The chemical induction of synaesthesia

This survey study (n=644, 187 synaesthetes) of (psychedelic) drug users studied the chemical induction of synaesthesia under their influence (28 different psychedelics). Its findings supported the hypothesized link between drug-induced synaesthesia and serotoninergic activity, however, it also suggests the possible alternative neurochemical pathways involved in the induction of synaesthesia. The conclusion suggests that in controls and developmental synaesthetes, the induction and modulation of synaesthesia may share overlapping mechanisms and that some persons may be more susceptible to feel induced synaesthesia with different drugs.

Abstract

“Objective Preliminary research suggests that experiences resembling synaesthesia are frequently reported under the influence of a diverse range of chemical substances although the incidence, chemical specificity, and characteristics of these effects are poorly understood.

Methods Here we surveyed recreational drug users and self-reported developmental synaesthetes regarding their use of 28 psychoactive drugs comprising 12 different drug classes and whether they had experienced synaesthesia under the influence of these substances.

Results The drug class tryptamines exhibited the highest incidence rates of drug-induced synaesthesia in controls and induction rates of novel forms of synaesthesia in developmental synaesthetes. Induction incidence rates in controls were strongly correlated with the corresponding induction and enhancement rates in developmental synaesthetes. In addition, the use of LSD was the strongest predictor of drug-induced synaesthesia in both controls and developmental synaesthetes. Clear evidence was observed for a clustering of synaesthesia-induction rates as a function of drug class in both groups, denoting non-random incidence rates within drug classes. Sound-colour synaesthesia was the most commonly observed type of induced synaesthesia. Further analyses suggest the presence of synaesthesia-prone individuals, who were more likely to experience drug-induced synaesthesia with multiple drugs.

Conclusions These data corroborate the hypothesized link between drug-induced synaesthesia and serotoninergic activity, but also suggest the possibility of alternative neurochemical pathways involved in the induction of synaesthesia. They further suggest that the induction and modulation of synaesthesia in controls and developmental synaesthetes share overlapping mechanisms and that certain individuals may be more susceptible to experiencing induced synaesthesia with different drugs.”

Authors: David P. Luke, Laura Lungu, Ross Friday & Devin B. Terhune

Summary

Abstract

Tryptamines induced the most synaesthesia in controls and developmental synaesthetes, and LSD was the strongest predictor of synaesthesia in both groups. Sound-colour synaesthesia was the most commonly observed type of induced synaesthesia.

These data suggest that serotoninergic activity is involved in the induction of synaesthesia, but also suggest that there may be other pathways involved.

Synaesthesia is a neurodevelopmental condition in which different stimuli reliably elicit atypical secondary experiences. It typically emerges in early stages of development, although there have been reports of adult-onset cases following stroke, drug use, physical trauma, and neuropathology. Research indicates that non-synaesthetes can temporarily experience the phenomenological and behavioural characteristics of synaesthesia through consumption of classic psychedelics such as LSD. This may be due to excessive levels of serotonin in cortical neurons, a common mechanism shared by developmental, acquired and drug-induced synaesthesia. Despite the consistent implication of the serotonin system in drug-induced synaesthesia, it remains unclear whether other neurochemicals play a role in drug-induced synaesthesia, and whether drug-induced synaesthesia occurs through similar neurochemical mechanisms to drug-induced synaesthesia in controls.

1568 participants were recruited through various channels, 644 completed the survey (41%), and the age ranged from 18 to 74 (MAge=30.0, SD=12.2). 457 individuals reported not having synaesthesia and were identified as controls, and 187 self-identified as synaesthetes.

A survey was used to gather demographic information and assess different features of drug-induced synaesthesia in controls and synaesthetes. Participants were also asked if they had ever experienced synaesthesia in the absence of drugs and if they had ever experienced “flashbacks” of drug-induced synaesthesia. Synaesthetes and recreational drug users were recruited through online advertisements in English language forums and social media platforms over a 6-month period.

All data are publicly available here: https://osf.io/x45yf/. Analyses were performed in MATLAB and Pearson correlations were computed along with bootstrap 95% confidence intervals. Drug-induced synaesthesia enhancement rates among developmental synaesthetes were calculated by subtracting self-reported suppression rates from enhancement rates for the entire sample for each drug. We computed a drug class incidence dissimilarity index that measures the similarity of incidence rates between drug classes. We then evaluated the statistical significance of the observed dissimilarity measures.

We used four exploratory stepwise logistic regression analyses to predict the experience of drug-induced synaesthesia in controls and developmental synaesthetes. We estimated participants’ propensity for experiencing drug-induced synaesthesia using a synaesthesia-proneness score. We adjusted the frequency of induced synaesthesia on a drug for the inverse of the incidence rate and compared controls and developmental synaesthetes on SP scores and binary synaesthesia-induction (across all drugs) using t-tests and Fisher’s exact tests, respectively.

Controls reported greater use of 19 of 28 drugs than synaesthetes, although the differences were minor. Most notable were the high incidence rates of synaesthesia among controls under the influence of LSD, ayahuasca, and psilocybin. The incidence of induced synaesthesia in controls did not significantly correlate with the corresponding incidence rate of usage, but synaesthetes had numerically higher incidence rates across all drugs except 2C-B and Amanita muscaria. In addition, the incidence of induced synaesthesia across drugs was highly correlated across groups.

Incidence rates of drug use and drug-induced synaesthesia among controls and synaesthetes correlate with incidence rates and enhancement rates across drugs among synaesthetes.

The incidence rates of induced synaesthesia in Figure 1 are characterized by similar induction report rates for drugs from the same classes, suggesting intra-class clustering. The within-class dissimilarity indices for the 7 drug classes that were represented with 2 or more different drugs were similar to 54% among controls. For individual drug classes among controls, tryptamines, phenethylamines, and dissociatives had statistically significant mean dissimilarity indices, whereas for other drug classes all indices were nonsignificant. These results suggest that the observed clustering of incidence rates within drug classes is unlikely to be random.

