 00:52:45,720 WE'VE NOT REALLY BEEN ABLE TO 1453 00:52:45,720 --> 00:52:47,040 TWEAK THAT OR CAPTURE THAT OR 1454 00:52:47,040 --> 00:52:55,440 UNDERSTAND WHAT IS CAUSING THAT. 1455 00:52:55,440 --> 00:52:57,120 SO IT REMAINS A MYSTERY AND IT'S 1456 00:52:57,120 --> 00:52:57,760 SOMETHING WE'RE CONCERNED ABOUT 1457 00:52:57,760 --> 00:52:58,000 AS WELL. 1458 00:52:58,000 --> 00:53:01,440 IN FACT, I THINK THE ADRENERGIC 1459 00:53:01,440 --> 00:53:04,000 COMPONENT MAY BE MORE IMPORTANT 1460 00:53:04,000 --> 00:53:07,720 FOR THE ENTIRE PLANT THAN THE 1461 00:53:07,720 --> 00:53:07,960 OPIOID. 1462 00:53:07,960 --> 00:53:09,960 AND IF YOU LOOK AT THE POISON 1463 00:53:09,960 --> 00:53:11,320 CONTROL CENTER CALL US, THAT 1464 00:53:11,320 --> 00:53:13,760 PLAYS ITSELF OUT IN THOSE CASES. 1465 00:53:13,760 --> 00:53:15,760 AND SO IT IS SOMETHING THAT WE 1466 00:53:15,760 --> 00:53:17,400 ARE VERY INTERESTED IN. 1467 00:53:17,400 --> 00:53:19,000 WE HAVE A LOT OF DATA THAT WE 1468 00:53:19,000 --> 00:53:21,200 HAVEN'T PUBLISHED YET, SO I 1469 00:53:21,200 --> 00:53:23,040 CAN'T GO INTO TOO MUCH MORE 1470 00:53:23,040 --> 00:53:25,560 DETAIL BUT MAYBE NEXT TIME. 1471 00:53:25,560 --> 00:53:28,520 >> BUT PRESUMABLY THESE 1472 00:53:28,520 --> 00:53:29,280 ADRENERGIC EFFECTS DON'T GO AWAY 1473 00:53:29,280 --> 00:53:32,880 AT THE HIGHER DOSES, EVEN 1474 00:53:32,880 --> 00:53:38,240 THOUGH, RIGHT, AND PART OF THAT 1475 00:53:38,240 --> 00:53:40,960 ADRENERGIC EFFECTS CAN BE 1476 00:53:40,960 --> 00:53:44,120 ANTINOCICEPTIVE, YOU KNOW, AT 1477 00:53:44,120 --> 00:53:45,160 THE SPINAL CORD LEVEL, I 1478 00:53:45,160 --> 00:53:45,760 BELIEVE. 1479 00:53:45,760 --> 00:53:46,160 >> CORRECT. 1480 00:53:46,160 --> 00:53:49,480 >> SO IT COULD BE THAT SOME OF 1481 00:53:49,480 --> 00:53:53,760 THE ANTINOCICEPTION IS COMING 1482 00:53:53,760 --> 00:53:54,560 FROM THAT. 1483 00:53:54,560 --> 00:53:56,040 ARE YOU THINKING ALONG THESE 1484 00:53:56,040 --> 00:53:56,960 LINES OR -- 1485 00:53:56,960 --> 00:53:59,400 >> WE THINK THAT IT'S MIXED 1486 00:53:59,400 --> 00:54:00,600 MODAL, RIGHT? 1487 00:54:00,600 --> 00:54:02,880 I THINK OPIOIDS ARE DEFINITELY 1488 00:54:02,880 --> 00:54:03,320 INVOLVED. 1489 00:54:03,320 --> 00:54:07,000 WE'VE SEEN THAT THROUGH RECEPTOR 1490 00:54:07,000 --> 00:54:07,880 BLOCKADE STUDIES, BUT WE'VE ALSO 1491 00:54:07,880 --> 00:54:11,720 BEEN ABLE TO TAKE KNOCKOUT 1492 00:54:11,720 --> 00:54:13,680 ANIMALS AND SEE ANALGESIA THAT 1493 00:54:13,680 --> 00:54:15,760 WE CAN BLOCK THROUGH ADRENERGIC 1494 00:54:15,760 --> 00:54:16,840 MECHANISMS, AND WE'VE ALSO SEEN, 1495 