Is Kambô psychoactive? Acute and subacute effects of the secretion of the Giant Maki Frog (Phyllomedusa bicolor) on human consciousness

Kambô is the name for the secretion of the Giant Leaf Frog (Phyllomedusa bicolor) containing a plethora of bioactive peptides. Originally, it is ritually used by different ethnicities from the Amazon basin as a remedy against bad luck in hunting. In the last twenty years, Kambô has spread to Western urban centers, often associated with the use of ayahuasca. Anecdotal reports claim beneficial effects on wellbeing and different medical and mental health conditions. However, to date it has been controversial if Kambô elicits altered states of consciousness. Here we retrospectively investigated acute and subacute psychological effects of Kambô in a sample of n = 22 anonymous users (n = 22, mean age: 39 years, ± 8.5; 45.5% female), administering standardized questionnaires for the assessment of psychoactive effects. Acutely, participants reported psychological effects which remained on a mild to moderate level, but no psychedelic-type distortions of perception or thinking. In contrast, persisting effects were predominantly described as positive and pleasant, revealing surprisingly high measures of personal and spiritual significance. Subacute and long-term effects showed some overlap with the “afterglow” phenomena that follow the use of serotonergic psychedelics.


INTRODUCTION 58
Kambô is the Matsé name for the secretion of the Giant Leaf Frog (Phyllomedusa bicolor), which is 59 ritually used by different ethnicities in the Amazon basin of Brazil and Peru 1 . A variety of potent 60 bioactive peptides have been identified in the frog´s secretion, including phyllocaeruelin, phyllokinin, 61 phyllomedusin, sauvagine, deltorphin 2 , adrenoregulin, and the potent opioids dermorphine and 62 caeruelin 1 . Kambô is obtained from the frog by carefully tying it up and rubbing its skin with a hard 63 instrument, collecting the secretion on a wooden stick. It has been emphasized that in most cases the 64 frog is treated with utmost respect and caution, in order to not harm it, and released it to its natural 65 habitat once that the secretion is collected 3 . 66 Given its low oral bioavailability, Kambô is most commonly applied by the applicator to the recipient 67 via several fresh superficial burns ("dots") on the arms, legs or chest 4 . Anecdotally, it has been 68 described that within minutes, the secretion likely enters the lymphatic system and subsequently the 69 blood, thereby inducing an intense reaction that includes hypotension, sweating, tachycardia, heavy 70 vomiting and edema, usually subsiding within an hour. This is followed by listlessness or sleep and, 71 subsequently, a state "perhaps to be described as euphoric", characterized by increased stamina and 72 clarity of thoughts with an increased capacity for hunting 1 . In Amazonian ethnicities, Kambô is used as 73 a cleansing ritual to liberate hunters from "bad principles" or bad luck in hunting ("panema"), 74 enhancing the recipient´s capacities once that cleansing has occurred and acute effects have subsided 5 . 75 During the last 20 years, Kambô has found its way to Western urban centers in Brazil and all over the 76 world 6 . Notably, to date none of the substances that have been identified in the Kambô secretion 77 display any serotonergic activity. However, from its Amazonian origins to its use in the context of 78 Brazilian syncretic religions like the Santo Daime and the União do Vegetal 5 and, finally, to its use in 79 Western healing circles, Kambô has often been associated with the spread of the serotonergic 80 psychedelic ayahuasca 7 . Ayahuasca is an Amazonian shamanic concoction of different plants, including 81 plants (e.g. Psychotria viridis) which contain the serotonergic psychedelic N,N-dimethyltryptamine 82 (N,N-DMT) and Banisteriopsis caapi, which contain inhibitors of monoaminoxidase (MAO-I) that render 83 N,N-DMT orally active 8 . Notably, Kambô does not necessarily have to be applied by a shaman and is 84 not considered as a shamanic ritual itself, in contrast to ayahuasca and other ritual plants, where use 85 is restricted to a shamanic framework 9 . During its spread to Western urban centers, however, the 86 Kambô ritual has been transformed from a hunting ritual into therapeutic approaches and a neo-87 shamanic healing ritual, a process which has been labeled as "shamanization of Kambô" 10 . 88 The association with ayahuasca, however, is not the only connection between Kambô and nature-89 derived serotonergic psychedelics. Notably, different names used for the frog´s secretion include 90 "Kambô", "kampu", "vaccino da floresta" and also "sapo", which incorrectly means "toad" in Spanish. 91 This variability of the terms has sometimes led to a confusion of Kambô with the secretion of the 92 Sonoran Desert Toad (Bufo alvarius), which is also referred to as "sapo" 7 . In contrast to Kambô, 93 however, the toad´s secretion contains the potent serotonergic psychedelics 5-methoxy-N,N-94 dimethyltryptamine (5-MeO-DMT) 11 and bufotenine, which is usually smoked or snorted, immediately 95 inducing strong psychedelic experiences 12 . Given the different application routes, the two substances 96 are usually not confused by users, even though ceremonies where secretions from Kambô and Bufo 97 alvarius are combined have recently been proposed in Western psychedelic circles. 98 Another interesting overlap between Kambô and the use of plant-derived psychedelics can be found 99 in anecdotal reports describing beneficial after-effects on wellbeing, medical and mental health 100 problems and personal and spiritual development 13 -attributes which have previously been 101 associated with the use of serotonergic psychedelics. Of note, the effects of serotonergic psychedelics 102 underlie unique temporal dynamics, with distinct acute ("psychedelic experiences" or "states") and 103 subacute effects ("afterglow" phenomena) 14 . Afterglow phenomena have been conceptualized as 104 states of "elevated and energetic mood with a relative freedom from concerns of the past and from 105 guilt and anxiety", which are associated with an enhanced willingness "to enter into close interpersonal 106 relationships", lasting between two weeks and a month 15 . If these effects are comparable to the after-107 effects of Kambô is an open question. 108 Despite the close cultural and sub-cultural associations between the use of Kambô and different 109 nature-derived psychedelics, no systematic characterization of the acute or subacute effects of Kambô 110 has been reported. Here, we report results of a paper-pencil study among Kambô users employing 111 standardized and validated questionnaires to retrospectively report acute and subacute effects of 112 Kambô. This assessment allows a direct comparison to data from other psychoactive substances and 113 answers in how far the effects of Kambô display similarities with serotonergic psychedelics 16 . 114 Our study was designed to (1) systematically characterize the acute effects of Kambô, enabling a direct 115 comparison to acute effects of e.g. plant-derived serotonergic psychedelics, (2) explore if Kambô 116 displays subacute effects which might be comparable to the psychedelic afterglow phenomena, 117 including retrospective appraisal of the experiences by the recipients. 118