We conducted four binary logistic regression analyses to examine whether drug-induced synaesthesia can be predicted on the basis of drug use. The first analysis included binary drug use in controls as a significant predictor, accounting for approximately 20% of the variance.

The model including frequency of drug use as predictors was significant, accounting for slightly less variance, but retaining four significant predictors. Four predictors were retained in the final model for both analyses, including psilocybin and GBL, which were replicable negative predictors. Only LSD and DXM were replicable predictors across both analyses in synaesthetes, and only methadone exhibited high replication rates in both models. However, only DXM was a replicable predictor across synaesthetes and non-synaesthetes.

The most commonly reported forms of drug-induced synaesthesia were sound-colour, sound-space, and sound-shape. The incidence of sound-colour synaesthesia scaled with the differential induction rates across different drug classes, but other types of synaesthesia did not seem to be specific to drug class.

The incidence of drug-induced synaesthesia is considerable and varies between individuals. The prevalence of highly prone individuals is estimated by calculating synaesthesia-proneness (SP) scores, which are heavily skewed in both controls and synaesthetes due to the relatively large proportions of the samples that had not experienced induced synaesthesia. Both sets of results suggest that those self-reporting as developmental synaesthetes are more prone to induced synaesthesia.

4 | DISCUSSION

We identified the incidence and characteristics of drug-induced synaesthesia in controls and the modulation of self-reported developmental synaesthesia across a range of recreational drugs. We found that sound-colour synaesthesia was the most common type of drug-induced synaesthesia.

Several studies have found that drugs that act on the serotonin system, such as LSD, mescaline, psilocybin, ayahuasca, or MDMA, induce synaesthesia. However, Salvia divinorum and dissociatives, which do not seem to act on the serotonin system, also induce synaesthesia.

Salvia divinorum and dissociatives seem to act on different receptors than serotonin receptors, and may have downstream effects convergent with 5-HT2a receptor agonists, such as increased glutamate release and neural excitation, leading to subjective experiences somewhat similar to classic psychedelics. The present results indicate that the same drug classes that induce synaesthesia in controls also seem to be reliably associated with the induction of novel forms of synaesthesia and the modulation of existing forms in self-reported developmental synaesthetes.

Developmental synaesthesia with LSD, mescaline, amyl nitrate, and alcohol may share some similarities with adult synaesthesia. Although there was an array of different drug classes that could induce synaesthesia, there was a clear pattern of induction rates within and across drug classes. This suggests that different drug classes produce synaesthesia through different systems. The present results show that drug use patterns are a reliable predictor of drug-induced synaesthesia, with LSD being the only replicable predictor across all four analyses in controls and synaesthetes. Although serotonin was the most reliably implicated neurochemical in drug-induced synaesthesia, other drugs were replicable predictors. A related pattern across the analyses seems to indirectly corroborate our clustering results, which suggest that different episodes of drug-induced synaesthesia seem to occur through multiple, at least partially independent, neurochemical pathways. A subset of survey respondents reported experiencing synaesthesia under the influence of different drug classes. These results suggest that some individuals are more likely to experience synaesthesia in response to various recreational drugs, and that this proneness is elevated among those self-identifying as developmental synaesthetes.

Research on drug-induced synaesthesia found that auditory-visual synaesthesias were the most common, but sound-colour synaesthesias were not found to be more common than grapheme-colour synaesthesias. We evaluated the types of induced synaesthesia among the four most potent synaesthesia-inducing drug classes and found that sound-colour synaesthesia was the most common form, followed by sound-shape and sound-space synaesthesia. There were no clear differences in the types of induced synaesthesia across different drug classes.

Two proposed neurochemical mechanisms for synaesthesia are serotonin cascades and reductions in default mode network integrity. The former may explain the experience of synaesthesia in congenital, acquired or drug-induced cases, while the latter may explain the experience in trained cases.

We maintain that the hallmark behavioural features of developmental synaesthesia (e.g., automaticity and inducer-concurrent consistency) arise from a consolidation process in which inducer-concurrent associations are driven by statistical regularities in one’s environment. A second hypothesis proposes that attenuated GABA results in disruption of inhibitory activity, which in turn gives rise to synaesthesia. The present results corroborate previous research implicating serotonin in drug-induced synaesthesias, and our data clearly point to the likely involvement of serotonin in induced synaesthesia.

Dopamine is unlikely to play a key role in inducing synaesthesia, as drugs known to modulate dopamine levels had low incidence rates of induced synaesthesia. Nevertheless, Salvia divinorum presents a challenge to a simple serotonergic hypothesis. Our results do not support GABAergic disinhibition models of synaesthesia, as GABA agonists were reliably associated with reports of induced synaesthesia in both controls and developmental synaesthetes. However, multiple potential neurochemical mechanisms may underlie spontaneous synaesthesia.

Online recruitment of samples and administration of the survey may have introduced biases, but the results are broadly commensurate with the extant literature and the non-random clustering of incidence rates across drug classes mitigates concerns regarding reporting accuracy and variations occurring with dosage. This study uses self-report to determine the incidence of developmental synaesthesia and the lack thereof, and diverges from the extant synaesthesia literature. However, the incidence of self-reported familial synaesthetes falls within the prevalence range of this condition (1-4%), suggesting that the false negative rate is unlikely to be high.

The present study expands upon previous research on drug-induced synaesthesia by studying a wider array of drugs than previous studies. It also raises new questions that warrant further attention, such as whether a small subset of individuals are especially prone to induced synaesthesia across different drug classes.