00:54:16,840 --> 00:54:18,880 AS I SHARED IN THE LAST SLIDE, 1496 00:54:18,880 --> 00:54:22,560 SOME SERITONERGIC ACTIVITY AS 1497 00:54:22,560 --> 00:54:24,360 WELL, ALL KNOWN TO BE TARGETS 1498 00:54:24,360 --> 00:54:27,280 FOR ANALGESIA IN THEIR OWN RITE. 1499 00:54:27,280 --> 00:54:31,600 SO YEAH, I THINK AS A MEDICINAL 1500 00:54:31,600 --> 00:54:33,960 CHEMIST, THIS IS LIKE SOMEBODY 1501 00:54:33,960 --> 00:54:35,160 OPENED UP THE CANDY STORE. 1502 00:54:35,160 --> 00:54:36,200 THERE'S SO MUCH INSPIRATION FOR 1503 00:54:36,200 --> 00:54:39,600 US TO MOVE FORWARD WITH. 1504 00:54:39,600 --> 00:54:41,920 >> THE FULL PICNIC. 1505 00:54:41,920 --> 00:54:42,680 THANK YOU. 1506 00:54:42,680 --> 00:54:45,520 >> THANK YOU. 1507 00:54:45,520 --> 00:54:47,040 >> SO WE HAVE A REAL RANGE OF 1508 00:54:47,040 --> 00:54:49,000 QUESTIONS AND COMMENTS, RANGING 1509 00:54:49,000 --> 00:54:50,320 FROM THANKING YOU FOR THE 1510 00:54:50,320 --> 00:54:52,600 WONDERFUL RESEARCH YOU'RE DOING 1511 00:54:52,600 --> 00:54:56,240 AND SO I THINK WE'LL START WITH 1512 00:54:56,240 --> 00:54:57,200 THIS QUESTION. 1513 00:54:57,200 --> 00:55:02,200 WHICH CAME IN WHICH IS, SO WHAT 1514 00:55:02,200 --> 00:55:03,400 IN YOUR OPINION IS CONTRIBUTING 1515 00:55:03,400 --> 00:55:05,800 TO THE ADVERSE EVENT REPORTS 1516 00:55:05,800 --> 00:55:09,200 AROUND KRATOM CONSIDERING DATA 1517 00:55:09,200 --> 00:55:13,320 THAT YOU'VE HAD OR SUGGESTIONS 1518 00:55:13,320 --> 00:55:16,120 THAT THERE'S A LIMITED ABUSE 1519 00:55:16,120 --> 00:55:17,080 POTENTIAL OR SAFETY CONCERNS. 1520 00:55:17,080 --> 00:55:18,080 SO THAT WAS ONE QUESTION THAT 1521 00:55:18,080 --> 00:55:18,600 CAME IN. 1522 00:55:18,600 --> 00:55:19,400 SO THOUGHTS THERE? 1523 00:55:19,400 --> 00:55:24,520 >> I THINK ANYTHING -- 1524 00:55:24,520 --> 00:55:26,240 EVERYTHING SHOULD BE TAKEN 1525 00:55:26,240 --> 00:55:29,360 WITHIN MODERATION, EVEN 1526 00:55:29,360 --> 00:55:30,320 MODERATION AS WINSTON CHURCHILL 1527 00:55:30,320 --> 00:55:30,520 SAID. 1528 00:55:30,520 --> 00:55:32,320 I THINK WHERE WE START TO SEE 1529 00:55:32,320 --> 00:55:35,280 THE ADVERSE EVENTS IS IN A 1530 00:55:35,280 --> 00:55:38,080 SUBSET OF USERS, AND I LIKE TO 1531 00:55:38,080 --> 00:55:40,440 THINK AND I HOPE TO THINK THAT'S 1532 00:55:40,440 --> 00:55:41,720 A VERY SMALL SUBSET OF 1533 00:55:41,720 --> 00:55:43,800 INDIVIDUALS THAT ARE USING THIS. 1534 00:55:43,800 --> 00:55:45,320 UNFORTUNATELY THEY'RE THE ONES 1535 00:55:45,320 --> 00:55:46,200 THAT WE HEAR ABOUT THE MOST 1536 00:55:46,200 --> 00:55:48,600 BECAUSE THEY'RE THE ONES THAT 1537 00:55:48,600 --> 00:55:53,600 END UP IN THE HOSPITAL OR 1538 00:55:53,600 --> 00:55:57,040 UNFORTUNATELY IN WORSE PLACES. 