Subacute subjective effects of Kambô 173
The PEQ and the CS were filled in only when the exemplary Kambô session happened 2 -3 weeks 174 before filling in the questionnaires. Together these questionnaires cover a broad spectrum of 175 subjectively experienced subacute effects. Results are summarized in Figure 2 and Table 3. 176 ***************************************** 177 FIGURE 2 approximately here 179 ***************************************** 180 When asked about the spiritual relevance of the Kambô experiences, n = 6 of 13 (46%) participants 181 rated it as strongly spiritually significant, including n = 2 participants who rated it as the single most or 182 among the five most spiritually significant experiences of their life. When asked how personally 183 meaningful the experience was, n = 7 of 13 (54%) participants rated the experience among the ten 184 most meaningful experiences of their life and n = 4 rated it among the five most personally meaningful 185 experience. One participant viewed it as the single most personally meaningful experience in his life. 186 Regarding change of well-being or life satisfaction, n = 8 of 13 (62%) participants stated that the 187 experience increased well-being or life satisfaction slightly, and n = 5 of 13 (38%) participants reported 188 an increase in well-being or life satisfaction between 'moderate' and 'very much'. 189  The Challenging Experience Questionnaire (CEQ) includes self-report items designed for the 227 investigation of challenging experiences under psilocybin and other serotonergic psychedelics. These 228 include fear, grief, physical distress, insanity, isolation, fear of death and paranoia, which are symptoms 229 that can occur in challenging experiences (also referred to as "bad trips") under serotonergic 230 psychedelics 21 . The challenging experiences reported for acute effects of Kambo were mostly limited 231 to "physical distress". Challenging experiences of a rather psychological nature were barely reported 232 -suggesting unspecific fearful reactions to the strong vegetative effects, but without induction of 233 psychedelic-type psychological crises including insanity, isolation, death or paranoid ideation in the 234 sense of "bad trips", reflecting distortions of ego functions and self-processing. 235 Ratings on the Phenomenology of Consciousness Inventory (PCI) allow for comparison of Kambo 236 experiences with hypnosis or meditation techniques to investigate potential shared aspects. Similar to 237 hypnotic or meditative states, participants reported a reduction of positive and negative affect in their 238 Kambô experiences (Pekala 2017). With regard to the question if or how Kambô elicits psychoactive 239 effects, it is noteworthy that the obtained scores on "self-awareness", "rationality", "attention" and 240 "memory" indicate that the participants did not feel confused or muddled, which would be expected 241 from centrally active drugs like alcohol or barbiturates. 242 Taken together, our study provides standardized data that allows a direct comparison of Kambô 243 experiences to the effects of well-known psychoactive substances. On the physiological level, the acute 244 Kambô experience is dominated by an intensive physical reaction, which is reflected in the reports of 245 "physical distress" by our participants and is also likely to have triggered psychological distress in some 246 participants. The process of characterizing acute Kambô effects with standardized questionnaires in 247 the present study revealed that Kambo induces a state of self-centered inwardness. This state does 248 not have typical characteristics of psychedelic-induced states. Although the pharmacodynamics of the 249 Kambô secretion have only been partially investigated, it has been suggested that Kambô´s 250 pharmacological effects are restricted to the cardiovascular, gastroenterological, endocrine and 251 immune systems, the autonomic nervous system (ANS) and the endogenous opioid system 9 . On the 252 one hand, this appears to be plausible given the compounds´ peptide structures which prevent them 253 from passing the blood-brain barrier. On the other hand, the authors hypothesize that the 254 neuropeptide opioids in Kambô (dermorphin, caerulein and deltorphin) could be responsible for the 255 observed "alterations of consciousness", suggesting psychoactive effects. However, given the 256 neuropeptide structure, these opioids have been reported to be centrally active via intrathecal 257 application only. In addition, the described acute and subacute effects of Kambô resemble stimulant 258 effects rather than those of substances with mu-receptor activity. Thus, the observed acute and 259 subacute effects in our sample are divergent from known psychoactive effects of mu-receptor 260 agonists, suggesting that other compounds or complex interactions between vegetative, neuro-261 endocrinological and psychological effects might be considered as underlying biological correlates of 262 the Kambô experience. Nevertheless, to date no compounds have been identified that could explain 263 the induction of an ASC during the acute period of Kambô effects and no such phenomena were 264 reported by our participants. 265