1539 00:55:57,040 --> 00:56:01,880 BUT DEFINITELY SEEMS TO BE THIS 1540 00:56:01,880 --> 00:56:03,800 ADRENERGIC ACTIVITY THAT'S 1541 00:56:03,800 --> 00:56:05,800 REALLY CONCERNING. 1542 00:56:05,800 --> 00:56:06,320 FOR US. 1543 00:56:06,320 --> 00:56:09,120 AND WHAT WE SEE IN TERMS OF 1544 00:56:09,120 --> 00:56:12,800 PEOPLE THAT HAVE INGESTED TOO 1545 00:56:12,800 --> 00:56:14,400 MUCH MATERIAL AND END UP EITHER 1546 00:56:14,400 --> 00:56:20,160 IN THE HOSPITAL OR HAVE PASSED 1547 00:56:20,160 --> 00:56:22,640 FROM OVERDOSE, WHETHER IT WAS IN 1548 00:56:22,640 --> 00:56:23,760 COMBINATION WITH MANY OTHER 1549 00:56:23,760 --> 00:56:26,800 SUBSTANCES OR NOT, THERE'S NOT 1550 00:56:26,800 --> 00:56:30,080 THE OPIOID-TYPE ISSUES 1551 00:56:30,080 --> 00:56:31,200 ASSOCIATED WITH IT, SO THERE'S 1552 00:56:31,200 --> 00:56:34,760 NO RESPIRATORY DEPRESSION THAT 1553 00:56:34,760 --> 00:56:35,840 HAS BEEN REPORTED OR VERY 1554 00:56:35,840 --> 00:56:37,880 LITTLE. 1555 00:56:37,880 --> 00:56:42,280 MOST OF THE REPORTS ARE REALLY 1556 00:56:42,280 --> 00:56:45,320 AGITATION SEIZURE ACTIVITY. 1557 00:56:45,320 --> 00:56:47,600 THAGE DATED DELIRIUM THAT YOU 1558 00:56:47,600 --> 00:56:50,120 SEE IN METHAMPHETAMINE USERS IN 1559 00:56:50,120 --> 00:56:51,440 THE EMERGENCY ROOM THAT HAVE 1560 00:56:51,440 --> 00:56:53,960 OVERDOSED, THESE ARE THE TYPES 1561 00:56:53,960 --> 00:56:57,800 OF REPORTS THAT IF YOU JUST MINE 1562 00:56:57,800 --> 00:57:02,880 THROUGH THE VAERS DATABASE 1563 00:57:02,880 --> 00:57:04,320 SYSTEM OR POISON CONTROL 1564 00:57:04,320 --> 00:57:05,080 CENTERS, YOU'LL SEE SOME OF 1565 00:57:05,080 --> 00:57:06,040 THESE BECOMING MORE FREQUENT. 1566 00:57:06,040 --> 00:57:10,400 SO I THINK OUR FOCUS HAS REALLY 1567 00:57:10,400 --> 00:57:12,040 BEEN ON OPIATE, WHICH I THINK IS 1568 00:57:12,040 --> 00:57:14,560 MOST OF THE RESEARCH FOCUS. 1569 00:57:14,560 --> 00:57:16,120 OUR FOCUS HAS SHIFTED MORE 1570 00:57:16,120 --> 00:57:17,600 RECENTLY TO REALLY TRYING TO 1571 00:57:17,600 --> 00:57:19,000 UNDERSTAND TRANSLATIONAL ASPECTS 1572 00:57:19,000 --> 00:57:21,920 OF OUR WORK AND HOW CAN WE 1573 00:57:21,920 --> 00:57:23,680 REALLY IMPACT THOSE THAT DO 1574 00:57:23,680 --> 00:57:26,360 INGEST TOO MUCH. 1575 00:57:26,360 --> 00:57:30,280 IS NALOXONE OR NALTREXONE THE 1576 00:57:30,280 --> 00:57:32,360 WAY TO REVERSE THIS OVERDOSE? 1577 00:57:32,360 --> 00:57:33,200 I CAN'T ANSWER THAT QUESTION 1578 00:57:33,200 --> 00:57:34,360 RIGHT NOW, BUT I DON'T THINK 1579 00:57:34,360 --> 00:57:35,520 IT'S THE APPROPRIATE MEASURE TO 1580 00:57:35,520 --> 00:57:36,640 TAKE. 1581 00:57:36,640 --> 00:57:37,800 >> OKAY. 1582 00:57:37,800 --> 00:57:42,240 WE'VE HAD A COUPLE OF COMMENTS 1583 00:57:42,240 --> 00:57:44,280 REGARDING THE FACT THAT IT SEEMS 1584 00:57:44,280 --> 00:57:47,560 LIKE KRATOM USE IN MALAYSIA, 1585 00:57:47,560 --> 00:57:49,080 SOUTHEAST ASIA, IS DISTINCTLY 1586 00:57:49,080 --> 00:57:53,000 DIFFERENT THAN U.S.-BASED USE, 1587 00:57:53,000 --> 00:57:59,120 AND SO IS IS THERE SOMETHING THERE 1588 00:57:59,120 --> 00:58:00,200 PLAYING INTO WHAT WE'RE SEEING? 1589 00:58:00,200 --> 00:58:01,800 SOME PEOPLE HAVE SAID HERE IN 1590 00:58:01,800 --> 00:58:04,320 THEIR COMMENTS THAT THEY'VE SEEN 1591 00:58:04,320 --> 00:58:05,240 THINGS WHERE KRATOM HAS BEEN 1592 00:58:05,240 --> 00:58:08,000 COMPARED TO MORPHINE, OR THAT 1593 00:58:08,000 --> 00:58:09,200 IT'S SEVERAL TIMES MORE POTENT 1594 00:58:09,200 --> 00:58:11,800 THAN MORPHINE. 1595 00:58:11,800 --> 00:58:13,880 SO IT SORT OF LIKE YOU'VE GOT 1596 00:58:13,880 --> 00:58:15,080 THIS STRANGE SET OF 1597 00:58:15,080 --> 00:58:16,400 CIRCUMSTANCES WHERE YOU HAVE 1598 00:58:16,400 --> 00:58:18,480 TRADITIONAL USE VERSUS HOW IT'S 1599 00:58:18,480 --> 00:58:20,560 USED HERE, AND THEN ALSO 1600 00:58:20,560 --> 00:58:22,240 COMMENTARY ABOUT HOW IT COMPARES 1601 00:58:22,240 --> 00:58:23,080 TO THINGS LIKE MORPHINE. 1602 00:58:23,080 --> 00:58:27,800 SO CAN YOU IMPACT UNPACK SOME OF THAT A 1603 00:58:27,800 --> 00:58:28,640 LITTLE BIT? 1604 00:58:28,640 --> 00:58:31,200 >> I'LL TRY TO DO IT IN AS SHORT 1605 00:58:31,200 --> 00:58:31,880 A TIME AS POSSIBLE. 1606 00:58:31,880 --> 00:58:33,720 >> WE DO HAVE A FEW EXTRA 1607 00:58:33,720 --> 00:58:34,600 MINUTES FOR QUESTIONS SO STICK 1608 00:58:34,600 --> 00:58:35,200 WITH US. 1609 00:58:35,200 --> 00:58:36,360 >> I'LL BE HERE ALL DAY IF YOU 1610 00:58:36,360 --> 00:58:37,120 WANT ME. 1611 00:58:37,120 --> 00:58:42,600 I WILL SAY THAT WE DON'T SEE 1612 00:58:42,600 --> 00:58:46,000 CONCENTRATED EXTRACT PRODUCTS, 1613 00:58:46,000 --> 00:58:47,600 THERE ARE TREMENDOUS AMOUNTS OF 1614 00:58:47,600 --> 00:58:48,960 EXTRACTS AND CONCENTRATED 1615 00:58:48,960 --> 00:58:50,200 EXTRACT PRODUCTS THAT ARE ON THE 1616 00:58:50,200 --> 00:58:53,000 MARKET IN THE U.S. 1617 00:58:53,000 --> 00:58:54,720 AND WE DON'T UNDERSTAND EVEN IN 1618 00:58:54,720 --> 00:58:56,720 ANIMALS WHAT THOSE CONCENTRATED 1619 00:58:56,720 --> 00:58:58,520 EXTRACTS DO. 1620 00:58:58,520 --> 00:59:00,640 SO WE'VE DONE SOME WORK, WE'VE 1621 00:59:00,640 --> 00:59:02,000 REALLY BEEN TRYING TO FIGURE OUT 1622 00:59:02,000 --> 00:59:03,560 WHAT'S THE REAL PLANT MATERIAL 1623 00:59:03,560 --> 00:59:05,000 DOING, NOT WHAT ARE SOME OF THE 1624 00:59:05,000 --> 00:59:07,720 OTHER OPTIONS IN THE 1625 00:59:07,720 --> 00:59:08,120 MARKETPLACE. 