The subacute effects of Kambô 266
In the second part of our study, we investigated subacute effects of Kambô up to 2-3 weeks after the 267 reported exemplary session to find first indications if these effects were comparable to psychedelic 268 afterglow phenomena (See 14 ). Since no systematic characterization of afterglow phenomena exists to 269 date, even for psychedelics, a quantitative comparison was not possible. Therefore, as a first 270 description of the subacute effects we used the PEQ, previously applied to characterize psychedelic 271 effects mainly in therapeutic contexts. Additionally, we used a questionnaire measuring 272 connectedness, which has not yet been validated. Interestingly, the ratings of items describing connectedness to internal aspects of oneself were high in 281 our sample, such as being connected to "my senses", "a range of emotions", "my body", "deeper 282 aspects of myself" and "insight/intuition", and to "have been fully able to experience emotion, 283 whether positive or negative". In contrast, ratings of items referring to connectedness to external 284 aspects (e.g. "a community", "strangers", "all humanity", "a purpose in life", "spiritual essence" and 285 "a source of universal love") were far less pronounced, except for the experience of being "connected 286 to nature". This is in line with anecdotal observations including participants´ subjective experiences of 287 an active interaction with a frog´s "spirit", which detects and eliminates toxins and bad energy from 288 their mind and body 9 . However, this finding is only partially comparable to mystical experiences 289 associated with acute and subacute effects of serotonergic psychedelics, where states of increased 290 connectedness to both the self and other beings have been reported 23 (i.e. the notion that "everything 291 is interconnected"). 292 Notably, even if the subacute effects were not comparable to those reported after the use of 293 serotonergic psychedelics regarding intensity and qualitative aspects 2223 , some of the phenomena 294 which outlasted the acute effects were surprisingly intensive and complex, showing overlaps with 295 psychedelic "afterglow phenomena", including increases in positive mood, behavior, attitudes and 296 social interaction. 297

Limitations 298
The effects of Kambô reported by our study participants could partially be related to the ritualistic 299 setting of consumption. Our data were collected retrospectively from a group of Western Kambô users 300 recruited through a public workshop on Kambô and a group of practitioners devoted to a specific ritual 301 setting. This might have induced a bias of expectations or motivations for use and thereby involved 302 the placebo dimension. The observed variability in the assessed acute effects suggests that 303 expectational factors and setting might have played a role for some reports. In order to make final 304 conclusions about the psychoactive properties of Kambô, randomized placebo-controlled trials are 305 necessary. 306

Conclusion 307
Our findings demonstrate that the acute effects of Kambô are very different from the effects of 308 serotonergic psychedelics. While the acute effects of Kambô are dominated by strong physical 309 reactions followed by a state of increased inwardness, psychedelic effects appear to facilitate 310 loosening of ego barriers and increased connectedness with oneself and the outer world. Our findings 311 are congruent with anecdotal reports that the subacute effects of Kambô include feelings of being 312 energized with increased stamina and clarity of thoughts, following an initial state of physical sickness 313 and exhaustion. Nevertheless, subacutely, Kambô does exhibit some overlap with serotonergic 314 psychedelics in regard to the reported "afterglow" phenomenon 15 . This finding is striking given the 315 unique temporal dynamics of subacute psychedelic effects, incomparable to any other group of 316 psychoactive substances. Kambô thereby appears to be associated with afterglow-like effects, but 317 without preceding psychedelic states. In agreement with our findings, it has been suggested that the 318 transformative and transpersonal effects of Kambô might be comparable to those associated with the 319 use of serotonergic psychedelics 9 . 320 321 METHODS 322

Participants and Procedure 323
All data of this study was collected anonymously. Potential participants were recruited at a drug 324 information event in Berlin and through Kambô practitioners who forwarded study material to their 325 clients. Participants were informed about the study aim and that data collection is fully 326 anonymously. They were handed out a printed set of paper/pencil-questionnaires together with a pre-327 paid envelope for returning completed sets of questionnaires and gave consent by filling the 328 questionnaire and sending it back anonymously. All procedures were conducted in accordance with 329 the Declaration of Helsinki and were approved by the Ethics committee of the Charité 330 Universitätsmedizin Berlin (EA2/185/17). All questionnaires were applied in German. The first set of 331 questions addressed person specific characteristics, such as age, gender and drug consumption history. 332 Apart from questions referring to demographic information, a set of questionnaires was given to the 333 participants that comprised the following two parts: (1) questionnaires on the acute effects of an 334 exemplary Kambô session, (2) questionnaires on subacute effects of the exemplary Kambô session. All 335 participants were requested to fill in demographic information and (1). Participants were asked to fill 336 in (2) only if the exemplary Kambô session that they reported about in (1) happened between 2 -3 337 weeks ago, as the questions on the acute effects addressed this period after the Kambô session. For comparability with previous reports, the means and SD for all questionnaire data are provided in 406