1626 00:59:08,120 --> 00:59:10,960 SO I THINK I WOULD SAY THAT AS I 1627 00:59:10,960 --> 00:59:12,920 ADDRESSED EARLIER, ONE, WE HAVE 1628 00:59:12,920 --> 00:59:18,600 DRIED LEAF MATERIAL THAT IS 1629 00:59:18,600 --> 00:59:20,400 SEVERAL WEEKS TO MONTHS PAST 1630 00:59:20,400 --> 00:59:21,800 HARVEST. 1631 00:59:21,800 --> 00:59:23,000 IT'S NOT GOING TO BE CHEMICALLY 1632 00:59:23,000 --> 00:59:25,880 THE SAME. 1633 00:59:25,880 --> 00:59:27,760 THERE'S JUST NO QUESTION ABOUT 1634 00:59:27,760 --> 00:59:28,640 THAT. 1635 00:59:28,640 --> 00:59:30,000 NOW WHETHER PHARMACOLOGICALLY 1636 00:59:30,000 --> 00:59:31,360 IT'S THE SAME OR DIFFERENT IS 1637 00:59:31,360 --> 00:59:34,080 STILL QUESTIONABLE. 1638 00:59:34,080 --> 00:59:35,800 HOWEVER, THE EXTRACTS, THE 1639 00:59:35,800 --> 00:59:36,680 CONCENTRATED EXTRACTS ARE 1640 00:59:36,680 --> 00:59:37,600 DEFINITELY SOMETHING WE DON'T 1641 00:59:37,600 --> 00:59:38,120 SEE. 1642 00:59:38,120 --> 00:59:43,400 AND MOST OF THE ISSUES THAT ARE 1643 00:59:43,400 --> 00:59:47,360 COMING FROM HARM IN THE U.S., I 1644 00:59:47,360 --> 00:59:48,560 BELIEVE ARE PEOPLE THAT ARE 1645 00:59:48,560 --> 00:59:49,600 REALLY TRYING TO PUSH THE LIMIT 1646 00:59:49,600 --> 00:59:52,240 TO SEE IF THEY CAN GET HIGH, SEE 1647 00:59:52,240 --> 00:59:54,560 IF THEY CAN GET THAT REPORTED 1648 00:59:54,560 --> 01:00:01,520 OPIATE EFFECT, AND I CAN'T -- 1649 01:00:01,520 --> 01:00:02,800 THAT'S SPECULATION ENOUGH. 1650 01:00:02,800 --> 01:00:05,680 BUT THAT'S KIND OF WHERE IT IS, 1651 01:00:05,680 --> 01:00:13,000 AND AS I REPORTED, WE'VE SEEN -- 1652 01:00:13,000 --> 01:00:14,760 WE'VE ANALYZED KRATOM LEAF 1653 01:00:14,760 --> 01:00:16,640 MATERIAL THAT HAS HAD 1654 01:00:16,640 --> 01:00:18,160 HYDROCODONE IN IT, THAT HAS HAD 1655 01:00:18,160 --> 01:00:19,120 MORPHINE IN IT. 1656 01:00:19,120 --> 01:00:20,160 IT'S QUITE FRIGHTENING WHEN YOU 1657 01:00:20,160 --> 01:00:21,880 THINK ABOUT IT. 1658 01:00:21,880 --> 01:00:23,600 THOSE ARE THE THINGS WE KNOW 1659 01:00:23,600 --> 01:00:23,800 ABOUT. 1660 01:00:23,800 --> 01:00:25,640 WHAT ABOUT FENTANYL-LACED 1661 01:00:25,640 --> 01:00:29,320 PRODUCT, WHAT ABOUT SYNTHETIC 1662 01:00:29,320 --> 01:00:31,720 LACED PRODUCTS? 1663 01:00:31,720 --> 01:00:33,800 AND SO JUST SO MANY THINGS. 1664 01:00:33,800 --> 01:00:39,840 WE DON'T SEE PEOPLE IN SOUTHEAST 1665 01:00:39,840 --> 01:00:41,160 ASIA EXPERIMENTING TOO MUCH, BUT 1666 01:00:41,160 --> 01:00:42,800 I HAVE TO TELL YOU EVER SINCE WE 1667 01:00:42,800 --> 01:00:44,000 STARTED THIS, A YOUNGER 1668 01:00:44,000 --> 01:00:45,520 GENERATION OF PEOPLE IN 1669 01:00:45,520 --> 01:00:46,640 SOUTHEAST ASIA HAVE STARTED TO 1670 01:00:46,640 --> 01:00:50,200 DEVELOP ISSUES WITH COMBINING 1671 01:00:50,200 --> 01:00:53,080 KRATOM TEAS WITH OTHER THINGS 1672 01:00:53,080 --> 01:00:55,800 LIKE ARAMIN5, WHICH IS A BEN 1673 01:00:55,800 --> 01:01:00,000 DOUGH SIGH AZ PEEN, ALCOHOL, 1674 01:01:00,000 --> 01:01:01,000 COUGH SYRUPS. 1675 01:01:01,000 --> 01:01:02,600 THIS HAS BECOME A PROBLEM 1676 01:01:02,600 --> 01:01:03,520 BECAUSE OF WHAT'S HAPPENING IN 1677 01:01:03,520 --> 01:01:03,840 THE WEST. 1678 01:01:03,840 --> 01:01:05,080 AND THEN LEARNING ABOUT IT OVER 1679 01:01:05,080 --> 01:01:05,600 THERE. 1680 01:01:05,600 --> 01:01:06,800 AND SO I THINK WE'RE STARTING TO 1681 01:01:06,800 --> 01:01:07,880 SEE THAT GO UP. 1682 01:01:07,880 --> 01:01:09,800 THE LAST THING I WOULD SAY ON 1683 01:01:09,800 --> 01:01:13,720 THIS IS, I THINK THE USER BASE 1684 01:01:13,720 --> 01:01:16,440 HAS GONE UP SO TREMENDOUSLY IN 1685 01:01:16,440 --> 01:01:17,400 THE UNITED STATES OVER THE LAST 1686 01:01:17,400 --> 01:01:19,760 FEW YEARS, PARTLY PROBABLY 1687 01:01:19,760 --> 01:01:25,840 BECAUSE OF COVID, BUT WE HAVEN'T 1688 01:01:25,840 --> 01:01:33,520 SEEN THE SAME RISE IN HARM. 1689 01:01:33,520 --> 01:01:34,400 AND SO THERE WAS TREMENDOUS 1690 01:01:34,400 --> 01:01:35,960 AMOUNTS OF POISON CONTROL CENTER 1691 01:01:35,960 --> 01:01:41,360 REPORTS THAT WENT FROM OVER 10 1692 01:01:41,360 --> 01:01:47,800 YEARS OR WHATEVER IT WAS WENT UP 1693 01:01:47,800 --> 01:01:48,800 PERCENTAGE, BUT I DON'T THINK 1694 01:01:48,800 --> 01:01:49,680 WE'RE SEEING THAT TREND 1695 01:01:49,680 --> 01:01:50,760 CONTINUING AND I DO BELIEVE IT'S 1696 01:01:50,760 --> 01:01:53,040 BECAUSE WE'RE SEEING A LITTLE 1697 01:01:53,040 --> 01:01:55,880 BIT BETTER -- BETTER IS -- CAN 1698 01:01:55,880 --> 01:02:00,400 BE TAKEN WITH A GRAIN OF SALT, 1699 01:02:00,400 --> 01:02:03,760 PRODUCT IN THE MARKETPLACE AS 1700 01:02:03,760 --> 01:02:07,280 THAT PURE -- LEAF PEOPLE ARE 1701 01:02:07,280 --> 01:02:08,120 UTILIZING FOR THE BENEFIT THAT 1702 01:02:08,120 --> 01:02:09,200 THEY'RE GOING FOR, NOT TO GET 1703 01:02:09,200 --> 01:02:09,800 HIGH. 1704 01:02:09,800 --> 01:02:12,280 I THINK THAT'S -- IT'S A 1705 01:02:12,280 --> 01:02:13,800 POPULATION THAT'S THERE, BUT I 1706 01:02:13,800 --> 01:02:17,200 DON'T THINK IT'S THE LARGER 1707 01:02:17,200 --> 01:02:18,080 POPULATION. 1708 01:02:18,080 --> 01:02:19,000 THE LEGITIMATE USERS OF THIS 1709 01:02:19,000 --> 01:02:20,800 WILL FIGHT TO THEIR DEATH TO 1710 01:02:20,800 --> 01:02:25,880 KEEP IT LEGAL BECAUSE IT'S BEEN 1711 01:02:25,880 --> 01:02:26,720 REVOLUTIONARY FOR THEM. 1712 01:02:26,720 --> 01:02:29,200 >> WELL, THANK YOU, CHRIS. 1713 01:02:29,200 --> 01:02:30,400 THE HOUR HAS PASSED SO I THINK 1714 01:02:30,400 --> 01:02:31,200 WE'LL LEAVE IT THERE. 1715 01:02:31,200 --> 01:02:32,680 WE DID HAVE A COUPLE OF OTHER 1716 01:02:32,680 --> 01:02:34,800 QUESTION, AND SO WHAT WE'LL DO 1717 01:02:34,800 --> 01:02:35,800 IS WE'LL GATHER THOSE AND WE'LL 1718 01:02:35,800 --> 01:02:37,400 SHARE THOSE WITH YOU, AND THE 1719 01:02:37,400 --> 01:02:38,560 EMAIL ADDRESSES THAT WE HAVE IN 1720 01:02:38,560 --> 01:02:39,800 CASE YOU WANT TO FOLLOW UP WITH 1721 01:02:39,800 --> 01:02:41,680 ANYBODY DIRECTLY. 1722 01:02:41,680 --> 01:02:43,840 BUT WITH THAT SAID, THEN, I DO 1723 01:02:43,840 --> 01:02:46,360 WANT TO THANK DR. MCCURDY FOR A 1724 01:02:46,360 --> 01:02:47,520 WONDERFUL TALK, AND THANK 1725 01:02:47,520 --> 01:02:49,640 EVERYBODY WHO JOINED US AS A 1726 01:02:49,640 --> 01:02:51,080 VIEWER TODAY, AND FOR SHARING 1727 01:02:51,080 --> 01:02:52,800 QUESTIONS. 1728 01:02:52,800 --> 01:02:54,600 THE PROGRAM WAS RECORDED BY NIH 1729 01:02:54,600 --> 01:02:55,600 VIDEOCAST AND SHOULD BE 1730 01:02:55,600 --> 01:02:58,400 AVAILABLE LATER ON THE NIH 1731 01:02:58,400 --> 01:03:00,200 VIDEOCAST SITE FOR VIEWING. 1732 01:03:00,200 --> 01:03:02,200 AND THEN JOIN US ON MAY 18TH, 1733 01:03:02,200 --> 01:03:05,200 WHEN OUR NEXT IMLS LECTURE TAKES 1734 01:03:05,200 --> 01:03:06,160 PLACE, AND WE'RE GOING TO HEAR 1735 01:03:06,160 --> 01:03:08,040 ABOUT WELL-BEING IN THE ECONOMIC 1736 01:03:08,040 --> 01:03:09,760 BURDEN OF DISEASE, WHAT WE ARE 1737 01:03:09,760 --> 01:03:11,600 LEARNING FROM CANCER SURVIVORS, 1738 01:03:11,600 --> 01:03:13,480 AND THAT TALK IS GOING TO BE 1739 01:03:13,480 --> 01:03:14,800 PRESENTED BY DR. MICHELLE MARTIN 1740 01:03:14,800 --> 01:03:16,600 OF THE UNIVERSITY OF TENNESSEE 1741 01:03:16,600 --> 01:03:17,400 HEALTH SCIENCE CENTER. 1742 01:03:17,400 --> 01:03:19,520 SO WITH THAT SAID, THANK YOU SO 1743 01:03:19,520 --> 01:03:24,280 MUCH, DR. MCCURDY, 1744 01:03:24,280 --> 01:03:25,680 DR. SHURTLEFF, DR. LANGEVIN AND 1745 01:03:25,680 --> 01:03:26,720 EVERYBODY WHO'S JOINED US TODAY 1746 01:03:26,720 --> 01:03:28,320 AND WE WILL SEE YOU IN MAY FOR 1747 01:03:28,320 --> 00:00:00,000 THE NEXT LECTURE.